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CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ESTROGEN RECEPTOR ALPHA VARIANTS AND
METHODS OF DETECTION THEREOF
RELATED APPLICATIONS
The present application claims priority to applications U.S. Serial Nos.
09/692,414,
filed October 20, 2000 (Atty. Docket CL000258); 09/768,184, filed January 24,
2001 (Atty.
Docket CL000258CIP); 09/804,076, filed March 13, 2001 (Atty. Docket
CL000258CI2); and
09/826,314, filed April 5, 2001 (Atty. Docket CL000258CI3).
FIELD OF THE INVENTION
The present invention is in the field of disease detection and therapy. The
present
invention specifically provides the identification of previously unknown
nucleic acid/amino
acid polymorphisms within the estrogen receptor alpha gene (ESR-alpha) and the
genomic
sequence of this gene for use in the development of diagnostics and therapies
for diseases and
disorders mediated/modulated by the estrogen receptor.
BACKGROUND OF THE INVENTION
Estrogen Receptor
The human estrogen receptor alpha belongs to the nuclear hormone receptor
family.
Nuclear hormone receptors are a family of hormone-activated transcription
factors that can
initiate or enhance the transcription of genes containing specific hormone
response elements.
The ER protein consists of 595 amino acids with a molecular weight of 66 kDa,
8
transcribed exons, with six different functional domains. Two of those domains
are highly
conserved in the primaxy sequence of members of the nuclear hormone receptor
superfamily.
One of the domains, the DNA binding domain (DBD), contains two zinc fingers
that mediate
receptor binding to hormone response elements in the promoters of hormone-
responsive
genes. In the C- terminal region, the hormone-binding domain (HBD) contains
two regions of
sequence homology with other hormone receptors and gives hormone specificity
and
selectivity. The human ER-alpha gene is located in chromosome 6q.25.1.
Estrogen receptors, like other steroid receptors, are transcription factors
that are
activated upon binding to steroids (estradiol) or steroid analogs such as
tamoxifen. Upon
activation the receptors dimerize to form homodimers or heterodimers that bind
to estrogen
receptor elements (EREs) located in the promoter region of estrogen-activated
genes and
coordinate transcription by interacting with host co-activators.
CA 02426405 2003-04-17
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Role of Estrogen in Cardiovascular Disease ,
Heart disease is the leading cause of mortality in women, a fact that is under
appreciated by both women and physicians. One in 9 women aged 45-65 have some
form of
cardiovascular disease and the number increases to 1 in 3 after age 65. Each
year, 240,000
U.S. women die from heart disease, and nearly 90,000 die of stroke. Moreover,
approximately 44% die within one year of suffering a heart attack, compared
with 26% of
men (Warren MP and Kulak J Clin Obs Gyn 1998 41 (4):976-987).
Estrogens exert a wide range of physiological effects on a large variety of
cell types.
For example, they regulate cell growth and apoptosis and a myriad of functions
related to
reproduction. There are two types of estrogen receptors, alpha and beta. Blood
vessels and
bone contain beta receptors, the liver has alpha receptors, and both alpha and
beta receptors
are found in the central nervous system. The interaction of these different
receptor sites
influences the biological effects of estrogen and selective estrogen receptor
modulators
(SERMs), such as raloxifene. The binding patterns dictate whether an estrogen
or a SERM
acts as an estrogen agonist or an antagonist (Mendelsohn ME and Karas RH New
Engl J Med
1999, 340(23):1801-181 l;Grese TA and Dodge JA Curr Pharm Design 1998, 4:71-
92).
Tissue-specific relationships exist between SERMs and the receptor binding
sites. Estrogens
also increase high-density lipoprotein cholesterol levels, decrease low-
density lipoprotein
cholesterol, and decrease plasminogen-activating inhibitor levels (Meisler JG
Jour Women's
Health 1999, 8(1):51-57). All estrogens require cellular receptors for their
expression. In
general, estrogen receptors are ligand-inducible transcription factors, which
regulate the
expression of target genes after hormone binding (Faustini-Fustini et al. Eur
J Endocrin 1999,
140:111-129). Estrogen may also have important effects on the vascular wall.
Estradiol and
progesterone receptors have been identified in arterial endothelial and smooth
muscle cells
(Campisi D et al. Int J Tiss React 1987, IX(5):393-398). Estrogens act on the
wall of the
artery to relax vascular smooth muscle and to decrease vascular resistance.
The mechanism
appears to be through stimulation of endothelial-derived relaxing factors and
an endogenous
nitrate (Warren MP and Kulak J Clin Obs Gyn 1998 41 (4):976-987). The
relaxation induced
by 17B-estradiol may play an important role in the regulation of coronaxy
tone, which
reduces the risk of coronary disease in postmenopausal women. The production
of nitric
oxide is mediated by the estrogen receptor, because when the receptor is
blocked by an
antiestrogen agent, nitric oxide is suppressed.
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Several studies have shown that estrogen therapy reduces the risk of heart
disease by
up to 50% (most recently reviewed by Mendelsohn ME and Karas RH New Engl J Med
1999, 340(23):1801-181 l;Rich-Edwards JW N Engl J Med, 1995, 332:1758-1765;
Gerhard
M, Ganz P, Circulation, 1995, 92:5-8; Grodstein F, et al N Engl J Med 1997,
336:1769-75;
Chasen-Taber L and Stampfer MJ Ann of Int Med, 1998, 128:467-477; Warren MP
and
I~ulak J Clin Obstet Gyn 1998, 41 (4):976-987). Loss of estrogen may be one of
the most
important factors in the development of cardiovascular disease in women.
While there is no direct evidence that estrogen prevents atherogenesis,
considerable
epidemiologic evidence exists that suggests that estrogens may have some
benefit in reducing
cardiovascular disease: (1) In all age groups, women have a lower incidence of
cardiovascular disease than do men; (2) women who undergo a premature surgical
menopause and do not take estrogens are twice as likely to have cardiovascular
disease are
age-matched premenopausal controls; (3) postmenopausal women who use estrogens
have a
significantly lower incidence of cardiovascular disease compared with those
who do not; and
(4) women with coronary artery disease detected by angiography have a higher
survival rate
if they are estrogen users.
In recent years, reports of favorable effects of estrogen therapy on
cardiovascular
morbidity and mortality have led to enthusiasm for widespread use of estrogens
by
postmenopausal women (Meinertz T Herz 1997, 22: 151-157). Guidelines for
estrogen
therapy issued by the American College of Physicians include the statement
"Women who
have coronary heart disease are likely to benefit from hormone therapy."
More than 30 prospective studies and 13 case controlled studies have examined
the
effect of estrogen replacement therapy on cardiovascular incidence or
prevalence and all
cause mortality (Stampfer MJ et al. New Engl J Med 1991, 325:756-62; Grady D
et al. Ann
Intern Med 1992, 117:1016-37). The majority of these studies showed lower
morbidity and
mortality from coronary heart disease among users of postmenopausal estrogens
than among
non-users. Specifically, they have shown that coronary artery disease in
estrogen takers is
approximately 50% that in women who do not take estrogen. Overall, the bulk of
the
evidence strongly supports a protective effect of estrogens yielding a
relative risk of 0.56
(95% confidence interval 0.50-0.61). However, a "healthy woman selection bias"
is present
in these studies and potentially may confound these results (estrogen takers
have better
weight control, exercise more, and smoke less than women who are not
prescribed estrogen).
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Moreover, other biases such as estrogen takers tend to have higher education,
higher income,
etc., are confounding these epidemiologic studies (Abrams J Clin Cardiol 1998,
21:218-222).
Since the earlier observational trials were not randomized, it is believed by
many that
as much as 25% of this 50% reduction in risk is due to these various
methodological biases
(Barrett-Conner E and Grady D 1998, Ann Rev Public Health 19:55-72). Recently,
2 meta-
analyses estimated the reduction in coronary heart disease associated with
estrogen use to be
in the range of 35 to 44 %, respectively (Grodstein F and Stampfer MJ Prog
Cardiol Dis
1995, 38: 199-210; Barrett-Conner E and Grady D 1998, Annu Rev Public Health
19:55-72).
Recent studies are exploring the issue of opposed vs unopposed estrogen,
because of a
documented increased risk for uterine cancer in women with an intact uterus
who are taking
estrogen alone. The new lines of evidence are suggesting that women taking
estrogen plus a
progestin (usually a medroxyprogesterone acetate) do not receive an equivalent
benefit from
the cardioprotective effects compared to women taking estrogen alone (Hulley S
et al 1998
JAMA 280:605-613; Abrams J Clin Cardiol 1998, 21:218-222).
The loss of estrogen at menopause is associated with a 6% decline in HDL
cholesterol
levels and a 5% rise in LDL cholesterol levels, which may explain the higher
cardiovascular
disease rate among postmenopausal women compared with premenopausal women. The
lower incidence of cardiovascular disease among postmenopausal women who take
estrogen
may be explained in part by the resultant 15% to 19% decrease in LDL
cholesterol levels and
the 16% to 18% increase in HDL cholesterol levels (JAMA 1995, 273:199-208).
The PEPI
(Postmenopausal Estrogen/Progestin Intervention, a randomized, double-blind
placebo-
controlled trial, showed that HDL cholesterol levels rose significantly more
in women
assigned to estrogen alone than in women assigned the combined estrogen (JAMA
1995,
273:199-208). Recent non-human primates studies substantiate these findings
(Clarkson TB
Lab An Sci 1998, 48(6):569-72). Statistical modeling of the effect of estrogen
on lipid
profiles indicates that 25 - 50% of the apparent cardioprotection due to
estrogen is mediated
by favorable changes in HDL-cholesterol (Bush TL et al. 1987 Circulation
75:1102-9;
Gruchow HW et al. 1988 Am Heart J 115:954-63).
Estrogen replacement therapy is not without risk. For years, studies have
shown a 3-4-
fold increased risk of venous thromboembolism (VTE) in users of oral
contraceptives
compared to non-users (Weiss G Am J Obstet Gynecol 1999 180:5295-301). One
study has
shown that intrinsic coagulation factors play a significant role in oral
contraceptive-
associated VTE (Vandenbrouclce JP et al. Lancet 1994 344:1453-7; Rosing J et
al. Br J
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Haematol 1997, 97:233-238). The Factor V Leiden mutation increases risk of VTE
5-10 fold
in non users, but 30-fold in third-generation oral contraceptive users.
Combined estrogens
appear to induce resistance to the body's natural anticoagulation system
(APC).
Heterozygotes for the Factor V Leiden mutation who take oral contraceptives
develop APC
resistance as high as that seen in women who are homozygous.
Estrogens increase the risk of endometrial carcinoma approximately 6-fold, an
effect
that is eliminated, for the most part, by the addition of progestins (Baxrett-
Conner E and
Grady D 1998, Ann Rev Public Health 19:55-72). Controversy continues over
whether
estrogen replacement increases the risk of breast cancer, but some studies
indicate risk is
elevated by as much as 30%. (Greendale GA et al. Lancet 1999, 353:571-80).
A number of prospective randomized studies designed to definitely establish
whether
estrogen replacement therapy reduces the risk of cardiovascular disease in
women and
whether it increases the risk of breast cancer, are underway. One recently
completed trial
(HERS - Heart and Estrogen/progestin Replacement Study) compared continuous
combined
estrogen plus medroxyprogesterone acetate to placebo in 2700 women with pre-
existing
coronary disease (Hully S et al. 1998 JAMA 280(7):605-13). Compared to
controls, the
intervention group had significantly more heart disease events- in year one of
the trial, but
significantly fewer events in years 4 and 5 of the trial. Moreover, a
significant increase in the
rate of thromboembolic events occurred in the early years of the study in
women taking
hormones. Based on these results, hormone replacement therapy is not
recommended for
secondary prevention of heart disease.
Two other large, ongoing clinical trials on primary prevention of
cardiovascular
disease using estrogens are underway. The Women's Health Initiative, due to be
completed
in 2005 and a U.K. study called WIS-DOM, due to be completed in 2010, should
shed new
light on the protective effects of estrogen on cardiovascular disease (Meisler
JG Jour
Women's Health 1999, 8(1):51-5).
In summary, ongoing research suggests that estrogen replacement therapy,
particularly involving recently formulated designer estrogens or SERMs, may
have beneficial
effects on the cardiovascular system as well as bone, without the untoward
effects on breast
and endometrial tissue. Caution still needs to be observed, nonetheless. Women
who take
estrogens are, on average, better educated, healthier, have higher incomes and
have better
access to health care. These differences rather than the estrogens may account
for much of the
lower risk of heart disease.
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For postmenopausal women without frank disease, estrogen replacement therapy
appears to have a beneficial effect when one considers the magnitude,
consistency, and
biological plausibility of the data. For women with pre-existing disease,
questions remain as
to the safety and efficacy of exogenous estrogens as protective agents against
cardiovascular
disease.
Estrogen and autoimmune diseases
A. S~~stemic Lupus Erythematosus
There is a widely held view that estrogens play a role in Systemic lupus
erythematosus because:
1. Women of child bearing age are nine times more likely to develop systemic
lupus
erythematosus than men. Prior to pubescence the rate is three fold higher in
females, while
post menopausal women have an equal chance of developing SLE as aged matched
males.
Many studies have been done that show that the reason for the differences in
the sexes is
probably estrogen related (Lahita R.G., 1986: Springer Seminars in
Immunopathology 9,
305-314; Krammer, G.M. and Tsokos, G.C. , 1998 Clinical Immunology and
Immunopathology 89: 192-195; Rider at al., 1998 Clinical Immunology and
Immunopathology 89: 171-180).
Clues to the role of estrogens in SLE came from studies that concluded that
oral
contraceptives adversely affected the morbidity of this illness (Buton, J.P.,
1996 Ann. Med.
Interne, 147:259-264; Julkunen, I99I: Scan. J. Rheumatol. 20:427=433).
2. Patients with Klinefelter syndrome (XXY), have been reported with SLE
(Stern
et al., 1977: Arthritis and Rheumatism 20:18-22).
3. Patients with SLE have anti-estrogen antibodies (Feldman, 1987: Biochem.
Biophys. Acta, 145:1342-1348: Bucala et al., 1987: Clin. Exp. Immunol. 67:167-
175)
In the past, oral contraceptives have been shown to cause flare ups of SLE,
their use
was discouraged in women with SLE, while the current thinking is that the
lower dose birth
control pills are safe for SLE patients (Julkunen HA Scand JRheumatol
1991;20(6):427-33).
As well hormone replacement therapy is considered safe for SLE patients (Mok
et al., Scand
JRheurnatol 1998;27(5):342-6: Kreidstein et al., 1997, JRheunaatol 1997
Nov;24(11):2149-
52)
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4. The estrogen antagonist tamoxofm seems to improve the course of the disease
(Sthoeger, 1997, Ahh N YAcad Sci 1997 Apr 5;815:367-8: Sthoeger, 1994,
JRheummatol 1994
Dec;21(12):2231-8).
B. Estrogen, Rheumatoid Arthritis (RA) and osteoarthritis
The literature surrounding the involvement of estrogens in Rheumatoid
arthritis is less
clear than with osteoarthritis. Epidemiological studies suggests that RA is
influenced by
female sex hormones, by one study states that the use of oral contraceptives
may postpone the
onset of RA, but that. estrogens alone no not alleviate the symptoms of RA
(Bijlsma Am J
Reprod Immu~ol 1992 Oct-Dec;28(3-4):231-4). Adjuvant oestrogen treatment does
increase
bone mineral density in postmenopausal women with RA, and may protect against
osteophoresis which is often a complication of RA (van den Brink: Anh Rheum
Dis 1993
Apr;52(4):302-5). While the study mentioned above indicated that estrogens did
not alleviate
RA symptoms, another study concluded that adjuvant estrogen therapy did not
even improve
the symptoms. One polymorphism has been reported in the estrogen receptor that
seems to
be associated with the age of onset of RA (Ushiyama Anh Rheum Dis 1999
Jan;58(1):7-10)
Osteoarthritis on the other hand is less prevalent in postmenopausal women who
take
estrogen replacement therapy (ERT) (Felson Curs Opin Rheumatol 1998
May;lO(3):269-72)
suggesting that ERT may be beneficial in preventing osteoarthritis.
C. Estrogen and Osteo op rosin
Osteoporosis is a metabolic bone disorder that leads to bone fragility and
subsequent
risk of fracture. Treatment for postmenopausal women with osteoporesis
includes hormone
replacement, in particular estrogen. Estrogen has shown to reduce the
incidence of bone loss
and fractures (Weiss et al., NEngl JMed 1980 Nov 20;303(21):1195-8 :Paganini-
Hill et al.,
Any Intern Med 1981 Ju1;95(1):28-31: Ettinger et al., Ann Inters Med 1985
Mar;102(3):319
24)
Further, polymorphisms in the estrogen receptor have been associated with bone
loss
in both humans and mice.( Kobayashi JBohe Mirae~ Res 1996 Marl 1(3):306-11
Kurabayashi Am J Obstet Gynecol 1999 May;180(5):1115-20; Deng Hum Genet 1998
Nov;103(5):576-85 )
Estro .ens and Cognitive function
Compared with men, women are at greater risk of developing Alzheimer's
disease.
Several studies show that women who take estrogen after menopause have a lower
incidence
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of Alzheimer's disease. Among women with Alzheimer's, those taking estrogen
suffer less
severe symptoms and slower mental deterioration. The duration of estrogen use
also seems to
be important in reducing risk. Women with a history of long-term use (more
than 10 years)
had the lowest risk. But even women who took estrogen for a short time also
benefited.
Estrogen and breast cancer
The major risk factors for the development of breast cancer axe sex, age,
family
history of breast cancer, age of menarche, age at first full-term pregnancy,
and age of
menopause. All of these factors, with the exception of family history, have
been shown to be
directly associated with lifetime exposure to estrogen, increased hormone
exposure being
associated with increased risk of developing breast cancer. The increased
cancer risk is
believed to be caused by an estrogen receptor-mediated proliferative response
in cells of the
mammary epithelium.
Tamoxifen, an estrogen receptor antagonist, has been shown to be an effective
agent
for both the prevention and treatment of breast cancer. Using
immunohistochemical methods,
it is possible to classify breast tumors as being estrogen receptor positive
or negative,
depending upon the amount of estrogen receptor protein expressed in the
tissue. Estrogen
receptor positive tumors are more likely to respond to treatment with
tamoxifen than estrogen
receptor negative tumors. Pre-menopausal women are more likely to develop
estrogen
receptor negative breast cancers than are post-menopausal women.
Mutations altering the structure and function of the estrogen receptor have
been
described in primary breast tumors or breast cancer cell lines. It is not
clear however whether
these changes are primary (and involved in the processes leading to
carcinogenesis) or
secondary (and a consequence of genetic instability in cancer tissues). In
addition to these
somatic mutations, some studies have pointed to a possible association between
inherited
DNA sequence changes and the development of breast cancer, but these studies
are also
controversial.
Further evidence for the role of estrogen receptors in breast cancer comes
from the
recent fording that the gene BRCAl, which when inherited in a mutant form
predisposes to
3 0 the development of breast cancer, inhibits estrogen receptor signaling.
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Estro~ens and endometrial cancer
Carcinoma of the endometrium is the most common pelvic malignancy in women,
however because in approximately 75% of cases it is confined to the body of
the uterus at the
time of diagnosis, it can usually be cured by hysterectomy. Unopposed exposure
of
endometrial cells to estrogens dramatically increases the chance of developing
this form of
uterine cancer and it is for this reason that hormone replacement therapy
consisting solely of
estrogen should not be given to women with intact uteri. Cyclical or
continuous co-
administration of progesterone serves to prevent excessive proliferation of
endometrial cells,
reducing the risk of endometrial cancer in post-menopausal women receiving
estrogen as part
of hormone replacement therapy regimens.
The majority of cases of endometrial cancers express estrogen receptor and, in
general, estrogen responsive tumors have a favorable prognosis. Acquired
(somatic)
mutations have been described in up to 8.5% of cases, however the role of
these mutations in
the development and progression of endometrial cancer is uncertain at present.
Although it remains somewhat controversial, studies suggest that use of
tamoxifen
may increase the chance of developing endometrial cancer. This may be because,
in addition
to its role in estrogen receptor blockade, tamoxifen has partial receptor
agonist activity and
results in low-grade induction of estrogen responsive genes that induce
endometrial
proliferation.
Given the involvement of the estrogen receptor in mediating/modulating various
disorders, it is critical to identify sequence polymorphisms in the estrogen
receptor and to
correlate these with disease states, therapeutic effectiveness and the like.
The present
invention advances the art by providing a variety of previously unidentified
polymorphisms
in the ESR-alpha protein.
SNPs
The genomes of all organisms undergo spontaneous mutation in the course of
their
continuing evolution, generating variant forms of progenitor sequences
(Gusella, Ann. Rev.
Biochem. 55, 831-854 (1986)). The variant form may confer an evolutionary
advantage or
disadvantage relative to a progenitor form or may be neutral. In some
instances, a variant
form confers a lethal disadvantage and is not transmitted to subsequent
generations of the
organism. In other instances, a variant form confers an evolutionary advantage
to the species
and is eventually incorporated into the DNA of many or most members of the
species and
effectively becomes the progenitor form. Additionally, the effect of a variant
form may be
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both beneficial and detrimental, depending on the circumstances. For example,
a
heterozygous sickle cell mutation confers resistance to malaria, but a
homozygous sickle cell
mutation is usually lethal. In many instances, both progenitor and variant
forms) survive and
co-exist in a species population. The coexistence of multiple forms of a
sequence gives rise to
polymorphisms, such as SNPs.
The reference allelic form is arbitrarily designated and may be, for example,
the most
abundant form in a population, 'or the first allelic form to be identified,
and other allelic forms
are designated as alternative, variant or polymorphic alleles. The allelic
form occurring most
frequently in a selected population is sometimes referred to as the "wild
type" form.
Approximately 90% of all polymorphisms in the human genome are single
nucleotide
polymorphisms (SNPs). SNPs axe single base pair positions in DNA at which
different
alleles, or alternative nucleotides, exist in some population. The SNP
position, or SNP site, is
usually preceded by and followed by highly conserved sequences of the allele
(e.g.,
sequences that vary in less than 1/100 or 1/1000 members of the populations).
An individual
may be homozygous or heterozygous for an allele at each SNP position. As
defined by the
present invention, the least frequent allele at a SNP position can have any
frequency that is
less than the frequency of the more frequent allele, including a frequency of
less than 1 % in a
population. A SNP can, in some instances, be referred to as a "cSNP" to denote
that the
nucleotide sequence containing the SNP is an amino acid coding sequence.
A SNP may arise due to a substitution of one nucleotide for another at the
polymorphic site. Substitutions can be transitions or transversions. A
transition is the
replacement of one purine nucleotide by another purine nucleotide, or one
pyrimidine by
another pyrimidine. A transversion is the replacement of a purine by a
pyrimidine, or vice
versa. A SNP may also be a single base insertion/deletion variant (referred to
as "indels"). A
substitution that changes a codon coding for one amino acid to a codon coding
for a different
amino acid is referred to as a non-synonymous codon change, or missense
mutation. A
synonymous codon change, or silent mutation, is one that does not result in a
change of
amino acid due to the degeneracy of the genetic code. A nonsense mutation is a
type of non-
synonymous codon change that results in the formation of a stop codon, thereby
leading to
3 0 premature termination of a polypeptide chain and a defective protein.
SNPs, in principle, can be bi-, tri-, or tetra- allelic. However, tri- and
tetra-allelic
polymorphisms are extremely rare, almost to the point of non-existence
(Brookes, Gene 234
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(1999) 177-186). For this reason, SNPs are often referred to as "bi-allelic
markers", or "di-
allelic markers".
Causative SNPs are those SNPs that produce alterations in gene expression or
in the
expression or function of a gene product, and therefore are most predictive of
a possible
clinical phenotype. One such class includes SNPs falling within regions of
genes encoding a
polypeptide product, i.e. cSNPs. These SNPs may result in an alteration of the
amino acid
sequence of the polypeptide product (i.e., non-synonymous codon changes) and
give rise to
the expression of a defective or other variant protein. Furthermore, in the
case of nonsense
mutations, a SNP may lead to premature termination of a polypeptide product.
Such variant
products can result in a pathological condition, e.g., genetic disease.
Examples of genes in
which a polymorphism within a coding sequence gives rise to genetic disease
include sickle
cell anemia and cystic fibrosis. Causative SNPs do not necessarily have to
occur in coding
regions; causative SNPs can occur in any region that can ultimately affect the
expression
and/or activity of the protein encoded by the nucleic acid. Such gene areas
include those
involved in transcription, such as SNPs in promoter regions, in gene areas
involved in
transcript processing, such as SNPs at intron-exon boundaries that may cause
defective
splicing, or SNPs in mRNA processing signal sequences such as polyadenylation
signal
regions. For example, a SNP may inhibit splicing of an intron and result in
mRNA containing
a premature stop codon, leading to a defective protein. Consequently, SNPs in
regulatory
regions can have substantial phenotypic impact.
Some SNPs that are not causative SNPs nevertheless are in close association
with, and
therefore segregate with, a disease-causing sequence. In this situation, the
presence of the
SNP correlates with the presence of, or susceptibility to, the disease. These
SNPs are
invaluable for diagnostics and disease susceptibility screening.
Clinical trials have shown that patient response to treatment with
pharmaceuticals is
often heterogeneous. Thus there is a need for improved approaches to
pharmaceutical agent
design and therapy. SNPs can be used to help identify patients most suited to
therapy with
particular pharmaceutical agents (this is often termed "pharmacogenomics")
Pharmacogenomics can also be used in pharmaceutical research to assist the
drug selection
process. (Linder et al. (1997), Clinical Chemistry, 43, 254; Marshall (1997),
Nature
Biotechnology, 15, 1249; International Patent Application WO 97/40462, Spectra
Biomedical; and Schafer et al. (I998), Nature Biotechnology, 16, 3.).
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Population Studies
Population Genetics is the study of how Mendel's laws and other genetic
principles
apply to entire populations. Such a study is essential to a proper
understanding of evolution
because, fundamentally, evolution is the result of progressive change in the
genetic
composition of a population. Population genetics thus seeks to understand and
to predict the
effects of such genetic phenomena as segregation, recombination, and mutation;
at the same
time, population genetics must take into account such ecological and
evolutionary factors as
population size, patterns of mating, geographic distribution of individuals,
migration and
natural selection.
Ideally, one would wish to know how to describe the types and frequencies of
genes
in a population, to explain how the population's genetic composition came to
be the way it is,
and to predict how the population would change as a result of natural
selection or as a result
of artificial selection.
In order to explain many of those issues it is important to understand the
existing
relation between loci denominated: Linkage.
Linkage is the coinheritance of two or more nonallelic genes because their
loci are in
close proximity on the same chromosome, such that after meiosis they remain
associated
more often than the 50% expected for unlinked genes. During meiosis, there is
a physical
crossing over, it is clear that during the production of germ cells there is a
physical exchange
of maternal and paternal genetic contributions between individual chromatids.
This exchange
necessarily separates genes in chromosomal regions that were contiguous in
each parent and,
by mixing them with retained linear order, results in "recombinants". The
process of forming
recombinants through meiotic crossing-over is an essential feature in the
reassortment of
genetic traits and is central to understanding the transmission of genes.
Recombination generally occurs between large segments of DNA. This means that
contiguous stretches of DNA and genes are likely to be moved together.
Conversely, regions
of the DNA that are far apart on a given chromosome are likely to become
separated during
the process of crossing-over.
It is possible to use molecular maxkers to claxify the recombination events
that take
place during meiosis. Some markers as (CA)n repeats of different lengths are
dispersed
throughout human DNA and there is little selective pressure in their lengths
axe used as
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position markers and regional identifying characters along chromosomes. Those
markers can
be used to distinguish paternally derived from maternally derived gene
regions.
Other markers are Single Nucleotide Polymorphism (SNP), those are biallelic
markers, also used to analyzed the transmission of those markers to offspring.
The pattern of a set of markers along a chromosome is referred to as a
"Haplotype".
Therefore sets of alleles on the same small chromosomal segment tend to be
transmitted as a
block through a pedigree. By analyzing the haplotypes in a series of offspring
of parents
whose haplotypes are known, it is possible to establish which parental segment
of which
chromosome was transmitted to which child. When not broken up by
recombinations,
haplotypes can be treated for mapping purposes as alleles at a single highly
polymorphic
locus.
The existance of a preferential occurrence of a disease gene in association
with
specific alleles of linked markers is called "Linkage Disequilibrium"(LD).
This sort of
disequilibrium generally implies that most of the disease chromosomes carry
the same
mutation and the markers being tested are quite close to the disease gene. Fox
example, there
is considerable linkage disequilibrium across the entire HLA locus. The A3
allele is in LD
with the B7 and B14 alleles, and as a result B7 and B14 are also highly
associated with
hemochromatosis. Thus, HLA typing alone can significantly alter the estimate
of risk for
hemochromatosis, even if other family members are not available for formal
linkage analysis.
As a result, using a combination of several markers surrounding the
presumptive location of
the gene, a haplotype can be determined for affected and unaffected family
members.
SNP-Based Association Analysis and Linkage Disequilibrium Mappin
SNPs are useful in association studies for identifying particular SNPs, or
other
polymorphisms, associated with pathological conditions, such as breast cancer.
Association
studies may be conducted within the general population and are not limited to
studies
performed on related individuals in affected families (linkage studies). An
association study
using SNPs involves determining the frequency of the SNP allele in many
patients with the
disorder of interest, such as breast cancer, as well as controls of similar
age and race. The
appropriate selection of patients and controls is critical to the success of
SNP association
studies. Therefore, a pool of individuals with well-characterized phenotypes
is extremely
desirable. For example, blood pressure and heart rate can be correlated with
SNP patterns in
hypertensive individuals in whom these physiological parameters are known in
order to find
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associations between particular SNP genotypes and known phenotypes.
Significant
associations between particular SNPs or SNP haplotypes and phenotypic
characteristics can
be determined by standard statistical methods. Association analysis can either
be direct or LD
based. In direct association analysis, causative SNPs are tested that are
candidates for the
pathogenic sequence itself.
In LD based SNP association analysis, random SNPs are tested over a large
genomic
region, possibly the entire genome, in order to find a SNP in LD with the true
pathogenic
sequence or pathogenic SNP. For this approach, high density SNP maps are
required in order
for random SNPs to be located close enough to an unknown pathogenic locus to
be in linkage
disequilibrium with that locus in order to detect an association. SNPs tend to
occur with great
frequency and are spaced uniformly throughout the genome. The frequency and
uniformity of
SNPs means that there is a greater probability, compared with other types of
polymorphisms
such as tandem repeat polymorphisms, that a SNP will be found in close
proximity to a
genetic locus of interest. SNPs are also mutationally more stable than tandem
repeat
polymorphisms, such as VNTRs. LD-based association studies are capable of
finding a
disease susceptibility gene without any a priori assumptions about what or
where the gene is.
Currently, however, it is not feasible to do SNP association studies over the
entire
human genome, therefore candidate genes associated with breast cancer are
targeted for SNP
identification and association analysis. The candidate gene approach uses a
priori knowledge
of disease pathogenesis to identify genes that are hypothesized to directly
influence
development of the disease. The candidate gene approach may focus on a gene
that is
directly targeted by a drug used to treat the disorder. To discover SNPs
associated with an
increased susceptibility to breast cancer, candidate genes can be selected
from systems
physiologically implicated in the disease pathway. SNPs found in these genes
are then tested
for statistical association with disease in individuals who have the disease
compared with
appropriate controls. The candidate gene approach has the.advantages of
drastically reducing
the number of candidate SNPs, and the number of individuals, that need to be
typed,
compaxed with LD-based association studies of random SNPs over large areas of,
or
complete, genomes. Furthermore, in the candidate gene approach, no assumptions
are made
about the extent of LD over any particular area of the genome.
Combined with the use of a high density map of appropriately spaced,
sufficiently
informative SNP markers, association studies, including linkage disequilibrium-
based
genome wide association studies, will enable the identification of most genes
involved in
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complex disorders, such as breast cancer. This will enhance the selection of
candidate genes
most likely to contain causative SNPs associated with a particular disease.
All of the SNPs
disclosed by the present invention can be employed as part of genome-wide
association
studies or as part of candidate gene association studies.
The present invention advances the state of the art and provides commercially
useful
embodiments by providing previously unidentified SNPs in the estrogen receptor
genes.
SUMMARY OF THE INVENTION
The present invention is based on sequencing genomic DNA from human
chromosome 6 and cDNAs to define the genomic structure of estrogen receptor
alpha genes,
novel polymorphisms in the estrogen receptor gene/protein and previously
unknown
haplotypes. Such polymorphisms/haplotypes can lead to a variety of disorders
that are
mediated/modulated by a variant estrogen receptor, such as a susceptibility to
cancer,
osteoporosis, cardiovascular disorders, etc. Based on this sequencing
approach, the present
invention provides genomic nucleotide sequences, cDNA sequences, amino acid
sequences,
sequence polymorphisms in the ESR-alpha gene, haplotypes of these
polymorphisms,
methods of detecting these sequences/polymorphisms in a sample, methods of
determining a
risk of having or developing a disorder mediated by a variant estrogen
receptor and methods
of screening for compounds used to treat disorders mediated by a variant
estrogen receptor.
DESCRIPTION OF THE FIGURES
Figure 1. Complete genomic sequence of the estrogen receptor alpha gene.
Figure 2. Sequence polymorphisms found in the ESR-alpha genomic DNA
(nucleotide position is based on the sequence provided in Figure 1.)
(a) SNPs in Liverpool clinical tissue samples.
(b) SNPs in Coriell Diversity panels.
(c) SNPs in Liverpool Control Population
(d) PCR primers.
(e) Sequencing primers.
Figure 3. Amino acid sequence of the estrogen receptor alpha protein.
Figure 4. Estrogen Receptor Haplotypes (See Haplotype Section).
(a) Liverpool samples from 48 patients, and each patient had a tumor and blood
sample typed. Coriell samples were control.
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(b) The non-singleton haplotype data fitted to a neighbor-joining tree (L is
Liverpool
sample).
Figure 5. The domain structure of the ESRl protein and the positions of the
SNPs
disclosed herein.
Figure 6. The distribution and frequency of many of the SNPs of the present
invention.
Figure 7. A graphic representation of the human ESR1 locus.
(a) Complete structure of the human estrogen receptor alpha (ERcc). Exons are
represented by filled boxes and introns by horizontal lines.
(b) Order and names of contigs used to complete the genomic sequence. GA
numbers
represent Celera contig numbers. Research Genetics BAC clones are represented
by standard plate and well numbering.
Figure 8. ESR-alpha SNPs Genotyping Results a) in Coriell Samples, b) in
Liverpool
Samples (T= tumor sample, B= blood sample, LC=Liverpool controls), c) in
Liverpool
Control sample
Figure 9. ESR-alpha exons with SNPs. (see Figure 2 for "N", "C", "I", "A", "S"
representations). Underlined sequences indicate the primer sequences.
DETAILED DESCRIPTION OF THE INVENTION
General Description
The present invention is based on sequencing genomic DNA from human
chromosome 6 and cDNAs to define the genomic structure of estrogen receptor
alpha genes
and novel polymorphisms and haplotypes in the estrogen receptor gene/protein.
Such
polymorphisms/haplotypes can lead to a variety of disorders that are
mediated/modulated by
a variant estrogen receptor, such as a susceptibility to cancer, osteoporosis,
cardiovascular
disorders, etc. Based on this sequencing approach, the present invention
provides genomic
nucleotide sequences, cDNA sequences, amino acid sequences and sequence
polymorphisms/haplotypes in the ESR-alpha gene, methods of detecting these
sequences/polymorphisms/haplotypes in a sample, methods of determining a risk
of having or
developing a disorder mediated by a variant estrogen receptor and methods of
screening for
compounds used to treat disorders mediated by a variant estrogen receptor.
Isolated SNP-Containing Nucleic Acid Molecules
The present invention provides isolated nucleic acid molecules that contain
one or
more SNPs disclosed by the present invention. The present invention further
provides
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isolated nucleic acid molecules that encode the variant protein. Such nucleic
acid molecules
will consist of, consist essentially of, or comprise one or more SNPs of the
present invention.
The nucleic acid molecule can have additional nucleic acid residues, such as
nucleic acid
residues that are naturally associated with it or heterologous nucleotide
sequences.
As used herein, an "isolated" SNP-containing nucleic acid molecule is one that
contains
a SNP of the present invention and is separated from other nucleic acid
present in the natural
source of the nucleic acid. Generally, the isolated SNP-containing nucleic
acid, as used herein,
will be comprised of one or more SNP positions disclosed by the present
invention with flanking
nucleotide sequence on either side of the SNP positions. Preferably the
flanking sequence is up
to about 300 bases, 100 bases, 50 bases, 30 bases, 15 bases, I O bases, or 4
bases on either side of
a SNP position for detection reagents or as long as the entire protein
encoding sequence if it is to
be used to produce a protein containing the coding variants disclosed in
Figures. The important
point is that the nucleic acid is isolated from remote and unimportant
flanking sequences and is
of appropriate length such that it can be subjected to the specific
manipulations or uses described
herein such as recombinant expression, preparation of probes and primers for
the SNP position,
and other uses specific to the SNP-containing nucleic acid sequences.
Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule
containing a
SNP of the present invention, can be substantially free of other cellular
material, or culture
medium when produced by recombinant techniques, or chemical precursors or
other chemicals
when chemically synthesized. However, the nucleic acid molecule can be fused
to other coding
or regulatory sequences and still be considered isolated. For example,
recombinant DNA
molecules contained in a vector are considered isolated. Further examples of
isolated DNA
molecules include recombinant DNA molecules maintained in heterologous host
cells or
purified (partially or substantially) DNA molecules in solution. Isolated RNA
molecules include
ih vivo or in vitro RNA transcripts of the isolated SNP-containing DNA
molecules of the present
invention. Isolated nucleic acid molecules according to the present invention
further include
such molecules produced synthetically.
Isolated SNP-containing nucleic acid molecules can be in the form of RNA, such
as
mRNA, or in the form DNA, including cDNA and genomic DNA obtained by cloning
or
produced by chemical synthetic techniques or by a combination thereof. The
nucleic acid,
especially DNA, can be double-stranded or single-stranded. Single-stranded
nucleic acid can
be the coding strand (sense strand) or the non-coding strand (anti-sense
strand).
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The present invention further provides related nucleic acid molecules that
hybridize
under stringent conditions to the nucleic acid molecules disclosed herein. As
used herein, the
term "hybridizes under stringent conditions" is intended to describe
conditions for hybridization
and washing under which nucleotide sequences encoding a peptide at least 60-
70% homologous
to each other typically remain hybridized to each other. The conditions can be
such that
sequences at least about 60%, at least about 70%, or at least about 80%, or at
least about 90% or
more homologous to each other typically remain hybridized to each other. Such
stringent
conditions are known to those skilled in the art and can be found in Current
Protocols in
Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. One example of
stringent
hybridization conditions are hybridization in 6X sodi .un chloride/sodium
citrate (SSC) at about
45 °C, followed by one or more washes in 0.2 X SSC, 0.1% SDS at 50-65
°C. Examples of
moderate to low stringency hybridization conditions are well known in the art.
~ecific Embodiments
Peptide Molecules
The present invention provides nucleic acid sequences that encode variants of
the
estrogen receptor. These variant molecule/sequences will be referred to herein
as the estrogen
receptor variants of the present invention, the estrogen receptor proteins of
the present
invention, or peptides/proteins of the present invention.
The present invention provides isolated estrogen receptor protein molecules
that
consist of, consist essentially of or are comprised of the amino acid
sequences of the estrogen
receptor variant proteins disclosed herein.
As used herein, a protein or peptide is said to be "isolated" or "purified"
when it is
substantially free of cellular material or free of chemical precursors or
other chemicals. The
peptides of the present invention can be purified to homogeneity or other
degrees of purity. The
level of purification will be based on the intended use. The critical feature
is that the preparation
allows for the desired function of the peptide, even if in the presence of
considerable amounts of
other components.
In some uses, "substantially free of cellular material" includes preparations
of the peptide
having less than about 30% (by dry weight) other proteins (i.e., contaminating
protein), less than
about 20% other proteins, less than about 10% other proteins, or less than
about 5% other
proteins. When the peptide is recombinantly produced, it can also be
substantially free of culture
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medium, i.e., culture medium represents less than about 20% of the volume of
the protein
preparation.
The language "substantially free of chemical precursors or other chemicals"
includes
preparations of the peptide in which it is separated from chemical precursors
or other chemicals
that are involved in its synthesis. In one embodiment, the language
"substantially free of
chemical precursors or other chemicals" includes preparations of the estrogen
receptor protein
having less than about 30% (by dry weight) chemical precursors or other
chemicals, less than
about 20% chemical precursors or other chemicals, less than about 10% chemical
precursors or
other chemicals, or less than about 5% chemical precursors or other chemicals.
The isolated estrogen receptor proteins can be purified from cells that
naturally express
it, purified from cells that have been altered to express it (recombinant), or
synthesized using
known protein synthesis methods. For example, a nucleic acid molecule encoding
the estrogen
receptor protein is cloned into an expression vector, the expression vector
introduced into a host
cell and the protein expressed in the host cell. The protein can then be
isolated from the cells by
an appropriate purification scheme using standard protein purification
techniques. Many of
these techniques are described in detail below.
Accordingly, the present invention provides proteins that consist of the amino
acid
sequences summarized in Figure 1, including one or more of the sequence
polymorphisms
provided in Figure 2. A protein consists of an amino acid sequence when the
amino acid
sequence is the final amino acid sequence of the protein.
The present invention further provides proteins that consist essentially of
the amino acid
sequences summarized in Figure 1, including one or more of the sequence
polymorphisms
provided in Figure 2. A protein consists essentially of an amino acid sequence
when such an
amino acid sequence is present with only a few additional amino acid residues
in the final
protein.
The present invention fiufiher provides a protein that is comprised of the
amino acid
sequences summarized in Figure 1, including one or more of the sequence
polymorphisms
provided in Figure 2. A protein is comprised of an amino acid sequence when
the amino acid
sequence is at least part of the final amino acid sequence of the protein. In
such a fashion, the
protein can be only the peptide or have additional amino acid molecules, such
as amino acid
residues (contiguous encoded sequence) that are naturally associated with it
or heterologous
amino acid residues/peptide sequences. Such a protein can have a few
additional amino acid
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residues or can comprise several hundred or more additional amino acids. A
brief description of
how various types of these proteins can be made/isolated is provided below.
The estrogen receptor protein of the present invention can be attached to
heterologous
sequences to form chimeric or fusion proteins. Such chimeric and fusion
proteins comprise a
estrogen receptor protein operatively linked to a heterologous protein having
an amino acid
sequence not substantially homologous to the estrogen receptor protein.
"Operatively linked"
indicates that the estrogen receptor protein and the heterologous protein are
fused in-frame. The
heterologous protein can be fused to the N-terminus or C-terminus of the
estrogen receptor
protein.
In some uses, the fusion protein does not affect the activity of the estrogen
receptor
protein per se. For example, the fusion protein can include, but is not
limited to, enzymatic
fusion proteins, for example beta-galactosidase fusions, yeast two-hybrid GAL
fusions, poly-His
fusions, MYC-tagged, HI-tagged and Ig fusions. Such fusion proteins,
particularly poly-His
fusions, can facilitate the purification of recombinant estrogen receptor
protein. In certain host
cells (e.g., mammalian host cells), expression andlor secretion of a protein
can be increased by
using a heterologous signal sequence.
A chimeric or fusion protein can be produced by standard recombinant DNA
techniques.
For example, DNA fragments coding for the different protein sequences are
ligated together in-
frame in accordance with conventional techniques. In another embodiment, the
fusion gene can
be synthesized by conventional techniques including automated DNA
synthesizers.
Alternatively, PCR amplification of gene fragments can be carried out using
anchor primers
which give rise to complementary overhangs between two consecutive gene
fragments which
can subsequently be annealed and re-amplified to generate a chimeric gene
sequence (see
Ausubel et al., Curre~rt Protocols ih Molecular Biology, 1992). Moreover, many
expression
vectors are commercially available that already encode a fusion moiety (e.g.,
a GST protein). A
estrogen receptor protein-encoding nucleic acid can be cloned into such an
expression vector
such that the fusion moiety is linleed in-frame to the estrogen receptor
protein.
Polypeptides often contain amino acids other than the 20 amino acids commonly
referred to as the 20 naturally-occurring amino acids. Further, many amino
acids, including
the terminal amino acids, may be modified by natural processes, such as
processing and other
post-translational modifications, or by chemical modification techniques well
known in the
art. Common modifications that occur naturally in polypeptides are described
in basic texts,
detailed monographs, and the research literature, and they are well known to
those of skill in
CA 02426405 2003-04-17
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the art. Accordingly, the polypeptides also encompass derivatives or analogs
in which a
substituted amino acid residue is not one encoded by the genetic code, in
which a substituent
group is included, in which the mature polypeptide is fused with another
compound, such as a
compound to increase the half life of the polypeptide (for example,
polyethylene glycol), or
in which the additional amino acids are fused to the mature polypeptide, such
as a leader or
secretory sequence or a sequence for purification of the mature polypeptide or
a pro-protein
sequence.
Known modifications include, but are not limited to, acetylation, acylation,
ADP-
ribosylation, amidation, covalent attachment of flavin, covalent attachment of
a heme moiety,
covalent attachment of a nucleotide or nucleotide derivative, covalent
attachment of a lipid or
lipid derivative, covalent attachment of phosphotidylinositol, cross-linking,
cyclization, disulfide
bond formation, demethylation, formation of covalent crosslinks, formation of
cystine,
formation of pyroglutamate, formylation, gamma carboxylation, glycosylation,
GPI anchor
formation, hydroxylation, iodination, methylation, myristoylation, oxidation,
proteolytic
I 5 processing, phosphorylation, prenylation, racemization, selenoylation,
sulfation, transfer-RNA
mediated addition of amino acids to proteins such as arginylation, and
ubiquitination.
Such modifications are well-known to those of skill in the art and have been
described in
great detail in the scientific literature. Several particularly common
modifications,
glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic
acid residues,
hydroxylation and ADP-ribosylation, for instance, are described in most basic
texts, such as
Pr~oteius - St~uctu~e ahd Molecular Properties, 2nd Ed., T.E. Creighton, W. H.
Freeman and
Company, New York (1993). Many detailed reviews are available on this subject,
such as by
Wold, F., Postt~anslatiohal Covalent Modification of Proteins, B.C. Johnson,
Ed., Academic
Press, New Yorlc 1-12 (1983); Seifter et al. (Meth. Enzymol. 182: 626-646
(1990)) and Rattan et
al. (Av~~c. N. Y. Acad. Sci. 663:48-62 (1992)).
The present invention further provides fragments of the estrogen receptor
proteins of the
present invention, in addition to proteins and peptides that comprise and
consist of such
fragments. The fragments to which the invention pertains, however, are not to
be construed as
encompassing fragments that may be disclosed publicly prior to the present
invention.
As used herein, a fragment comprises at least 8 or more contiguous amino acid
residues
from a estrogen receptor protein. Such fragments can be chosen based on the
ability to retain
one or more of the biological activities of the estrogen receptor protein or
could be chosen for
the ability to perform a function, e.g. act as an immunogen. Particularly
important fragments are
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biologically active fragments, peptides which are, for example, about 8 or
more amino acids in
length, that contain a variant amino acid residue (Figure 2). Such fragments
will typically
comprise a domain or motif of the estrogen receptor proteins of the present
invention, e.g., active
site, ligand binding domain or DNA binding domain. Further, possible fragments
include, but
are not limited to, domain or motif containing fragments, soluble peptide
fragments, and
fragments containing immunogenic structures. Predicted domains and functional
sites are readily
identifiable by computer programs well-known and readily available to those of
skill in the art
(e.g., PROSITE analysis).
Protein/Peptide Uses
The proteins of the present invention can be used in assays to determine the
biological
activity of the protein, including in a panel of multiple proteins for high-
throughput
screening; to raise antibodies or to,elicit another immune response; as a
reagent (including the
labeled reagent) in assays designed to quantitatively determine levels of the
protein (or its
binding partner or receptor) in biological fluids; and as maxkers for tissues
in which the
corresponding protein is preferentially expressed (either constitutively or at
a particular stage
of tissue differentiation or development or in a disease state). Any or all of
these research
utilities are capable of being developed into reagent grade or kit format for
commercialization
as research products. Methods for performing the uses listed above are well
known to those
skilled in the art. References disclosing such methods include "Molecular
Cloning: A
Laboratory Manual", 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J.,
E. F.
Fritsch and T. Maniatis eds., 1989, and "Methods in Enzymology: Guide to
Molecular
Cloning Techniques", Academic Press, Berger, S. L. and A. R. Kimmel eds.,
1987.
The estrogen receptor proteins of the present invention are useful for
biological assay.
Such assays involve any of the known estrogen receptor functions or activities
or properties
useful for the diagnosis and treatment of estrogen receptor-related
conditions.
The estrogen receptor proteins of the present invention are also useful in
drug screening
assays, in cell-based or cell-free systems. Cell-based systems can be native,
i.e., cells that
normally express the receptor protein, as a biopsy or expanded in cell
culture. In one
embodiment, however, cell-based assays involve recombinant host cells
expressing the receptor
protein.
The estrogen receptor proteins of the present invention can be used to
identify
compounds that modulate receptor activity. Both the estrogen receptor protein
of the present
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invention and appropriate fragments can be used in high-throughput screens to
assay candidate
compounds for the ability to bind and/or modulate the activity of the
receptor. These
compounds can be further screened against a functional receptor to determine
the effect of the
compound on the receptor activity. Further, these compounds can be tested in
animal or
invertebrate systems to determine activity/effectiveness. Compounds can be
identified that
activate (agonist) or inactivate (antagonist) the receptor to a desired
degree. Such compounds
can be selected for the ability to act on one or more of the variant estrogen
receptor proteins of
the present invention.
Further, the receptor polypeptides can be used to screen a compound for the
ability to
stimulate or inhibit interaction between the receptor protein and a target
molecule that normally
interacts with the receptor protein, e.g. estrogen. The target can be ligand
or a binding partner
that the receptor protein normally interacts (for example, an estrogen ligand
or a DNA
sequence). Such assays typically include the steps of combining the receptor
protein with a
candidate compound under conditions that allow the receptor protein, or
fragment, to interact
with the target molecule, and to detect the formation of a complex between the
protein and the
target or to detect the biochemical consequence of the interaction with the
receptor protein and
the target, such as any of the associated effects of DNA binding or signal
transduction.
Candidate compounds include, for example, 1 ) peptides such as soluble
peptides,
including Ig-tailed fusion peptides and members of random peptide libraries
(see, e.g., Lam et
al., Nature 354:82-84 (1991); Houghten et al., Nature 354:84-86 (1991)) and
combinatorial
chemistry-derived molecular libraries made of D- and/or L- configuration amino
acids; 2)
phosphopeptides (e.g., members of random and partially degenerate, directed
phosphopeptide
libraries, see, e.g., Songyang et al., Cell 72:767-778 (1993)); 3) antibodies
(e.g., polyclonal,
monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies
as well as Fab,
F(ab')2, Fab expression library fragments, and epitope-binding fragments of
antibodies); and 4)
small organic and inorganic molecules (e.g., molecules obtained from
combinatorial and natural
product libraries). .
One candidate compound is a soluble fragment of the receptor that competes for
ligand
binding. Other candidate compounds include mutant receptors or appropriate
fragments
containing mutations that affect receptor function and thus compete for
ligand. Accordingly, a
fragment that competes for ligand, for example with a higher affinity, or a
fragment that binds
ligand but does not allow release, is encompassed by the invention.
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The invention further includes other end point assays to identify compounds
that
modulate (stimulate or inhibit) receptor activity. The assays typically
involve an assay of events
in the signal transduction pathway that indicate receptor activity. Thus, the
expression of genes
that are up- or down-regulated in response to the receptor protein dependent
signal cascade can
be assayed. In one embodiment, the regulatory region of such genes can be
operably linked to a
marker that is easily detectable, such as luciferase. Alternatively,
phosphorylation of the
receptor protein, or a receptor protein target, could also be measured. Any of
the biological or
biochemical functions mediated by the receptor can be used as an endpoint
assay. These include
all of the biochemical or biochemical/biological events described herein, in
the references cited
herein, incorporated by reference for these endpoint assay targets, and other
functions known to
those of ordinary skill in the art.
The receptor polypeptides are also useful in competition binding assays in
methods
designed to discover compounds that interact with the receptor. Thus, a
compound is exposed to
a receptor polypeptide under conditions that allow the compound to bind or to
otherwise interact
with the polypeptide. Ligands to the receptor is also added to the mixture. If
the test compound
interacts with the receptor or ligand, it decreases the amount of complex
formed or activity from
the receptor target. This type of assay is particularly useful in cases in
which compounds are
sought that interact with specific regions of the receptor.
To perform cell free drug screening assays, it is sometimes desirable to
immobilize
either the receptor protein, or fragment, or its target molecule to facilitate
separation of
complexes from uncomplexed forms of one or both of the proteins, as well as to
accommodate
automation of the assay.
Techniques for immobilizing proteins on matrices can be used in the drug
screening
assays. In one embodiment, a fusion protein can be provided which adds a
domain that allows
the protein to be bound to a matrix. For example, glutathione-S-
transferase/15625 fusion
proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St.
Louis, MO) or
glutathione derivatized microtitre plates, which are then combined with the
cell lysates (e.g., 35S-
labeled) and the candidate compound, and the mixture incubated under
conditions conducive to
complex formation (e.g., at physiological conditions for salt and pH).
Following incubation, the
beads are washed to remove any unbound label, and the matrix immobilized and
radiolabel
determined directly, or in the supernatant after the complexes are
dissociated. Alternatively, the
complexes can be dissociated from the matrix, separated by SDS-PAGE, and the
level of
receptor-binding protein found in the bead fraction quantitated from the gel
using standard
24
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electrophoretic techniques. For example, either the polypeptide or its target
molecule can be
immobilized utilizing conjugation of biotin and streptavidin using techniques
well known in the
art. Alternatively, antibodies reactive with the protein but which do not
interfere with binding of
the protein to its target molecule can be derivatized to the wells of the
plate, and the protein
trapped in the wells by antibody conjugation. Preparations of a receptor-
binding protein and a
candidate compound are incubated in the receptor protein-presenting wells and
the amount of
complex trapped in the well can be quantitated. Methods for detecting such
complexes, in
addition to those described above for the GST-immobilized complexes, include
immunodetection of complexes using antibodies reactive with the receptor
protein target
molecule, or which are reactive with receptor protein and compete with the
target molecule, as
well as enzyme-linked assays which rely on detecting an enzymatic activity
associated with the
target molecule.
Agents that modulate the protein of the present invention can be identified
using one or
more of the above assays, alone or in combination. It is generally preferable
to use a cell-based
or cell free system first and then confirm activity in an animal or other
model system. Such
model systems are well known in the art and can readily be employed in this
context.
Modulators of receptor protein activity identified according to these drug-
screening
assays can be used to treat a subject with a disorder mediated by the receptor
pathway, by
treating cells that express the estrogen receptor protein. These methods of
treatment include the
steps of administering the modulators of protein activity in a pharmaceutical
composition as
described herein, to a subject in need of such treatment.
This invention further pertains to novel agents identified by the above-
described
screening assays. Accordingly, it is within the scope of this invention to
further use an agent
identified as described herein in an appropriate animal model. For example, an
agent
identified as described herein (e.g., an estrogen receptor modulating agent,
an antisense
estrogen receptor nucleic acid molecule, an estrogen receptor-specific
antibody, or an
estrogen receptor-binding partner) can be used in an animal model to determine
the efficacy,
toxicity, or side effects of treatment with such an agent. Alternatively, an
agent identified as
described herein can be used in an anirrial model to determine the mechanism
of action of
such an agent. Furthermore, this invention pertains to uses of novel agents
identified by the
above-described screening assays for treatments as described herein.
The estrogen receptor proteins of the pr esent invention are also useful to
provide a target
for diagnosing a disease or predisposition to disease mediated by the estrogen
receptor.
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Accordingly, the invention provides methods for detecting the presence, or
levels of, the
estrogen receptor variants of the present invention (or encoding mRNA) in a
cell, tissue, or
organism. The method involves contacting a biological sample with a compound
capable of
interacting with the receptor protein (or gene or mRNA encoding the receptor)
such that the
interaction can be detected.
One agent for detecting a protein in a sample is an antibody capable of
selectively
binding to a variant form of the estrogen receptor protein. Such samples
include tissues, cells
and biological fluids isolated from a subject, as well as tissues, cells and
fluids present within a
subject.
The estrogen receptor proteins of the present invention also provide targets
for
diagnosing active disease, or predisposition to disease, in a patient having a
variant estrogen
receptor, particularly a disease involving the estrogen pathway, such as bone
growth, cell
differentiation, etc. Thus, the receptor can be isolated from a biological
sample and assayed for
the presence of a genetic mutation that results in aberrant receptor activity.
This includes amino
acid substitution, deletion, insertion, rearrangement, (as the result of
aberrant splicing events),
and inappropriate post-translational modification as provided in Figure 2.
Analytic methods
include altered electrophoretic mobility, altered tryptic peptide digest,
altered receptor activity in
cell-based or cell-free assay, alteration in ligand or antibody-binding
pattern, altered isoelectric
point, direct amino acid sequencing, and any other of the known assay
techniques useful for
detecting mutations in a protein. Particularly useful are the variation
provided in Figure 2.
In vitro techniques for detection of peptide include enzyme linked
immunosorbent
assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence.
Alternatively,
the peptide can be detected in vivo in a subject by introducing into the
subject a labeled anti-
peptide antibody. For example, the antibody can be labeled with a radioactive
marker whose
presence and location in a subject can be detected by standard imaging
techniques. Particularly
useful are methods that detect the specific allelic variants of the estrogen
receptor disclosed
herein that are expressed in a subject and methods that detect fragments of a
peptide in a sample.
The peptides are also useful in pharmacogenomic analysis. Pharmacogenomics
deal
with clinically significant hereditary variations in the response to drugs due
to altered drug
disposition and abnormal action in affected persons. See, e.g., Eichelbaum, M.
(Clip. Exp.
Pharw2acol. Physiol. 23(I0-11) :983-985 (1996)), and Linder, M.W. (Clip.
Chena. 43(2):254-266
(1997)). The clinical outcomes of these variations result in severe toxicity
of therapeutic drugs
in certain individuals or therapeutic failure of drugs in certain individuals
as a result of
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individual variation in metabolism. Thus, the genotype of the individual can
determine the way
a therapeutic compound acts on the body or the way the body metabolizes the
compound.
Further, the activity of drug metabolizing enzymes effects both the intensity
and duration of
drug action. Thus, the pharmacogenomics of the individual permit the selection
of effective
S compounds and effective dosages of such compounds for prophylactic or
therapeutic treatment
based on the individual's genotype. The discovery of genetic polymorphisms in
some drug
metabolizing enzymes has explained why some patients do not obtain the
expected drug effects,
show an exaggerated drug effect, or experience serious toxicity from standard
drug dosages.
Polymorphisms can be expressed in the phenotype ofthe extensive metabolizer
and the
phenotype of the poor metabolizer. Accordingly, genetic polymorphism may lead
to allelic
protein variants of the receptor protein in which one or more of the receptor
functions in one
population is different from those in another population. The peptides thus
allow a target to
ascertain a genetic predisposition that can affect treatment modality. Thus,
in a ligand-based
treatment, polymorphism may give rise to amino terminal extracellular domains
and/or other
I 5 Iigand-binding regions that are more or less active in ligand binding, and
receptor activation.
Accordingly, ligand dosage would necessarily be modified to maximize the
therapeutic effect
within a given population containing a polymorphism/haplotype. As an
alternative to
genotyping, specific polymorphic peptides could be identified.
Antibodies
The invention also provides antibodies that selectively bind to the estrogen
receptor
proteins of the present invention as well as fragments thereof. As used
herein, an antibody
selectively binds a target protein when it binds the target protein and does
not significantly bind
to unrelated proteins. An antibody is still considered to selectively bind a
protein even if it also
binds to other proteins that are not substantially homologous with the target
protein so long as
such proteins share homology with a fragment or domain of the protein target
of the antibody.
In tlus case, it would be understood that antibody binding to the protein is
still selective despite
some degree of cross-reactivity.
As used herein, an antibody is defined in terms consistent with that recoguzed
within
3 0 the art: they are multi-subunit proteins produced by a mammalian organism
in response to an
antigen challenge. The antibodies of the present invention include polyclonal
antibodies and
monoclonal antibodies, as well as fragments of such antibodies, including, but
not limited to,
Fab or F(ab')2, and Fv fragments.
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Many methods are known for generating and/or identifying antibodies to a given
target
peptide. Several such methods are described by Harlow, Antibodies, Cold Spring
Harbor Press,
(1989). In general, to generate antibodies, an isolated peptide is used as an
immunogen and is
administered to a mammalian organism, such as a rat, rabbit or mouse. The full-
length protein,
an antigenic peptide fragment or a fusion protein can be used.
Antibodies are preferably prepared from regions or discrete fragments of the
estrogen
receptor protein. Antibodies can be prepared from any region of the peptide as
described
herein. However, preferred regions will include those involved in
function/activity and/or
receptor/binding partner interaction. An antigenic fragment will typically
comprise at least 10
contiguous amino acid residues. The antigenic peptide can comprise, however,
at least 12, 14,
or more amino acid residues. Such fragments can be selected on a physical
property, such as
fragments correspond to regions that are located on the surface of the
protein, e.g., hydrophilic
regions or can be selected based on sequence uniqueness.
Detection on an antibody of the present invention can be facilitated by
coupling (i.e.,
15 physically linking) the antibody to a detectable substance. Examples of
detectable substances
include various enzymes, prosthetic groups, fluorescent materials, luminescent
materials,
bioluminescent materials, and radioactive materials. Examples of suitable
enzymes include
horseradish peroxidase, alkaline phosphatase, (3-galactosidase, or
acetylcholinesterase; examples
of suitable prosthetic group complexes include streptavidin/biotin and
avidin/biotin; examples of
20 suitable fluorescent materials include umbelliferone, fluorescein,
fluorescein isothiocyanate,
rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or
phycoerythrin; an example of
a luminescent material includes luminol; examples of bioluminescent materials
include
luciferase, luciferin, and aequorin, and examples of suitable radioactive
material include lash
i3ih ass or 3H.
Antibod,
The antibodies can be used to isolate the estrogen receptor protein of the
present
invention by standard techniques, such as affinity chromatography or
immunoprecipitation. The
antibodies can facilitate the purification of the natural protein from cells
and recombinantly
3 0 produced protein expressed in host cells. In addition, such antibodies are
useful to detect the
presence of the estrogen receptor protein of the present invention in cells or
tissues to determine
the pattern of expression of the protein among various tissues in an organism
and over the course
of normal development. Further, such antibodies can be used to detect protein
in situ, in vitro, or
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in a cell lysate or supernatant in order to evaluate the abundance and pattern
of expression.
Also, such antibodies can be used to assess abnormal tissue distribution or
abnormal expression
during development. Antibody detection of circulating fragments of the full
length estrogen
receptor protein can be used to identify turnover.
Further, the antibodies can be used to assess expression in disease states
such as in active
stages of the disease or in an individual with a predisposition toward disease
related to the
protein's function, particularly diseases involving bone
growth/formation/degeneration. When a
disorder is caused by an inappropriate tissue distribution, developmental
expression, level of
expression of the protein, or expressed/processed form, the antibody can be
prepared against the
normal protein. If a disorder is characterized by a specific mutation in the
protein, antibodies
specific for tlus mutant protein can be used to assay for the presence of the
specific mutant
protein.
The antibodies can also be used to assess normal and aberrant subcellular
localization of
cells in the various tissues in an organism. The diagnostic uses can be
applied, not only in
genetic testing, but also in monitoring a treatment modality. Accordingly,
where treatment is
ultimately aimed at correcting the expression level or the presence of
aberrant sequence and
aberrant tissue distribution or developmental expression, antibodies directed
against the protein
or relevant fragments can be used to monitor therapeutic efficacy.
Additionally, antibodies are useful in pharmacogenomic analysis. Thus,
antibodies
prepared against polymorphic proteins can be used to identify individuals that
require modified
treatment modalities. The antibodies are also useful as diagnostic tools as an
immunological
marker for aberrant estrogen receptor protein analyzed by electrophoretic
mobility, isoelectric
point, tryptic peptide digest, and other physical assays known to those in the
art.
The antibodies are also useful for inhibiting protein function, for example,
blocking the
binding of the estrogen receptor protein to a binding partner such as a
ligand. These uses can
also be applied in a therapeutic context in which treatment involves
inhibiting the protein's
function. An antibody can be used, for example, to block binding, thus
modulating (agonizing
or antagonizing) the peptides activity. Antibodies can be prepared against
specific fragments
containing sites required for function or against intact protein that is
associated with a cell or cell
3 0 membrane.
The invention also encompasses kits for using antibodies to detect the
presence of a
protein in a biological sample. The kit can comprise antibodies such as a
labeled or labelable
antibody and a compound or agent for detecting estrogen receptor protein in a
biological sample;
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CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
means for determining the amount of protein in the sample; means for comparing
the amount of
estrogen receptor protein in the sample with a standard; and instructions for
use.
Nucleic Acid Molecules
The present invention fiu-ther provides isolated nucleic acid molecules that
encode any of
the estrogen receptor proteins of the present invention. Such nucleic acid
molecules will consist
of, consist essentially of, or comprise a nucleotide sequence that encodes one
of the estrogen
receptor proteins of the present invention.
As used herein, an "isolated" nucleic acid molecule is one that is separated
from other
nucleic acid present in the natural source of the nucleic acid. Preferably, an
"isolated" nucleic
acid is free of sequences which naturally flank the nucleic acid (i.e.,
sequences located at the 5'
and 3' ends of the nucleic acid) in the genomic DNA of the organism from which
the nucleic
acid is derived. However, there can be some flanking nucleotide sequences, for
example up to
about SKB, 4KB, 3KB, 2I~B, or 1KB or less, particularly contiguous peptide
encoding
sequences and peptide encoding sequences within the same gene but separated by
introns in the
genomic sequence. The important point is that the nucleic acid is isolated
from remote and
unimportant flanking sequences such that it can be subjected to the specific
manipulations
described herein such as recombinant expression, preparation of probes and
primers, and other
uses specific to the nucleic acid sequences.
Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be
substantially free of other cellular material, or culture medium when produced
by recombinant
techniques, or chemical precursors or other chemicals when chemically
synthesized. However,
the nucleic acid molecule can be fused to other coding or regulatory sequences
and still be
considered isolated.
For example, recombinant DNA molecules contained in a vector are considered
isolated.
Further examples of isolated DNA molecules include recombinant DNA molecules
maintained
in heterologous host cells or purified (partially or substantially) DNA
molecules in solution.
Isolated RNA molecules include in vivo or i~ vitro RNA transcripts of the
isolated DNA
molecules of the present invention. Isolated nucleic acid molecules according
to the present
invention further include such molecules produced synthetically.
Accordingly, the present invention provides nucleic acid molecules that
consist of the
nucleotide sequences shown in Figure l, including one or more of the sequence
polymorphisms
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
provided in Figure 2. A nucleic acid molecule consists of a nucleotide
sequence when the
nucleotide sequence is the complete nucleotide sequence of the nucleic acid
molecule.
The present invention fiufiher provides nucleic acid molecules that consist
essentially of
the nucleotide sequence shown in Figure 1, including one or more of the
sequence
polymorplusms provided in Figure 2. A nucleic acid molecule consists
essentially of a
nucleotide sequence when such a nucleotide sequence is present with only a few
additional
nucleic acid residues in the final nucleic acid molecule.
The present invention fuxther provides nucleic acid molecules that are
comprised of the
nucleotide sequences shown in Figure 1, including one or more of the sequence
polymorphisms
provided in Figure 2. A nucleic acid molecule is comprised of a nucleotide
sequence when the
nucleotide sequence is at least part of the final nucleotide sequence of the
nucleic acid molecule.
In such a fashion, the nucleic acid molecule can be only the nucleotide
sequence or have .
additional nucleic acid residues, such as nucleic acid residues that are
naturally associated with it
or heterologous nucleotide sequences. Such a nucleic acid molecule can have a
few additional
nucleotides or can comprise several hundred or more additional nucleotides. A
brief description
of how various types of these nucleic acid molecules can be readily
made/isolated is provided
below.
The isolated nucleic acid molecules can encode the mature protein plus
additional amino
or carboxyl-terminal amino acids, or amino acids interior to the mature
peptide (when the
mature form has more than one peptide chain, for instance). Such sequences may
play a role in
processing of a protein from precursor to a mature form, facilitate protein
trafficking, prolong or
shorten protein half life or facilitate manipulation of a protein for assay or
production, among
other things. As generally is the case ih situ, the additional amino acids may
be processed away
from the mature protein by cellular enzymes.
As mentioned above, the isolated nucleic acid molecules include, but are not
limited to,
the sequence encoding the estrogen receptor protein alone, the sequence
encoding the mature
peptide and additional coding sequences, such as a leader or secretory
sequence (e.g., a pre-pro
or pro-protein sequence), the sequence encoding the mature peptide, with or
without the
additional coding sequences, plus additional non-coding sequences, for example
introns and
3 0 non-coding 5' and 3' sequences such as transcribed but non-translated
sequences that play a role
in transcription, mRNA processing (including splicing and polyadenylation
signals), ribosome
binding and stability of mRNA, as well as genomic regulatory sequences such as
promoters. In
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WO 02/34945 PCT/USO1/25990
addition, the nucleic acid molecule may be fused to a marker sequence
encoding, for example, a
peptide that facilitates purification.
Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in
the
form DNA, including cDNA and genomic DNA obtained by cloning or produced by
chemical
synthetic techniques or by a combination thereof. The nucleic acid, especially
DNA, can be
double-stranded or single-stranded. Single-stranded nucleic acid can be the
coding strand (sense
strand) or the non-coding strand (anti-sense strand).
The invention further provides nucleic acid molecules that encode fragments of
the
proteins of the present invention. A fragment comprises a contiguous
nucleotide sequence
greater than 12 or more nucleotides. Further, a fragment could at least 30,
40, 50, 100, 250 or
500 nucleotides. in length. The length of the fragment will be based on its
intended use. For
example, the fragment can encode epitope-bearing regions of the peptide, or
can be useful as
DNA probes and primers. Such fragments can be isolated using the known
nucleotide
sequence to synthesize an oligonucleotide probe. A labeled probe can then be
used to screen
1 S a cDNA library, genomic DNA library, or mRNA to isolate nucleic acid
corresponding to the
coding region. Further, primers can be used in PCR reactions to clone specific
regions of
gene.
A probe/primer typically comprises substantially a purified oligonucleotide or
oligonucleotide pair. The oligonucleotide typically comprises a region of
nucleotide sequence
that hybridizes under stringent conditions to at least about 12, 20, 25, 40,
50 or more consecutive
nucleotides.
As used herein, the term "hybridizes under stringent conditions" is intended
to describe
conditions for hybridization and washing under which nucleotide sequences
encoding a peptide
at least 50-55% homologous to each other typically remain hybridized to each
other. The
conditions can be such that sequences at least about 65%, at least about 70%,
or at least about
75% or more homologous to each other typically remain hybridized to each
other. Such
stringent conditions are known to those skilled in the art and can be found in
Current Protocols
i~ Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. One example
of stringent
hybridization conditions are hybridization in 6X sodium chloride/sodium
citrate (SSC) at about
45C, followed by one or more washes in 0.2 X SSC, 0.1% SDS at 50-65C.
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Nucleic Acid Molecule Uses
The nucleic acid molecules of the present invention are useful for probes,
primers,
chemical intermediates, and in biological assays. The probe can correspond to
any sequence
along the entire length of the nucleic acid molecules provided in Figure l,
including one or more
of the sequence polymorphisms provided in Figure 2. Accordingly, it could be
derived from 5'
noncoding regions, the coding region, and 3' noncoding regions. However, as
discussed,
fragments are not to be construed as encompassing fragments disclosed prior to
the present
invention.
The nucleic acid molecules are also useful as primers for PCR to amplify any
given
region of a nucleic acid molecule and are useful to synthesize antisense
molecules of desired
length and sequence.
The nucleic acid molecules are also useful for constructing recombinant
vectors. Such
vectors include expression vectors that express a portion of, or all of, the
peptide sequences.
Vectors also include insertion vectors, used to integrate into another nucleic
acid molecule
sequence, such as into the cellular genome, to alter in situ expression of a
gene and/or gene
product. For example, an endogenous coding sequence can be replaced via
homologous
recombination with all or part of the coding region containing one or more
specifically
introduced mutations.
The nucleic acid molecules are also useful for expressing antigenic portions
of the
proteins.
The nucleic acid molecules are also useful for designing ribozymes
corresponding to all,
or a part, of the mRNA produced from the nucleic acid molecules described
herein.
The nucleic acid molecules are also useful for constructing host cells
expressing a part,
or all, of the nucleic acid molecules and peptides.
The nucleic acid molecules are also useful for constructing transgenic animals
expressing all, or a part, of the nucleic acid molecules and peptides.
The nucleic acid molecules are also useful for making vectors that express
part, or all, of
the peptides.
The nucleic acid molecules are also useful as hybridization probes for
determining the
presence, level, form and distribution of nucleic acid expression.
Accordingly, the probes can be
used to detect the presence of, or to determine levels of, a specific nucleic
acid molecule in cells,
tissues, and in organisms. The nucleic acid whose level is determined can be
DNA or RNA.
Accordingly, probes corresponding to the peptides described herein can be used
to assess
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expression and/or, gene copy number in a given cell, tissue, or organism.
These uses are relevant
for diagnosis of disorders involving an increase or decrease in estrogen
receptor protein
expression relative to normal results.
1h vitro techniques for detection of mRNA include Northern hybridizations and
iu situ
hybridizations. In vitro techniques for detecting DNA include Southern
hybridizations and in
situ hybridization.
Probes can be used as a part of a diagnostic test kit for identifying cells or
tissues that
express a estrogen receptor proteins of the present invention, such as by
measuring a level of a
receptor-encoding nucleic acid in a sample of cells from a subject e.g., mRNA
or genomic
DNA, or determining if a receptor gene has been mutated.
Nucleic acid expression assays are useful for drug screening to identify
compounds that
modulate estrogen receptor nucleic acid expression.
The invention thus provides a method for identifying a compound that can be
used to
treat a disorder associated with nucleic acid expression of the estrogen
receptor gene. The
method typically includes assaying the ability of the compound to modulate the
expression of
the estrogen receptor nucleic acid and thus identifying a compound that can be
used to treat a
disorder characterized by undesired estrogen receptor nucleic acid expression.
The assays can
be performed in cell-based and cell-free systems. Cell-based assays include
cells naturally
expressing the estrogen receptor nucleic acid or recombinant cells genetically
engineered to
express specific nucleic acid sequences.
The assay for estrogen receptor nucleic acid expression can involve direct
assay of
nucleic acid levels, such as mRNA levels, or on collateral compounds involved
in the signal
pathway. Further, the expression of genes that are up- or down-regulated in
response to the
estrogen receptor protein signal pathway can also be assayed. In this
embodiment the regulatory
regions of these genes can be operably linked to a reporter gene such as
luciferase.
Thus, modulators of estrogen receptor gene expression can be identified in a
method
wherein a cell is contacted with a candidate compound and the expression of
mRNA
determined. The level of expression of estrogen receptor mRNA in the presence
of the
candidate compound is compared to the level of expression of estrogen receptor
mRNA in the
3 0 absence of the candidate compound. The candidate compound can then be
identified as a
modulator of nucleic acid expression based on this comparison and be used, for
example to treat
a disorder characterized by aberrant nucleic acid expression. When expression
of mRNA is
statistically significantly greater in the presence of the candidate compound
than in its absence,
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the candidate compound is identified as a stimulator of nucleic acid
expression. When nucleic
acid expression is statistically significantly less in the presence of the
candidate compound than
in its absence, the candidate compound is identified as an inhibitor of
nucleic acid expression.
The invention fw-ther provides methods of treatment, with the nucleic acid as
a target,
using a compound identified through drug screening as a gene modulator to
modulate estrogen
receptor nucleic acid expression. Modulation includes both up-regulation (i.e.
activation or
agonization) or down-regulation (suppression or antagonization) or nucleic
acid expression.
Alternatively, a modulator for estrogen receptor nucleic acid expression can
be a small
molecule or drug identified using the screening assays described herein as
long as the drug or
small molecule inhibits the estrogen receptor nucleic acid expression.
The nucleic acid molecules are also useful for monitoring the effectiveness of
modulating compounds on the expression or activity of the estrogen receptor
gene in clinical
trials or in a treatment regimen. Thus, the gene expression pattern can serve
as a barometer for
the continuing effectiveness of treatment with the compound, particularly with
compounds to
which a patient can develop resistance. The gene expression pattern can also
serve as a marker
indicative of a physiological response of the affected cells to the compound.
Accordingly, such
monitoring would allow either increased administration of the compound or the
administration
of alternative compounds to which the patient has not become resistant.
Similarly, if the level of
nucleic acid expression falls below a desirable level, administration of the
compound could be
commensurately decreased.
The nucleic acid molecules are also useful in diagnostic assays for
qualitative changes in
estrogen receptor nucleic acid, and particularly in qualitative changes that
lead to pathology.
The nucleic acid molecules can be used to detect mutations in estrogen
receptor genes and gene
expression products such as mRNA. The nucleic acid molecules can be used as
hybridization
probes to detect naturally-occurring genetic mutations in the estrogen
receptor gene and thereby
to determine whether a subject with the mutation is at risk for a disorder
caused by the mutation.
Mutations include deletion, addition, or substitution of one or more
nucleotides in the gene,
chromosomal rearrangement, such as inversion or transposition, modification of
genomic DNA,
such as aberrant methylation patterns or changes in gene copy number, such as
amplification.
3 0 Detection of a mutated form of the estrogen receptor gene associated with
a dysfunction
provides a diagnostic tool for an active disease or susceptibility to disease
when the disease
results from overexpression, underexpression, or altered expression of a
estrogen receptor
protein.
CA 02426405 2003-04-17
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Individuals carrying mutations in the estrogen receptor gene can be detected
at the
nucleic acid level by a variety of techniques. Genomic DNA can be analyzed
directly or can be
amplified by using PCR prior to analysis. RNA or cDNA can be used in the same
way. In some
uses, detection of the mutation involves the use of a probe/primer in a
polymerase chain reaction
(PCR) (see, e.g. U.S. Patent Nos. 4,683,195 and 4,683,202), such as anchor PCR
or RACE PCR,
or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et
al., Science
241:1077-1080 (1988); and Nakazawa et al., PNAS 91:360-364 (1994)), the latter
of which can
be particularly useful for detecting point mutations in the gene (see Abravaya
et al., Nucleic
Acids Res. 23:675-682 (1995)). This method can include the steps of collecting
a sample of cells
from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the
cells of the
sample, contacting the nucleic acid sample with one or more primers which
specifically
hybridize to a gene under conditions such that hybridization and amplification
of the gene (if
present) occurs, and detecting the presence or absence of an amplification
product, or detecting
the size of the amplification product and comparing the length to a control
sample. Deletions
and insertions can be detected by a change in size of the amplified product
compared to the
normal genotype. Point mutations can be identified by hybridizing amplified
DNA to normal
RNA or antisense DNA sequences.
Alternatively, mutations in a estrogen receptor gene can be directly
identified, for
example, by alterations in restriction enzyme digestion patterns determined by
gel
electrophoresis.
Further, sequence-specific ribozymes (U.S.Patent No. 5,498,531) can be used to
score
for the presence of specific mutations by development or loss of a ribozyme
cleavage site.
Perfectly matched sequences can be distinguished from mismatched sequences by
nuclease
cleavage digestion assays or by differences in melting temperature.
Sequence changes at specific locations can also be assessed by nuclease
protection
assays such as RNase and S 1 protection or the chemical cleavage method.
Furthermore,
sequence differences between a mutant estrogen receptor gene and a wild-type
gene can be
determined by direct DNA sequencing. A variety of automated sequencing
procedures can be
utilized when performing the diagnostic assays ((1995) Biotechniques 19:448),
including
sequencing by mass spectrometry (see, e.g., PGT International Publication No.
WO 94/16101;
Cohen et al., Adv. Chy~onaatogy~. 36:127-162 (1996); and Griffin et al., Appl.
Biochem.
Biotechhol. 38:147-159 (1993)).
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WO 02/34945 PCT/USO1/25990
Other methods for detecting mutations in the gene include methods in which
protection
from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA
duplexes
(Myers et al., Science 230:1242 (1985)); Cotton et al., PNAS 85:4397 (1988);
Saleeba et al.,
Meth. Evczymol. 217:286-295 (1992)), electrophoretic mobility of mutant and
wild type nucleic
acid is compared (Orita et al., PNAS 86:2766 (1989); Cotton et al., Mutat.
Res. 285:125-144
(1993); and Hayashi et al., Genet. Anal. Tech. Appl. 9:73-79 (1992)), and
movement of mutant
or wild-type fragments in polyacrylamide gels containing a gradient of
denaturant is assayed
using denaturing gradient gel electrophoresis (Myers et al., Nature 313:495
(1985)). Examples
of other techniques for detecting point mutations include, selective
oligonucleotide
hybridization, selective amplification, and selective primer extension.
The nucleic acid molecules are also useful for testing an individual for a
genotype that
while not necessarily causing diseases; nevertheless affects the treatment
modality. Thus, the
nucleic acid molecules can be used to study the relationship between an
individual's genotype
and the individual's response to a compound used for treatment
(pharmacogenomic relationship).
Accordingly, the nucleic acid molecules described herein can be used to assess
the mutation
content of the estrogen receptor gene in an individual in order to select an
appropriate compound
or dosage regimen for treatment.
Thus nucleic acid molecules displaying genetic variations that affect
treatment provide a
diagnostic target that can be used to tailor treatment in an individual.
Accordingly, the
production of recombinant cells and animals containing these
polymorphism/haplotypes allow
effective clinical design of treatment compounds and dosage regimens.
The nucleic acid molecules are thus useful as antisense constructs to control
estrogen
receptor gene expression in cells, tissues, and organisms. A DNA antisense
nucleic acid
molecule is designed to be complementary to a region of the gene involved in
transcription,
preventing transcription and hence production of estrogen receptor protein. An
antisense RNA
or DNA nucleic acid molecule would hybridize to the mRNA and thus block
translation of
mRNA into estrogen receptor protein.
Alternatively, a class of antisense molecules can be used to inactivate mRNA
in order to
decrease expression of estrogen receptor nucleic acid. Accordingly, these
molecules can treat a
disorder characterized by abnormal or undesired estrogen receptor nucleic acid
expression. This
technique involves cleavage by means of ribozymes containing nucleotide
sequences
complementary to one or more regions in the mRNA that attenuate the ability of
the mRNA to
be translated. Possible regions include coding regions and particularly coding
regions
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WO 02/34945 PCT/USO1/25990
corresponding to the catalytic and other functional activities of the estrogen
receptor proteins of
the present invention, such as ligand binding.
The nucleic acid molecules also provide vectors for gene therapy in patients
containing
cells that are aberrant in estrogen receptor gene expression. Thus,
recombinant cells, which
include the patient's cells that have been engineered ex vivo and returned to
the patient, are
introduced into an individual where the cells produce the desired estrogen
receptor protein to
treat the individual.
The invention also encompasses kits for~detecting the presence of a estrogen
receptor
nucleic acid in a biological sample. For example, the kit can comprise
reagents such as a labeled
or labelable nucleic acid or agent capable of detecting estrogen receptor
nucleic acid in a
biological sample; means for determining the amount of estrogen receptor
nucleic acid in the
sample; and means for comparing the amount of estrogen receptor nucleic acid
in the sample
with a standard. The compound or agent can be packaged in a suitable
container. The kit can
fzxrther comprise instructions for using the kit to detect estrogen receptor
protein mRNA or
I S DNA.
Design of SNP-Containing Nucleic Acids Detection Methods
The SNP-containing nucleic acid molecules of the present invention are useful
as probes,
primers, chemical intermediates, and in biological assays for SNPs of the
present invention. The
probes/primers can correspond to one or more of the SNPs provided in Figure 2
or can
correspond to a specific region 5' and/or 3' to a SNP position. However, as
discussed above,
fragments are not to be construed as encompassing fragments that are not
associated with SNPs
of the present invention or those known in the art for SNP detection. The SNP-
containing
nucleic acid molecules and information provided herein are also useful for
designing primers for
PCR to amplify any given SNP of the present invention and to design any
formatted SNP
detection reagent/kits.
A probe/primer typically comprises substantially a purified oligonucleotide or
oligonucleotide pair. The oligonucleotide typically comprises a region of
nucleotide sequence
that hybridizes under stringent conditions to at least about 12, 20, 25, 40,
50 or more consecutive
nucleotides. Depending on the particular application, the consecutive
nucleotides can either
include the target SNP position, or be a specific region in close enough
proximity 5' and/or 3' to
the SNP position to carry out the desired assay.
Preferred primer and probe sequences can readily be determined using the
sequences
provided in Figures l, 2, and 9. It will be apparent to one of skill in the
art that such primers
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WO 02/34945 PCT/USO1/25990
and probes are useful as diagnostic probes or amplification primers for
genotyping SNPs of
the present invention, and can be incorporated into a kit format.
For analyzing SNPs, it may be appropriate to use oligonucleotides specific to
alternative
SNP alleles (referred to as "allele-specific oligonucleotides", "allele-
specific probes", or "allele-
s specific primers"). The design and use of allele-specific probes for
analyzing polymorphisms
is described by e.g., Saiki et al., Nature 324, 163-166 (1986); Dattagupta, EP
235,726, Saiki,
WO 89/11548.
In a hybridization-based assay, allele-specific probes can be designed that
hybridize to
a segment of target DNA from one individual but do not hybridize to the
corresponding
segment from another individual due to the presence of different polymorphic
forms in the
respective segments from the two individuals. Hybridization conditions should
be sufficiently
stringent that there is a significant difference in hybridization intensity
between alleles, and
preferably an essentially binary response, whereby a probe hybridizes to only
one of the
alleles. Some probes are designed to hybridize to a segment of target DNA such
that the
polymorphic site aligns with a central position (e.g., in a 15-mer at the 7
position; in a 16-
mer, at either the 8 or 9 position) of the probe. This design of probe
achieves good
discrimination in hybridization between different allelic forms.
Allele-specific probes are often used in pairs, the "pairs" may be identical
except for a
one nucleotide mismatch that represents the allelic variants at the SNP
position. One member
of a pair perfectly matches a reference form of a target sequence and the
other member
perfectly matches a variant form. In the case of an array, several pairs of
probes can then be
immobilized on the same support for simultaneous analysis of multiple
polymorphisms
within the same target sequence.
In one type of PCR-based assay, an allele-specific primer hybridizes to a site
on target
DNA overlapping the SNP position and only primes amplification of an allelic
form to which
the primer exhibits perfect complementarity. See Gibbs, Nucleic Acid Res. 17
2427-2448
(1989). This primer is used in conjunction with a second primer that
hybridizes at a distal
site. Amplification proceeds from the two-primers, resulting in a detectable
product that
indicates the particular allelic form is present. A control is usually
performed with a second
pair of primers, one of which shows a single base mismatch at the polymorphic
site and the
other of which exhibits perfect complementarity to a distal site. The single-
base mismatch
prevents amplification and no detectable product is formed. The method works
best when the
mismatch is included in the 3'-most position of the oligonucleotide aligned
with the
39
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
polymorphism because this position is most destabilizing to elongation from
the primer (see,
e.g., WO 93/22456). This PCR-based assay can be utilized as part of the TaqMan
assay,
described below.
SNP Detection Kits, Nucleic Acid Arrays, and Integrated Systems
The present invention further provides SNP detection kits, such as arrays or
microarrays of nucleic acid molecules, or probe/primer sets, that are based on
the SNPs
provided in Figures l, 2, 4, 8, 9
In one embodiment of the present invention, kits are provided which contain
the
necessary reagents to carry out one or more assays that detect one or more
SNPs disclosed
herein. The present invention also provides multicomponent integrated systems
for analyzing
the SNPs provided by the present invention.
SNP detection kits may contain one or more oligonucleotide probes, or pairs of
probes, that hybridize at or near each SNP position. Multiple pairs of allele-
specific
oligonucleotides may be included in the kit to simultaneously assay large
numbers of SNPs,
at least one of which is one of the SNPs of the present invention. In some
kits, such as
arrays, the allele-specific oligonucleotides are provided immobilized to a
substrate. For
example, the same substrate can comprise allele-specific oligonucleotide
probes for detecting
at least l; 10; 100; 1000; 10,000; 100,000; 300,000 or substantially all of
the polymorphisms
shown in Figures l, 2, 4, 8 and 9.
Specifically, the invention provides a compartmentalized kit to receive, in
close
confinement, one or more containers which comprises: (a) a first container
comprising one of
the nucleic acid probes, for example an allele-specific oligonucleotide, that
can bind to a
fragment of the human genome containing a SNP disclosed herein; and (b) one or
more other
containers comprising one or more of the following: wash reagents or reagents
capable of
detecting the presence of a bound probe.
Tn detail, a compartmentalized kit includes any kit in which reagents are
contained in
separate containers. Such containers include small glass containers, plastic
containers, strips
of plastic, glass or paper, or arraying material such as silica. Such
containers allow one to
3 0 efficiently transfer reagents from one compartment to another compartment
such that the
samples and reagents are not cross-contaminated, and the agents or solutions
of each
container can be added in a quantitative fashion from one compartment to
another. Such
containers may include a container which will accept the test sample, a
container which
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
contains the SNP probe, containers which contain wash reagents (such as
phosphate buffered
saline, Tris-buffers, etc.), and containers which contain the reagents used to
detect the bound
probe. The kit can further comprise reagents for PCR or other enzymatic
reactions, and
instructions for using the kit. One skilled in the art will readily recognize
that the previously
unidentified SNPs of the present invention can be routinely identified using
the sequence
information disclosed herein and can be readily incorporated into one of the
established kit
formats which are well known in the art.
The present invention further provides arrays or microarrays of nucleic acid
molecules that are based on the sequence information provided in Figures l,
including one or
more of the variations provided in Figure 2.
As used herein "Arrays" or "Microarrays" refers to an array of distinct
polynucleotides or oligonucleotides synthesized on a substrate, such as paper,
nylon or other
type of membrane, filter, chip, glass slide, or any other suitable solid
support. In one
embodiment, the microarray is prepared and used according to the methods
described in US
Patent 5,837,832, Chee et al., PCT application W095/11995 (Chee et al.),
Lockhart, D. J. et
al. (1996; Nat. Biotech. 14: 1675-1680) and Schena, M. et al. (1996; Proc.
Natl. Acad. Sci.
93: 10614-10619), all of which are incorporated herein in their entirety by
reference. In other
embodiments, such arrays axe produced by the methods described by Brown et
al., US Patent
No. 5,807,522. Arrays or microarrays are commonly referred to as "DNA chips".
Any number of oligonucleotide probes, such as allele-specific
oligonucleotides, may be
implemented in an array, wherein each probe or pair of probes corresponds to a
different SNP
position. The oligonucleotides are synthesized at designated areas on a
substrate using a light-
directed chemical process. The substrate may be paper, nylon or other type of
membrane, filter,
chip, glass slide or any other suitable solid support.
Hybridization assays based on oligonucleotide arrays rely on the differences
in
hybridization stability of short oligonucleotides probes to perfectly matched
and mismatched
target sequence variants. Efficient access to polymorphism information is
obtained through a
basic structure comprising high-density arrays of oligonucleotide probes
attached to a solid
support (e.g., a chip) at selected positions. Each DNA chip can contain
thousands to millions
3 0 of individual synthetic DNA probes arranged in a grid-like pattern and
miniaturized to the
size of a dime, each corresponding to a particular SNP position or allelic
variant. Preferably,
probes are attached to a solid support in an ordered, addressable array.
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WO 02/34945 PCT/USO1/25990
The array/chip technology has already been applied with success in numerous
cases.
For example, the screening of mutations has been undertaken in the BRCA1 gene,
in S.
cerevisiae mutant strains, and in the protease gene of HIV- I virus (Hacia et
al., 1996;
Shoemaker et al., 1996 ; I~ozal et al., 1996). Chips of various formats for
use in detecting
SNPs can be produced on a customized basis.
An array-based tiling strategy useful for detecting SNPs is described in EP
785280.
Briefly, arrays may generally be "tiled" for a large number of specific
polymorphisms.
"Tiling" refers to the synthesis of a defined set of oligonucleotide probes
that are made up of
a sequence complementary to the target sequence of interest, as well as
preselected variations
of that sequence, e.g., substitution of one or more given positions with one
or more members
of the basis set of monomers, i.e. nucleotides. Tiling strategies are further
described in PCT
application No. WO 95/11995. In a particular aspect, arrays are tiled for a
number of specific
SNPs. In particular, the array is tiled to include a number of detection
blocks, each detection
block being specific for a specific SNP or a set of SNPs. For example, a
detection block may
be tiled to include a number of probes that span the sequence segment that
includes a specific
SNP. To ensure probes that are complementary to each allele, the probes are
synthesized in
pairs differing at the SNP position. In addition to the probes differing at
the SNP position,
monosubstituted probes are also generally tiled within the detection block.
Such methods can
readily be applied to the SNP information disclosed herein.
These monosubstituted probes have bases at and up to a certain number of bases
in
either direction from the polymorphism, substituted with the remaining
nucleotides (selected
from A, T, G, C and U). Typically the probes in a tiled detection block will
include
substitutions of the sequence positions up to and including those that are 5
bases away from
the SNP. The monosubstituted probes provide internal controls for the tiled
array, to
distinguish actual hybridization from artefactual cross-hybridization. Upon
completion of
hybridization with the target sequence and washing of the array, the array is
scanned to
determine the position on the array to which the target sequence hybridizes.
The
hybridization data from the scanned array is then analyzed to identify which
allele or alleles
of the SNP are present in the sample. Hybridization and scanning may be
carried out as
described in PCT application No. WO 92/10092 and WO 95/11995 and US patent No.
5,424,186.
Thus, in some embodiments, the chips may comprise an array of nucleic acid
sequences of fragments of about 15 nucleotides in length. In further
embodiments, the chip
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CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
may comprise an array including at least one of the sequences selected from
the group
consisting of those disclosed in the Figuresl, 2, 8, 9, and the sequences
complementary
thereto, or a fragment thereof, said fragment comprising at least about 8
consecutive
nucleotides, preferably 10, 15, 20, more preferably 25, 30, 40, 47, or 50
consecutive
nucleotides and containing a polymorphic base. In some embodiments the
polymorphic base
is within 5, 4, 3, 2, or 1 nucleotides from the center of the polynucleotide,
more preferably at
the center of said polynucleotide. In other embodiments, the chip may comprise
an array
containing any number of polynucleotides of the present invention.
An oligonucleotide may be synthesized on the surface of the substrate by using
a
chemical coupling procedure and an ink jet application apparatus, as described
in PCT
application W095/251116 (Baldeschweiler et al.) which is incorporated herein
in its entirety by
reference. In another aspect, a "gridded" array analogous to a dot (or slot)
blot may be used to
arrange and link cDNA fragments or oligonucleotides to the surface of a
substrate using a
vacuum system, thermal, UV, mechanical or chemical bonding procedures. An
array, such as
those described above, may be produced by hand or by using available devices
(slot blot or dot
blot apparatus), materials (any suitable solid support), and machines
(including robotic
instruments), and may contain 8, 24, 96, 384, 1536, 6144 or more
oligonucleotides, or any other
number which lends itself to the efficient use of commercially available
instrumentation.
Using such arrays, the present invention provides methods of identifying the
SNPs of the
present invention in a sample. Such methods comprise incubating a test sample
with an array
comprising one or more oligonucleotide probes corresponding to at least one
SNP position of
the present invention, and assaying for binding of a nucleic acid from the
test sample with one or
more of the oligonucleotide probes. Such assays will typically involve arrays
comprising
oligonucleotides probes corresponding to many SNP positions and/or allelic
variants of those
SNP positions, at least one of which is a SNP of the present invention.
Conditions for incubating a nucleic acid molecule with a test sample vary.
Incubation
conditions depend on the format employed in the assay, the detection methods
employed, and
the type and nature of the nucleic acid molecule used in the assay. One
skilled in the art will
recognize that any one of the commonly available hybridization, amplification
or array assay
3 0 formats can readily be adapted to employ the novel SNPs disclosed herein.
Examples of such
assays can be found in Chard, T, An Introduction to Radioimmunoassay and
Related
Techniques, Elsevier Science Publishers, Amsterdam, The Netherlands (1986);
Bullock, G. R.
et al., Techniques in hnmunocytochemistry, Academic Press, Orlando, FL Vol. 1
(1 982), Vol. 2
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WO 02/34945 PCT/USO1/25990
(1983), Vol. 3 (1985); Tijssen, P., Practice and Theory of Enzyme
Immunoassays: Laboratory
Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers,
Amsterdam,
The Netherlands (1985).
The test samples of the present invention include, but are not limited to,
nucleic acid
extracts, cells, and protein or membrane extracts from cells, which may be
obtained from any
bodily fluids (such as blood, urine, saliva, phlegm, gastric juices, etc.),
cultured cells,
biopsies, or other tissue preparations. The test sample used in the above-
described methods
will vary based on the assay format, nature of the detection method and the
tissues, cells or
extracts used as the sample to be assayed. Methods of preparing nucleic acid,
protein, or cell
extracts are well known in the art and can be readily be adapted in order to
obtain a sample
that is compatible with the system utilized.
Multicomponent integrated systems may also be used to analyze SNPs. Such
systems
miniaturize and compartmentalize processes such as PCR and capillary
electrophoresis
reactions in a single functional device. An example of such technique is
disclosed in US
. patent 5,589,136, which describes the integration of PCR amplification and
capillary
electrophoresis in chips.
Integrated systems can be envisaged mainly when microfluidic systems are used
These systems comprise a pattern of microchannels designed onto a glass,
silicon, quartz, or
plastic wafer included on a microchip. The movements of the samples are
controlled by
electric, electroosmotic or hydrostatic forces applied across different areas
of the microchip
to create functional microscopic valves and pumps with no moving parts.
Varying the voltage
controls the liquid flow at intersections between the micro-machined channels
and changes
the liquid flow rate for pumping across different sections of the microchip.
For genotyping SNPs, the microfluidic system may integrate, for example,
nucleic
acid amplification, minisequencing primer extension, capillary
electrophoresis, and a
detection method such as laser induced fluorescence detection.
In a first step, the DNA samples are amplified, preferably by PCR. Then, the
amplification products are subjected to automated minisequencing reactions
using ddNTPs
(specific fluorescence for each ddNTP) and the appropriate oligonucleotide
minisequencing
primers which hybridize just upstream of the targeted polymorphic base. Once
the extension
at the 3' end is completed, the primers are separated from the unincorporated
fluorescent
ddNTPs by capillary electrophoresis. The separation medium used in capillary
electrophoresis can be, for example, polyacrylamide, polyethyleneglycol or
dextran. The
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CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
incorporated ddNTPs in the single nucleotide primer extension products are
identified by
laser-induced fluorescence detection. This microchip can be used to process at
least 96 to 3~4
samples, or more, in parallel.
Vectors/host cells
The invention also provides vectors containing the nucleic acid molecules
described
herein. The term "vector" refers to a vehicle, preferably a nucleic acid
molecule, that can
transport the nucleic acid molecules. When the vector is a nucleic acid
molecule, the nucleic
acid molecules are covalently linked to the vector nucleic acid. With this
aspect of the
invention, the vector includes a plasmid, single or double stranded phage, a
single or double
stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC,
PAC, YAC, OR
MAC.
A vector can be maintained in the host cell as an extrachromosomal element
where it
replicates and produces additional copies of the nucleic acid molecules.
Alternatively, the vector
may integrate into the host cell genome and produce additional copies of the
nucleic acid
molecules when the host cell replicates.
The invention provides vectors for the maintenance (cloning vectors) or
vectors for
expression (expression vectors) of the nucleic acid molecules. The vectors can
function in
procaryotic or eukaryotic cells or in both (shuttle vectors).
Expression vectors contain cis-acting regulatory regions that are operably
linked in the
vector to the nucleic acid molecules such that transcription of the nucleic
acid molecules is
allowed in a host cell. The nucleic acid molecules can be introduced into the
host cell with a
separate nucleic acid molecule capable of affecting transcription. Thus, the
second nucleic acid
molecule may provide a trans-acting factor interacting with the cis-regulatory
control region to
allow transcription of the nucleic acid molecules from the vector.
Alternatively, a traps-acting
factor may be supplied by the host cell. Finally, a traps-acting factor can be
produced from the
vector itself. It is understood, however, that in some embodiments,
transcription and/or
translation of the nucleic acid molecules can occur in a cell-free system.
The regulatory sequence to which the nucleic acid molecules described herein
can be
3 0 operably linked include promoters for directing mRNA transcription. These
include, but are not
limited to, the left promoter from bacteriophage 7~, the lac, TRP, and TAC
promoters from E.
coli, the early and late promoters from SV40, the CMV immediate early
promoter, the
adenovirus early and late promoters, and retrovirus long-terminal repeats.
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
In addition to control regions that promote transcription, expression vectors
may also
include regions that modulate transcription, such as repressor binding sites
and enhancers.
Examples include the SV40 enhancer, the cytomegalovirus immediate early
enhancer, polyoma
enhancer, adenovirus enhancers, and retrovirus LTR enhancers.
In addition to containing sites for transcription initiation and control,
expression vectors
can also contain sequences necessary for transcription termination and, in the
transcribed region
a ribosome binding site for translation. Other regulatory control elements for
expression include
initiation and termination codons as well as polyadenylation signals. The
person of ordinary
skill in the art would be aware of the numerous regulatory sequences that are
useful in
expression vectors. Such regulatory sequences are described, for example, in
Sambrook et al.,
Molecular Cloning: A Labo~ato~y Manual. 2nd. ed., Cold Spring Harbor
Laboratory Press, Cold
Spring Harbor, NY, (1989).
A variety of expression vectors can be used to express a nucleic acid
molecule. Such
vectors include chromosomal, episomal, and virus-derived vectors, for example
vectors derived
from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast
chromosomal
elements, including yeast artificial chromosomes, from viruses such as
baculoviruses,
papovaviruses such as SV40, Vaccinia viruses, adenoviruses, poxviruses,
pseudorabies viruses,
and retroviruses. Vectors may also be derived from combinations of these
sources such as those
derived from plasmid and bacteriophage genetic elements, eg. cosmids and
phagemids.
Appropriate cloning and expression vectors for prokaryotic and eukaryotic
hosts are described in
Sambrook et al., Moleculaf° Cloning: A Labo~ato~y Manual. 2nd. ed.,
Cold Spring Harbor
Laboratory Press, Cold Spring Harbor, NY, (1989).
The regulatory sequence may provide constitutive expression in one or more
host cells
(i.e. tissue specific) or may provide for inducible expression in one or more
cell types such as by
temperature, nutrient additive, or exogenous factor such as a hormone or other
ligand. A variety
of vectors providing for constitutive and inducible expression in prokaryotic
and eulcaryotic
hosts are well known to those of ordinary skill in the art.
The nucleic acid molecules can be inserted into the vector nucleic acid by
well-known
methodology. Generally, the DNA sequence that will ultimately be expressed is
joined to an
3 0 expression vector by cleaving the DNA sequence and the expression vector
with one or more
restriction enzymes and then ligating the fragments together. Procedures for
restriction enzyme
digestion and ligation are well known to those of ordinary skill in the art.
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WO 02/34945 PCT/USO1/25990
The vector containing the appropriate nucleic acid molecule can be introduced
into an
appropriate host cell for propagation or expression using well-known
techniques. Bacterial cells
include, but are not limited to, E. colt, Streptomyces, and Salmorzella
typhimur ium. Eukaryotic
cells include, but are not limited to, yeast, insect cells such as Drosophila,
animal cells such as
COS and CHO cells, and plant cells.
As described herein, it may be desirable to express the peptide as a fusion
protein.
Accordingly, the invention provides fusion vectors that allow for the
production of the peptides.
Fusion vectors can increase the expression of a recombinant protein, increase
the solubility of
the recombinant protein, and aid in the purification of the protein by acting
for example as a
ligand for affinity purification. A proteolytic cleavage site may be
introduced at the junction of
the fusion moiety so that the desired peptide can ultimately be separated from
the fusion moiety.
Proteolytic enzymes include, but are not limited to, factor Xa, thrombin, and
enterokinase.
Typical fusion expression vectors include pGEX (Smith et al., Gehe 67:31-40
(1988)), pMAL
(New England Biolabs, Beverly, MA) and pRITS (Pharmacia, Piscataway, NJ) which
fuse
glutathione S-transferase (GST), maltose E binding protein, or protein A,
respectively, to the
target recombinant protein. Examples of suitable inducible non-fusion E. colt
expression vectors
include pTrc (Amann et al., Gene 69:301-315 (1988)) and pET 1 1d (Studier et
al., Gene
Expression Technology: Methods iu E~zzymology 185:60-89 (1990)).
Recombinant protein expression can be maximized in a host bacteria by
providing a
genetic background wherein the host cell has an impaired capacity to
proteolytically cleave the
recombinant protein. (Gottesman, S.; Gene Expz°essio>z Techv~ology:
Methods in Enzymology
185, Academic Press, San Diego, California (1990) 119-128). Alternatively, the
sequence of
the nucleic acid molecule of interest can be altered to provide preferential
codon usage for a
specific host cell, for example E. colt. (Wada et al., Nucleic Acids Res.
20:2111-2118 (1992)).
The nucleic acid molecules can also be expressed by expression vectors that
are
operative in yeast. Examples of vectors for expression in yeast e.g., S.
cerevisiae include
pYepSecl (Baldari, et al., EMBO J. 6:229-234 (1987)), pMFa (T~urjan et al.,
Cell 30:933-
943(1982)), pJRY88 (Schultz et al., Gevze 54:113-123 (1987)), and pYES2
(Invitrogen
Corporation, San Diego, CA).
The nucleic acid molecules can also be expressed in insect cells using, for
example,
baculovirus expression vectors. Baculovirus vectors available for expression
of proteins in
cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al.,
Mol. Cell Biol. 3:2156-
2165 (1983)) and the pVL series (Lucklow et al., Virology 170:31-39 (1989)).
47
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In certain embodiments of the invention, the nucleic acid molecules described
herein are
expressed in mammalian cells using mammalian expression vectors. Examples of
mammalian
expression vectors include pCDM8 (Seed, B. Nature 329:840(1987)) and pMT2PC
(Kaufman et
al., EMBO J. 6:187-195 (1987)).
The expression vectors listed herein are provided by way of example only of
the well-
known vectors available to those of ordinary skill in the art that would be
useful to express the
nucleic acid molecules. The person of ordinary skill in the art would be aware
of other vectors
suitable for maintenance propagation or expression of the nucleic acid
molecules described
herein. These are found for example in Sambrook, J., Fritsh, E. F., and
Maniatis, T. Molecular
Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold
Spring Harbor
Laboratory Press, Cold Spring Harbor, NY, 1989.
The invention also encompasses vectors in which the nucleic acid sequences
described
herein are cloned into the vector in reverse orientation, but operably linked
to a regulatory
sequence that permits transcription of antisense RNA. Thus, an antisense
transcript can be
produced to all, or to a portion, of the nucleic acid molecule sequences
described herein,
including both coding and non-coding regions. Expression of this antisense RNA
is subject to
each of the parameters described above in relation to expression of the sense
RNA (regulatory
sequences, constitutive or inducible expression, tissue-specific expression).
The invention also relates to recombinant host cells containing the vectors
described
herein. Host cells therefore include prokaryotic cells, lower eukaryotic cells
such as yeast, other
eukaryotic cells such as insect cells, and higher eukaryotic cells such as
mammalian cells.
The recombinant host cells are prepared by introducing the vector constructs
described
herein into the cells by techniques readily available to the person of
ordinary skill in the art.
These include, but are not limited to, calcium phosphate transfection, DEAF-
dextran-mediated
transfection, cationic lipid-mediated transfection, electroporation,
transduction, infection,
lipofection, and other techniques such as those found in Sambrook, et al.
(Molecular Cloning: A
Laboratory Manual. 2nd, ed.,' Cold Spring Harbor Labof°ato~y, Cold
Spring Harbor Laboratory
Press, Cold Spring Harbor, NY, 1989).
Host cells can contain more than one vector. Thus, different nucleotide
sequences can
be introduced on different vectors of the same cell. Similarly, the nucleic
acid molecules can be
introduced either alone or with other nucleic acid molecules that are not
related to the nucleic
acid molecules such as those providing traps-acting factors for expression
vectors. When more
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than one vector is introduced into a cell, the vectors can be introduced
independently, co-
introduced or joined to the nucleic acid molecule vector.
In the case of bacteriophage and viral vectors, these can be introduced into
cells as
packaged or encapsulated virus by standard procedures for infection and
transduction. Viral
vectors can be replication-competent or replication-defective. In the case in
which viral
replication is defective, replication will occur in host cells providing
functions that complement
the defects.
Vectors generally include selectable markers that enable the selection of the
subpopulation of cells that contain the recombinant vector constructs. The
marker can be
contained in the same vector that contains the nucleic acid molecules
described herein or may be
on a separate vector. Markers include tetracycline or ampicillin-resistance
genes for prokaryotic
host cells and dihydrofolate reductase or neomycin resistance for eukaryotic
host cells.
However, any maxker that provides selection for a phenotypic trait will be
effective.
While the mature proteins can be produced in bacteria, yeast, mammalian cells,
and
other cells under the control of the appropriate regulatory sequences, cell-
free transcription and
translation systems can also be used to produce these proteins using RNA
derived from the
DNA constructs described herein.
Where secretion of the peptide is desired, which is difficult to achieve with
multi-
transmembrane domain containing proteins such as estrogen receptors,
appropriate secretion
signals are incorporated into the vector. The signal sequence can be
endogenous to the peptides
or heterologous to these peptides.
Where the peptide is not secreted into the medium, which is typically the case
with
estrogen receptors, the protein can be isolated from the host cell by standard
disruption
procedures, including freeze thaw, sonication, mechanical disruption, use of
lysing agents and
the like. The peptide can then be recovered and purified by well-known
purification methods
including ammonium sulfate precipitation, acid extraction, anion or cationic
exchange
chromatography, phosphocellulose chromatography, hydrophobic-interaction
chromatography,
affinity chromatography, hydroxylapatite chromatography, lectin
chromatography, or high
performance liquid chromatography.
3 0 It is also understood that depending upon the host cell in recombinant
production of the
peptides described herein, the peptides can have various glycosylation
patterns, depending upon
the cell, or maybe non-glycosylated as when produced in bacteria. In addition,
the peptides may
include an initial modified methionine in some cases as a result of a host-
mediated process.
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Uses of vectors and host cells
The recombinant host cells expressing the peptides described herein have a
variety of
uses. First, the cells are useful for producing a estrogen receptor protein or
peptide that can be
further purified to produce desired amounts of estrogen receptor protein or
fragments. Thus,
host cells containing expression vectors are useful for peptide production.
Host cells are also useful for conducting cell-based assays involving the
estrogen
receptor protein or estrogen receptor protein fragments, such as those
described above as well as
other formats known in the art. Thus, a recombinant host cell expressing a
native estrogen
receptor protein is useful for assaying compounds that stimulate or inhibit
estrogen receptor
protein function.
Host cells are also useful for identifying estrogen receptor protein mutants
in which these
functions are affected. If the mutants naturally occur and give rise to a
pathology, host cells
containing the mutations are useful to assay compounds that have a desired
effect on the mutant
estrogen receptor protein (for example, stimulating or inhibiting function)
which may not be
indicated by their effect on the native estrogen receptor protein.
Genetically engineered host cells can be further used to produce non-human
transgenic
animals. A transgenic animal is preferably a mammal, for example a rodent,
such as a rat or
mouse, in which one or more of the cells of the animal include a transgene. A
transgene is
exogenous DNA which is integrated into the genome of a cell from which a
transgenic animal
develops and which remains in the genome of the mature animal in one or more
cell types or
tissues of the transgenic animal. These animals are useful for studying the
function of a estrogen
receptor protein and identifying and evaluating modulators of estrogen
receptor protein activity.
Other examples of transgenic animals include non-human primates, sheep, dogs,
cows, goats,
chickens, and amphibians.
A transgenic animal can be produced by introducing nucleic acid into the male
pronuclei
of a fertilized oocyte, e.g., by microinjection, retroviral infection, and
allowing the oocyte to
develop in a pseudopregnant female foster animal. Any of the estrogen receptor
protein
nucleotide sequences can be introduced as a transgene into the genome of a non-
human animal,
such as a mouse.
Any of the regulatory or other sequences useful in expression vectors can form
part of
the transgenic sequence. This includes intronic sequences and polyadenylation
signals, if not
CA 02426405 2003-04-17
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already included. A tissue-specific regulatory sequences) can be operably
linked to the
transgene to direct expression of the estrogen receptor protein to particular
cells.
Methods for generating transgenic animals via embryo manipulation and
microinjection,
particularly animals such as mice, have become conventional in the art and axe
described, for
S example, in U.S. Patent Nos. 4,736,866 and 4,870,009, both by Leder et al.,
U.S. Patent No.
4,873,191 by Wagner et al. and in Hogan, B., Manipulating the Mouse Embryo,
(Cold Spring
Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986). Similar methods are
used for
production of other transgenic animals. A transgenic founder animal can be
identified based
upon the presence of the transgene in its genome and/or expression of
transgenic mRNA in
tissues or cells of the animals. A transgenic founder animal can then be used
to breed additional
animals carrying the transgene. Moreover, transgenic animals carrying a
transgene can further
be bred to other transgenic animals carrying other transgenes. A transgenic
animal also includes
animals in which the entire animal or tissues in the animal have been produced
using the
homologously recombinant host cells described herein.
In another embodiment, transgenic non-human animals can be produced which
contain
selected systems that allow for regulated expression of the transgene. One
example of such a
system is the crelloxP recombinase system of bacteriophage P 1. For a
description of the
crelloxP recombinase system, see, e.g., Lakso et al. PNAS 89:6232-6236 (1992).
Another
example of a recombinase system is the FLP recombinase system of S. cerevisiae
(O'Gorman et
al. Science 251:1351-1355 (1991). If a c~elloxP recombinase system is used to
regulate
expression of the transgene, animals containing transgenes encoding both the
Cre recombinase
and a selected protein is required. Such animals can be provided through the
construction of
"double" transgenic animals, e.g., by mating two transgenic animals, one
containing a transgene
encoding a selected protein and the other containing a transgene encoding a
recombinase.
Clones of the non-human transgenic animals described herein can also be
produced
according to the methods described in Wilmut, I. et al. Nature 385:810-813
(1997) and PCT
International Publication Nos. WO 97/07668 and WO 97/07669. In brief, a cell,
e.g., a somatic
cell, from the transgenic animal can be isolated and induced to exit the
growth cycle and enter
Go phase. The quiescent cell can then be fused, e.g., through the use of
electrical pulses, to an
enucleated oocyte from an animal of the same species from which the quiescent
cell is isolated.
The reconstructed oocyte is then cultured such that it develops to morula or
blastocyst and then
transferred to pseudopregnant female foster animal. The offspring born of this
female foster
animal will be a clone of the animal from which the cell, e.g., the somatic
cell, is isolated.
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Transgenic animals containing recombinant cells that express the peptides
described
herein are useful to conduct the assays described herein in an in vivo
context. Accordingly, the
various physiological factors that are present ih vivo and that could effect
ligand binding,
estrogen receptor protein activation, and signal transduction, may not be
evident from ih vitwo
cell-free or cell-based assays. Accordingly, it is useful to provide non-human
transgenic animals
to assay in vivo estrogen receptor protein function, including ligand
interaction, the effect of
specific mutant estrogen receptor protein on estrogen receptor protein
function and ligand
interaction, and the effect of chimeric estrogen receptor protein. It is also
possible to assess the
effect of null mutations, that is mutations that substantially or completely
eliminate one or more
estrogen receptor protein functions.
EXAMPLES:
1. SNP Identification and Characterization
Individual exons of estrogen receptor alpha (ESRl) were PCR amplified using
primers flanking each adjacent sequence of exon (exon/intron boundaries), and
the sequence
of amplified fragments was analyzed. As the PCR template, genomic DNA from
Coriell
Diversity Panels (10 individuals in each of 5 ethnic groups) (see Figure 2
(b)), and/or
Liverpool clinical breast tumor and matching blood samples from 48 patients
(from tissue
obtained in Liverpool, England, see Figure 2 (a)) was used. PolyPhred version
2.0 (D. A.
Nickerson, S. Taylor, N. I~olker, Univ. of Washington, 1998) was run on the
sequences (with
default settings) to visualize potential heterozygotes. Tagged sites were
examined for quality
to verify polymorphisms.
36 SNPs with a frequency greater than 2 and a quality score greater than 20
were
found with 13 being unique to the clinical samples. 15 of the SNPs showed at
least one
instance of a change in heterozygosity in the clinical samples, and 4 showed
at least one
instance of a loss in heterozygosity. For the analysis, PCR primers were used
for SNP
identification and detection (see Figure 2 (e))
Additionally, the primer set in Figure 2(d) and M13 primers were used for
overlapping PCR and clone sequencing.
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Table 1. Summary of SNPs found in the clinical samples. All SNPs had a
frequency greater
than 2 and a quality score greater than 20 (see Figure 8).
Number of SNPs 39
Number in Liverpool 34
Number in Coriell 26
Number unique to Coriell 5
Number unique in Liverpool12
Table 2: Summary of changes in heterozygosity in clinical samples. SNPs had a
frequency
greater than two and a quality score greater than 20 (See Figure 8).
Number of Liverpool SNPs 15
With >1 Change in Heterozygosity
Number of Liverpool SNPs 4
With >1 case of Loss of Heterozygosity
Figure 2 (c) included analysis SNPs in Liverpool control population vs. blood
or
tumor populations. There were 23 sites that were typed in both cases and
controls.
Figure 5 shows the domain structure of the ESR1 protein and the position of
many of
the SNPs disclosed herein. Figure 6 provides a graphical representation of the
SNPs and
frequency of occurance in the samples tested.
Figure 8 (a)(1) shows the SNPs and frequency of occurance in Coriell Samples
wherein
the samples are collected from Northern European, Chinese, Indo-Pakistani,
Africa American
and Southwestern Native American ethnic groups. In 3' flanking Exon 8, the
positions of the
SNPs are based on the sequence of AL078582 that is in Genbank. The result can
be used for
detection proposes among the specific ethnic groups. Figure 8 (a)(2) shows the
genotyping of
SNP on cite 167989 (intron 1D, #9) in the Coriell panel. This panel comprises
100
Caucasians, wherein 51 are males and 49 are females. The result shows that the
frequency of
the minor allele is 9%.
Figure 8 (b)(1) shows the SNPs and frequence of occurance in Liverpool samples
wherein the samples are selected from the groups of blood samples and breast
cancer samples
from Norther Europeans.
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Figure 8 (b)(2) shows the Taq Man genotyping results for SNP cite 167, 989
(intron
1D, #9) in additional 60 Liverpool patients. The result shows that the
frequency of the minor
allele (G) was 14% in blood and 10% in tumors. This is similar to the SNP
genotyping in
Coriell samples shown in Figure 8(b)(1), wherein the frequency at the minor
allele was 16%
in blood and 17% in tumors. The Liverpool control population (95 cases) shows
that the
frequency at the minor allele was 10.5% (Figure 2(c)).
2. Haplotype Analysis
The method developed for SNP discovery was designed to recover haplotype data.
SNPs could be associated into a specific haplotype. The sample cDNA was from a
random
population present in unknown proportions. SNPs coming from a specific clone
were
clustered and built into haplotyes.
Data consist of two sample types (Figure 4(a) and (b)). Liverpool samples axe
from
48 patients, and each patient had a tumor and blood sample typed. Coriell
samples were
controls, but they were not matched controls. Rather they included a mix of
Europeans,
Chinese, Indo-Pakistani, and African Americans. 46 SNPs in ESR1 were scored in
the
Liverpool samples. The same 46 SNPs plus an additional 6 SNPs at 3' of the
RSR1 gene
were scored in the Coriell sample.
These data were subjected to an analysis to infer the most likely haplotype
phase of
the individuals. The results appear in Figure 4 (a) where each haplotype has a
number and
the number after the dash is a count (or frequency) of that haplotype.
Figure 4 (b) is the non-singleton haplotype data that were fitted to a
neighbor joining
tree. If a tree were cut at the arrow, the Glade including 3L, 10-4, ... 73L
would be
partitioned from the rest of the tree, as "Glade X". The following table will
illustrate a
difference in the incidence of tumors in haplotypes on Glade X vs. the rest of
the tree. The
incidence of each haplotype was first counted by adding the numbers after the
dashes,
wherein L represented the tumorous Liverpool samples and the non-L represented
Coriell
controls.
Glade X Rest of tree
3 0 Tumor 49 64
Control 4 49
A Chi-square was calculated based on the 2 x 2 table as of 21.29, which, with
one
degree of freedom that has a probability less than 0.0001. Therefore, the
Glade X of the ERl
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gene has a much greater chance of being associated with a tumor. This entire
Glade is so rare
elsewhere in the world. Even among Europeans, it was present only once out of
20
haplotypes.
The sites that identified the Glade with a large frequency difference between
Coriell
controls, Liverpool controls, Liverpool tumor samples were:
5 ESRl-exon 1A 170487 ; 9 ESRl-intron 1D 167989 ;
11 ESRl-exon 1E 64331 ; 17 ESRl-exon Intrn 3 243187 ;
20 ESR1-exon 4 306382 ; 24 ESRl-exon Intrn 6 423220 ;
28 ESRl-exon Intrn 7 459832 ; 29 ESRl-intron 7 459913 ;
35 ESRl-exon 8 460929 ; 45 ESRl-exon 8 462949
3. Promoter region and SNP on Estrogen receptor 1
CAAT and TATA boxes are found in the first 200 b.p. of the sequence and a
distance
between them lead to believe that they might be functional as a basal
promoter.
The distance between CAAT-TATA sites and actual identified start of
transcription is
about 300 b.p. (usually it is about 20-40 b.p.) and this region contains
multiple TF sites such
NFAT, NFKB, SPl-family, CEBP and EBOX, majority of them involved in a
differential
(tissue, cell type) regulation of expression.
Region with T (SNP) has interesting properties. Not only it has conservative
(TC)6-
repeat, but also (CA)6 on the 5-prime. A conservative motif for is CACAYTCTC
at the same
region. There is no significant match from known TF sites to this region, and
it is likely to be
a novel TF site. Very close to T (SNP) is TF site called AHRARNT 02 for aryl
hydrocaxbon/Arnt heterodimers. It is possible that CACAYTCTC site is either a
binding
point for the co-factor or help to properly position Arnt complex. It is also
known that a
single mutation in TF-binding site could decrease affinity of the protein
binding several folds
and as such may lead into a disease pathway.
In the present invention, the SNP occurs just l3bp upstream of exon 1 C in a
short GA
repeat (GAGAGAGA). Among SNPs of interest in the Glades (Figure 4), three are
silent
mutations, one is in the 3' UTR, and the rest are in intron regions.
The important T to G SNP (#9) is in the site 167989 (Intron ID) of the
promoter
region (Figure 2 (a), (b), and (c)). Loss of a gene copy is associated with
cancer risk. A
promoter mutation that decreases gene expression could cause a similar effect.
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G- to T transversion is in an alternate promoter site. There is some effect on
estrogen
physiology, possible on overall levels of signaling at the nucleus. The
predition would be
that the "effect" of the relevant Glade (and cladistic haplytypes) (Figure 4)
is to increase
overall estrogen receptor sensitivity and responsiveness or possible to lead
in the direction of
S alternative growth processes that cycle in the direction of unregulated (non-
physiologic)
growth signals. Estrogen exposure plays a critical role in breast cancer
causation in virtually
every epidemiologic study.
In addition, the TF binding sites and SNPs were detected in the ESRl gene
wherein 5
SNPs occured in transcription binding sites as shown below:
SNP position Gene structure Transcription factor
167989 intron 1D PAX- 3
64331 exon 1E CDP
423220 intron 6 MEF-2
423232 intron 6 MEF-2
423258 intron 6 SRF,AGL3
4. ESRl Genomic Sequencing:- The Complete Genomic Structure of Estrogen
Receptor alpha
Estrogen receptor (ER) is a member of the nuclear hormone receptor gene
superfamily. This family of genes is characterized by a modular structure with
three distinct
domains: a variable (N)-terminal domain, a highly conserved DNA binding
domain, and a
conserved (C)-terminal domain (reviewed in 1, 2). Functionally, the (N)-
terminus domain
regulates transactivation, the DNA binding domain regulates dimerization and
DNA binding,
and the (C)-terminus domain regulates transactivation, dimerization, ligand
binding, nuclear
translocation, silencing, and Heat Shock Protein binding. It was shown that
the functions of
the individual domains of the nuclear hormone gene superfamily are independent
of the
receptor in which they are found, and that the domains retain their function
even when placed
into different heterologous proteins (3,4,5). The domain modularity in the
nuclear hormone
receptor gene superfamily exists because the major subfamilies of these genes
evolved
3 0 through a
simple gene duplication early in evolution (6). The nuclear hormone receptor
gene family
can be separated according to two different classification schemes, one based
on hormone
binding, the other based on dimerization and how the receptors bind to their
respective DNA
response elements (for a review, see 2).
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The cDNA for ERa was first cloned and sequenced from the MCF-7 breast cancer
cell line and was found to have 27% identity and 41 % conservation to the v-
erb-A gene (7).
ERa was mapped to chromosome 6q25. l using Fluorescence In Situ Hybridization
(FISH)
and chromosome banding (8). In 1996, a novel estrogen receptor (ER(3) was
identified by
degenerate PCR (9) and mapped to 14q22-24 by FISH (10). ERa and ER(3 were
shown to
have 96% sequence identity in the DNA binding domain, 58% identity in the
ligand-binding
domain, and low similarity in the 5' and 3' ends as well as in the hinge
(domain D). A
variety of ERa and ER(3 variants have since been described, including single
and multiple
exon deletions, truncated transcripts, and transcripts containing insertions (
11,12,13). These
variants were isolated from a variety of sources, including normal tissues,
tumor tissues and
cell lines. The ER status of tumors in breast cancer patients has been used as
an indicator of
response to endocrine therapy (14,15), and many studies have examined the role
of ER in
breast cancer tumor progression, ER-negative status, and hormone antagonist
resistance (for a
complete review, see 16).
Because of the importance of the ER gene, we set about to clone it in its
entirety and
determine its complete structure. Initially, we used standard Bacterial
Artificial Chromosome
(BAC) sequencing to generate sequence information for the coding regions of
the genes. As
Celera's sequencing of the human genome progressed, the remaining regions of
ER were
filled in using Celera regional assemblies. A small region of less than 25 kb
was filled in on
ERa using a public BAC (A1353611.6, positions 1,497-25,941)
Materials and Methods
1 ) BAC Screening
Appropriate markers were designed for ERa and ER(3 exons and used to obtain
commercially available BAC clones from Research Genetics (Huntsville, AL). A
number of
positive BACs were selected and individual clones were re-screened for
verification.
2) DNA Isolation and Library Preparation
BAC DNA was isolated from verified clones using QIAGEN columns (QIAGEN,
Inc., Valencia, CA) according to the manufacturer's specifications. Shotgun
libraries were
prepared following standard protocols (17). Briefly, isolated BAC DNA was
sonicated,
polished, and size fractionated. Size selected DNA fragments were then
subcloned into
pUCl9 using standard ligation techniques. Ligated DNA was transformed into
Electrocompetent cells (Life Technologies, Rockville, MD) and grown overnight.
3) DNA Sequencing and Annotation
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Sequencing reactions were performed using Big Dye Terminator chemistry
(Applied
Biosystems, Foster City, CA) and run on an ABI PRISM 3700 DNA Analyzer
(Applied
Biosystems). Phred (18), Phrap and Consed (19) were used for base calling,
assembly, and
finishing, respectively. Exon locations were determined using Cross Match to
compare the
published gene sequences to the genomic contig.
Results
1. Estrogen Receptor a
Alignment of the genomic sequence for ERa and published mRNA sequences for
ERa show the gene consists of 14 exons and covers 446,296 by of genomic
sequence (Figure
7, Table 3).
2. Estrogen Receptor (3
Alignment of the genomic sequence for ER(3 and published mRNA sequences for
ER(3 show the gene consists of 17 exons and covers 253,748 by of genomic
sequence (figure
2, table 1). By analysis with the Celera Genome Browser, we were able to
identify a gene,
human synaptic nuclei expressed gene 2 (syne-2, accession number NM 015180.1),
that is
completely contained within intron 9 of ER/3, on the opposite strand. Further
analysis of the
syne-2 gene showed it consists of 21 exons, and covers 51,471 by of genomic
sequence.
Discussion
Alignment of the complete ERa genomic sequence and various ER(3 transcripts
shows that the gene covers 446,296 by of genomic sequence and consists of 14
exons. The
alignment of the published sequence for exon 1E (AJ002561) (20) and the ER a
genomic
sequence revealed that exon 1 E actually consists of two separate exons. The
newly
delineated exon is referred to here as exon 1 G to conform to the naming
convention
previously established. Exon 1G is located approximately 45 kb upstream of
exon 1E and
conforms to the GT/AG splice site consensus sequence (Figure 1, table 1).
Alignment of the various ER(3 transcripts to the complete ER~3 genomic
sequence
reveals a more complex organization than was previously accepted (13). The 5'
UTR of the
ER(3cx variant (AB006589) actually consists of seven untranslated exons
(referred to here as
exons -1 through -7), all of which conform to the GT/AG splice site consensus
sequence
(figure 2, table 1). Sequence alignment ofER(3 variants AF061055 and AF061054
(12)
showed that these transcripts both contain intron sequence and were probably
partially mature
transcripts. Both of these partially mature transcripts contain exon 7 and a
portion of exon 9,
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but do not conform to the splice site consensus sequence at the sites where
intron sequence is
present.
By examining the ER genomic sequences using the Celera Genome Browser, we were
able to identify a separate gene contained entirely within intron 9 of ER(3.
This gene was
identified as human synaptic nuclei expressed gene 2 (syne-2) and was shown to
cover over
50 Kb of genomic sequence and consist of 21 exons, all of which conform to the
GT/AG
splice site consensus sequence (Table 4). The syne-2 gene is located on the
antisense strand
of ER(3.
Completion of the sequence and structures for ERa and ERj3 should contribute
to
further understanding and characterization of these important receptors.
Table 3: Exon-Intron Boundaries and Locations in the Human Estrogen Receptor:
Exon
sequences are shown in upper case and intron sequences are shown in lower
case. Splice
sites are shown in bold.
Exon Contig Contig Exon Size """"
Gene no, Splice varient Start end 5' splice donor 3' splice acceptor b size
p) (Kb)
ER1 1G AJ0025611894119032- AcCAAAGAAGgtaagttttt91 33.79
1F AJ0025625281852940- TTCTCTTCAAgtaggtactc122 11.21
1E AJ0025616415064280aaaacaaaagGAAGAAGAAACATCACTGAGgtatgtgtga130 101.95
1D AJ002560166228166322- GAGAGAGCCAgtaagtcacg94 1.68
1C X62462 168002168120- ATCCAGCAGGgtaggcttgt118 1.55
1B AJ002559169674169825- GACAAGTAAAgtaaagttca151 0.04
1A X03635 169867170678- CATTCTACAGgtacccgcgc811 34.23
2 X03635 204912205102ttccccccagGCCAAATTCAAGTATTCAAGgtaatagtgt190 37.87
3 X03635 242970243086cttttaatagGACATAACGAATGAAAGGTGgtaggtacat116 63.08
4 X03635 306168306503gtgttttcagGGATACGAAAAGGGTGCCAGgtaagaatgc335 67.14
5 X03635 373640373778ttgttttcagGCTTTGTGGATCTTGGACAGgtaagtgacc138 49.19
6 X03635 422964423097gttttcatagGAACCAGGGACTTAATTCTGgtgagttgat133 33.26
7 X03635 456354456537gcgcattcagGAGTGTACACGGCACATGAGgtgaggcatc183 4.16
8 X03635 460701465237ccacctacagTAACAAAGGC- 4536 -
ER2 -7 AB0065894955249750- GGTTCTGAAGgtgcgtggtt198 1.18
-6 AB0065895092851235tgcctcttagACATCCAAGTTGTTTGTAAGgtaataaaaa307 32.62
-5 AB0065898385884041tatccactagAGGGAGACATGAGAACACAGgtgaacttca183 1.90
-4 AB0065898594286154ctctccatagAAATCCTGGGATTAGCCCTGgtaaggagct212 2.88
-3 AB0065898903789130cattcaacagTATCTGGGCTGTGCAGGTAGgtaggtaaag93 0.67
-2 AB0065898980389988ccttttacagGGTTTTGTTTGTGTTGACAGgtaagatgag185 3.12
-1 AF0605559311193488- TATCTGCAAGgtaagcgccc377 10.96
1 AF060555104446104897ttctttacagCCATTATACTCTGTAAACAGgtaagtccag451 2.47
2 AF060555107368107540tgctccctagAGAGACACTGAGCATTCAAGgtacaagaga172 11.07
3 AF060555118610118726tctgctatagGACATAATGAGTGAAGTGTGgtgagtgctt116 8.05
4 AF060555126774127073tcctcttcagGCTCCCGGAGAAGATTCCCGgtagggcttt299 3.09
5 AF060555130158130296ctttccccagGCTTTGTGGATTCTGGACAGgtgagaaaaa138 7.56
6 AF060555137853137986acttttgtagGGATGAGGGGCTCAATTCCAgtaagtaatc133 14.39
7 AF060555152379152559ctttgtccagGTATGTACCCGGCATGCGAGgtacgcgccc180 1.65
8 X99101 154206154500gtccccatagTAACAAGGGC- 826 5.42
9 AB006589159915160827tctacttaagGGCAGAAAAG- 912 141.65
10 AF060555302474303300gtcttgacagCTCTCTCTCA- 826 -
IS
59
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Table 4: Exon-Intron Boundaries and Locations in the Human Synaptic Nuclei
Expressed
Gene 2. Exon sequences are shown in upper case and intron sequences are shown
in lower
case. Splice sites are shown in bold.
Exon Splice Contig Contig Exon "'n "
Gene no. varient start end 5~ splice donor 3' splice acceptor Size size
(bP) ~Kw
Syne-21 NM_015180212563212391- CACTGTAGAGgtaaactcac172 2.22
2 NM 210175210044tttcaaatagACCTGGGACCGCTGATTAAGgtattgaaat131 8.94
015180
3 NM_015180201109200946ttaaatgcagGAACTAGAACCTGCTTAAGGgtaagtcagc163 1.97
4 NM_015180198981198819tcatttgcagGTGGCCATACGTTACAGAAGgtaagggagg162 1.36
NM 197462197290cctttgccagGACTGCATGGTCGGATCAAGgtaagaaatg172 12.56
015180
6 NM_015180184732184564atatgtgtagGGTGAAGAAGTGAGCAGCAGgtgggacaat168 5.79
7 NM_015180178777178584gtaatcacagGATCTACAGCGGCGCATGAAgtaagaacta193 0.48
8 NM 178101177949ctcccatcagAATCGAGGAGGAGGTTTGAGgtaaacacct152 0.36
015180
9 NM_015180177591177405tgtgatgcagGCCTTTCAGCGAGACTCAGGgtgagctcct186 1.84
NM_015180175570175429acttttgcagCATTTCACCACCAACTGAATgtgagggctg141 0.71
11 NM_015180174718174522ctctcaacagGGCTTCCAACCTGCACTCCGgtacgggcac196 1.19
12 NM_015180173337173051tgtggtttagGGCTTGGAAGGCACTGTCAGgtaacagctg286 1.76
13 NM_015180171289171140ttcgtttcagGTAAATCCATACCACCCTATgtaagtctta149 2.00
14 NM 169139169013ctcattctagGGAAAGCTACCAGCAGTCAGgtactgcctg126 0.69
015180
NM 168327168117ttaattccagGTGCCTTCGAGAGACTGCAGgtgagttaga_ 1.02
015180 210
16 NM 167096166890tctctggtagGAGATACTGAGCAGTGCCAGgtacgctgac206 0.93
015180
17 NM_015180165957165825gttttttaagGACTTCCACCGGAACTAATGgtaagtttcc132 1.48
18 NM_015180164342164149ctgttttcagCAACTGGAAAGGGAACCCAGgtgagtctac193 1.08
19 NM 163074162982tgaatttcagAACCCAGCCTCCGAGCAAAGgtaagaagcc92 0.45
015180
NM_015180162537162482ctttacccagCAGTTCAGAGCAGAGAGCAGgtaacggggc55 0.27
21 NM 162214161092ctgttggcagGGTCCCCGGC- 1122-
015180
5 References
1. Ribeiro RC, Kushner PJ, Baxter JD, Tenbaum S, Baniahmad A. The nuclear
hormone receptor gene superfamily. Annu Rev Med 1995;46:443-53.
2. Tenbaum S, Baniahmad A. Nuclear receptors: structure, function and
involvement
in disease. Int J Biochem Cell Biol. 1997 Dec;29(12):1325-41.
10 3. Baniahmad C, Baniahmad A, O'Malley BW. A rapid method combining a
functional test of fusion proteins in vivo and their purification.
Biotechniques. 1994
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4. Parker MG, White R. Nuclear receptors spring into action. Nat Struct Biol.
1996
Feb;3(2):113-5.
15 S. Schwabe JW. Transcriptional control: how nuclear receptors get turned
on. Curr
Biol. 1996 Apr 1;6(4):372-4.
6. Laudet V, Hanni C, Coll J, Catzeflis F, Stehelin D. Evolution of the
nuclear
receptor gene superfamily. EMBO J. 1992 Mar;l1(3):1003-13.
7. Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P, Chambon P. Human
20 oestrogen receptor cDNA: sequence, expression and homology to v-erb-A.
Nature. 1986 Mar
13-19;320(6058):134-9.
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8. Menasce LP, White GR, Harrison CJ, Boyle JM. Localization of the estrogen
receptor locus (ESR) to chromosome 6q25.1 by FISH and a simple post-FISH
banding
technique. Genomics 1993 Ju1;17(1):263-5.
9. Mosselman S, Polman J, Dijkema R. ER beta: identification and
characterization of
a novel human estrogen receptor. FEBS Lett. 1996 Aug 19;392(1):49-53.
10. Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried
G,
Nordenskjold M, Gustafsson JA. Human estrogen receptor beta-gene structure,
chromosomal
localization, and expression pattern. J Clin Endocrinol Metab. 1997
Dec;82(12):4258-65.
11. Murphy LC, Dotzlaw H, Leygue E, Douglas D, Coutts A, Watson PH. Estrogen
receptor variants and mutations. J Steroid Biochem Mol Biol. 1997 Aug;62(5-
6):363-72.
12. Moore JT, McKee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, Su JL,
Kliewer SA, Lehmann JM, Willson TM. Cloning and characterization of human
estrogen
receptor beta isoforms. Biochem Biophys Res Commun. 1998 Jun 9;247(1):75-8.
13. Ogawa S, moue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M.
Molecular cloning and characterization of human estrogen receptor betacx: a
potential
inhibitor of estrogen action in human. Nucleic Acids Res. 1998 Aug
1;26(15):3505-12.
14. Osborne CK, Yochmowitz MG, Knight WA 3d, McGuire WL. The value of
estrogen and progesterone receptors in the treatment of breast cancer. Cancer
1980 Dec
15;46(12 Suppl):2884-8.
15. DeSombre ER, Carbone PP, Jensen EV, McGuire WL, Wells SA Jr, Wittliff JL,
Lipsett M Special report. Steriod receptors in breast cancer. N Engl J Med
1979 Nov
1;301(18):1011-2.
16. Parl, Fritz F., Estrogens, Estrogen receptor, and Breast Cancer. IOS
Press,
Amsterdam, Netherlands, 2000.
17. Birren B, Green ED, Klapholz S, Myers, R, Riethman H, Roskams J, (eds.)
(1997), Genome Analysis: A Laboratory Manual. Cold Spring Harbor Laboratory
Press,
Cold Spring Harbor, NY.
18. Ewing B, Hillier L, Wendl MC, Green P. Base-calling of automated sequencer
traces using phred. I. Accuracy assessment. Genome Res 1998 Mar;B(3):175-85.
19. Gordon D, Abajian C, Green P. Conned: a graphical tool for sequence
finishing.
Genome Res 1998 Mar;B(3):195-202.
61
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20. Flouriot G, Griffin C, Kenealy M, Sonntag-Buck V, Gannon F. Differentially
expressed messenger RNA isoforms of the human estrogen receptor-alpha gene are
generated
by alternative splicing and promoter usage. Mol Endocrinol 1998
Dec;l2(12):1939-54.
All publications and patents mentioned in the above specification are herein
incorporated by reference. Various modifications and variations of the
described method and
system of the invention will be apparent to those skilled in the art without
departing from the
scope and spirit of the invention. Although the invention has been described
in connection
with specific preferred embodiments, it should be understood that the
invention as claimed
should not be unduly limited to such specific embodiments. Indeed, various
modifications of
the above-described modes for carrying out the invention which are obvious to
those skilled
in the field of molecular biology or related fields are intended to be within
the scope of the
following claims.
62
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SEQUENCE LISTTNG
<110> Kalush, Francis et a1.
<120> Estrogen receptor alpha variants and
methods of detection thereof
<130> CL000258PCT2
<150> 09/692414
<151> 2000-10-20
<150> 09/768184
<151> 2001-01-24
<150> 09/804076
<151> 2001-03-13
<150> 09/826314
<151> 2001-04-5
<160> 2
<170> FastSEQ for Windows Version 4.0
<210> 1
<211> 465237
<212> DNA
<213> human
<400> 1
ctgttgcttc acctcagaat cttgggagaa gcaggctcaa caatgaggga atcatccatg 60
acacccactg tcccaatgac catctttgcc tccacctgtt tgtgcccttt cacaatcatc 120
aagatattgt gatcttgatt tcgattcttt tggatacata tcctgaagtg ggaaggctgg 180
gttacatggt aataagagat atcagcactt ccatgtttat agcagcacta ttcacagtgg 240
ccaagatatg aaatacggta tatgcataca atggagtatt atgcagccat gaaaaagaag 300
gatattctgc ttcttctatc atatggcatg acattgatgg acctttagga cattatccta 360
aatgaaataa gccggtcaaa gaaagacaaa tactgcatga ttccacttat ataagatatc 420
tgaaatagtc acattcatag aatcaaagag agaaatggtg gttttcaggg gctggaggca 480
aagggaaaca ggggagttac taagaaatgg gcataatgtt ccagttaaac aagttgaata 540
agctcagaga tttgatatac aacattctac ctagaggtga caatgtacgg tgcacttaaa 600
aatttgttaa gggggtagat ctcatgttaa atgttcttac cacattaaga gaaaacaaac 660
aaacaaaaga tactgtagtg ttggagaatt ctcacaatgg ctgaactggt ctccactgag 720
cctggtggca aaagcagacg ggggaggctc ctctctcaga tcagttttgt agagttgagg 780
gaggggcacc ttgaatgaac ataatacttg gagagagtgt tgcagttaga ggacagaaaa 840
caaaagcaca tcatcaagag tgcctcctgc tatgtttatg cctattttac tgtccttttc 900
aaagaaaagc tttaagttta attgatcaac aatttttgaa tttttctttt agttgtgttt 960
tcaaatttat tgatttctgc atttctattt atttgttcct ttgttatgct tttttggggg 1020
gggaggctta ttttgttgtt ctttaatttc ttgagttgaa agtttatccc atttattttt 1080
agtctttttg gtttttaatg aatatattta agcctctgaa ttttttctct gaatactgct 1140
ttagtggtat tgcactagtt tttttttaac cccttgttct tggtttatta acagcctttt 1200
cagcataatt caatgcttat aacactgtct acatattgtt tttaaaatgg ttttgaagat 1260
tagttttttt aaaactaatt tctttctttt atttatttat ttttgagaca gggtcttgct 1320
gcattgccta ggctggagtc cagtggcgtg atcatggctc actgcagctt tgactccctg 1380
gcctcaggtg attctcccat ctcagcctcc agagtagctg ggactacaga aatgtgccac 1440
tacacctggc taatttttat atttttgtat tttttttgtt gttgttgttg tagagatgag 1500
gtttcaccat gttgcccagg ctgatctcga actcctgtgt ttaagccatc cacatacctt 1560
ggcctcccaa agtgctggta ttacaggtgt cagctaccat acctggctaa aaactaattt 1620
aaaacaacgt cattatggaa atacaattta cactgcttac agctcactaa ttaaaagtgt 1680
gcattttcat gttcttaaaa gtatattcaa aaagtttgtg accatcaaca caatttcatt 1740
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ttagaatgct tttgtctttt ctaaaagaaa cccatccttt tcctcccaca actttcccta 1800
cctttaagcc accagtaatc tactttttgt ctttatgtat ttgcctattc tagaaatttc 1860
atataaatgg aatcatataa tatgtcgcct tttgtgactg gctgctttca cttagcataa 1920
cttttttgaa gttcatccat attgtagtgc ttcagtcctt gttatggggg aataatattc 1980
cattgtatgg atatactaca tttaaaaaat ctatttgtta ttggtaaaca ttagagctgt 2040
ttctactttt tggttattat gagtaatgct gctaaaaaca ttgtatacaa gttcttgtgt 2100
gaatgtgtgc ttttatttgt cttgttgata tacctaggag tggaattgtt aggtcacata 2160
gtaatgctat gtttaccttt tgagacattg caaaactttt ttccaaagca gctgcaccat 2220
tataaattcc caccagcaat gcatgaggat tcaatttctc cacattgttg tcaacacttg 2280
ttactgtctg gagccagcct agtgggtgtg aagtggtatt tcattgtggt tctgatttgc 2340
atgtctctaa taactaataa tgttgagcgt attttcatgt gctcactggc catttgtaca 2400
tcttctttgg aaatatatct attcacccct tttgcccatt ttaaatgttg tattattttt 2460
ctttttatta ttgcattgta agagctcttt agatcttcta gatgcaaatc ttttatcaga 2520
tatatgattt gcaaatattt tctactgttc tgtgtgttgt ctttcatttt taaataatat 2580
tctgtgaagc caaaagtttt aattttgatg aagtctaaat tatcattatt ctttgttttg 2640
ttgtttgtac ttttggtgtc atagctaaga'aataattgcc taatccaatg tcatgaagat 2700
ttatgtcttt ctttcttttt ctttccttct ttctcttttt ctttctttct ctttctttct 2760
ttCtttCtCt ttCCCCttCC ttCCttCCtt CCttCCttCC ttCCttCCtt CCttCCttCC 2820
ttccttcctt cctatctcgc gctctctttc tttctctctc tgtctctctc ttttttttag 2880
gcaaggtctt attatgttgc ccaggtgggt cataaactcc tgggttcaaa agtgatactt 2940
tcatctcagc ctcctgagta gctgggacta caggcatatg acactgtgcc tggattaaga 3000
gttttataat tttagctttt gcccttaagt ctttgatctg ttttgagtta aaatttgtat 3060
agcgtgaggt aggtgtccaa cttctttctt ttgcatgtgg ctatctagtt gctccagcac 3120
catttgttga aaaggctctc tttctccctt gaattttctt gttgcccttg tcgatgtcag 3180
ttgactataa attcctgagt ttatttctga attctcaatt ccactccact gatctaagtt 3240
tattcttatt ctagtagtca ccattatttt gatcttcttt ctgtgtctca gattttttcc 3300
ccctgtagaa catctccagt aatggtttat ataagtttgt gattagtgat gttatagtgt 3360
gataatgtgt ttatttgctc ttacactttg gctgagctta gaaatatttg tattttgacc 3420
tttgatacgg tttggatatt tgtctcctcc aaatctcatg ttgaaatgta atcactaatg 3480
ttggaggttg ggcctaatgc aaggtatttg ggtcatgggg gtggatccct catggcttgg 3540
tgctgtcctt gggatagtga atgagttctc atgagatctg gttgtttaaa agtgagcggt 3600
acctccttcc tctctctctt gctcctgctc tgccaagtga tgtgcctgct tccgctttac 3660
cttccaccat gagtaaaagc ttcctgaggc ctcaccagaa gcttagcaga tgcaggtgcc 3720
atgattcctg tatagcctgc agaactgtaa gccaattaaa cctctcttct tgataaatta 3780
cccagcctca tatatgtttt atagcaatgg aagaatggcc gaatacaacc tttgagatgt 3840
ctgtttcact gtcatctttg cttcagagtt actgaagaaa agtctgatga tctcattctg 3900
ttttcttagt tgataattgg tttttatttt atctctttct ctgcaagact ttcagatttt 3960
ctctttatat ttagcgttct gaaattttta cagtactgtt ttgcgtgatt cattttttat 4020
tcatcttttg tcttttcaat ctgaggattt ttgtttgttc tggagtattt ctttattatt 4080
gctttgagta ctgcctttct tccattctat tctttccttc aggcactcat attttcaaat 4140
attagaattt ttggatctgg tctaaaaagg aaataaaaaa atctataatc agactagaat 4200
agaaggggta cccttgacag tccaagaaat aagagaaagc cctgacatgc caaacagatg 4260
ttacgagata aacttgtaag acagaaatac tgcagctggg gcgcagtggc tcatgcctgt 4320
aatcctagca ctttgggagg ccaaggtggg tggatcactt gaggtcaggt gttcaagacc 4380
agcctggcca acatgatgaa accctgtctc tactaaaaat acaaaaattt gcctggcctg 4440
gtggcgggcg cctgtaatcc cagctactcg ggaggctgag gcaggagaat tgcttgaacc 4500
tgggaggcag aggttgccat gagctgagat agtgccactg cactccagcc tgggtgacag 4560
tgagagactc catttcaaaa agataaaaaa tgacacaaga aagatgatag aaatgacagg 4620
atgtggagac acaactcaaa ttctaggttc cagatcttga catcttccca ctgtcttact 4680
gctctgcatc atgttagctt agaaagttac tcaacctctt tgatctttgg attcatgatc 4740
taaaaatgga gtgttggggg gcgtggttaa agtgataatt ttgaataagt cttcaaaccc 4800
aacatgtcat gagccttcct tgaattgcat cttcatttat agattaaacg ttttgataaa 4860
ttcactatgg gctcttaact gtattattaa aattgtggtg acaaccagct gttattttat 4920
ggtagaacat aagtatctct tttcattgcc attcttcact aaaaggatac tttgtccccc 4980
tttttctttt tccataggtt attggggtac aggtggtgtt tggttatatg agtaagttct 5040
ttagtggtga tttgtgagat tttggtccac ccatcacctg agcagtatac actgcaccct 5100
atttgcagta ttttattcct tgccccctcc aacccttccc tccaaatccc caaactcctt 5160
tgtatcattt tatgcctttg catcctcata gcttagctcc catataacag taggaacata 5220
tgatgtttgt ttttccattc ctgagttact tcacttagaa taatagtctc caatctcatc 5280
caggtcactg cgaatgccgt taattctctt ctttttatag ctgagtagta atccctagta 5340
tatatatact acagaatctt tatccactca ttgattgatg ggcatttggg ttggttccac 5400
2
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gattttgcaa ttgtgaattg tgccactata aacatgcgtg tgcaagtatc ttttttgtat 5460
aatgacttat tttcctctga gtagataccc agtagtggga ttgctggatc aaatggtagt 5520
tctacttttg gttctttaag gaatctccac gctcttttcc atagcggttg tactagttta 5580
cattcccatc agcaatgtag aagtgttccc tgatcaccac atccacgtca acatctactg 5640
ttttttgatt ttttgattat ggccgttttt acaggagtaa ggtggtatgg cattgcggtt 5700
ttgatttgca ttgccctgat cattagtgat gttgagcatt tttttttgaa tgtttcttgg 5760
ccatttgtat atcttctttt gagaattgtc tattcatgtc cttagcccac tttctgaagg 5820
gattttttaa aattgctgat ttgtttgagt taattgtaga ttttggatat tagtcttttg 5880
tcagatgtat agattgtgag gattttctcc cattctgtgg gttgtctgtt tactctgctg 5940
actgttcttt ttgcggtgca aaagctcttt agtttaatta ggtcccggct atttatcttt 6000
gtttttattg aatttgcttt tgggttcttg gtcatgaaat ccttgcctaa gccaatgtct 6060
agaagggttt ttccagtgtt atcctctaga atttttagag tttcaggtct gaaagtcctt 6120
aatccatcta gagttgattt ttgtataagg tgagaaatga gaatccagtt tcattctcct 6180
acattcggct agccaattat cccagcacca tttgttcaaa agggtgttct ttccccactt 6240
tatgttttca tttgctttgt tgaagatcag ttgactgtaa gtatttgggt ttatttctgg 6300
gttatctatt ctgttccatt ggtctatgtg cctattttta taccagtacc atgctgtttt 6360
ggtgactgtg gccttataat acagtttgaa atctggtagt gtgatgcctc cagatttgtt 6420
ctttttgctt agtcttgctt tggctatgca ggcttttttt gggttccgta tgagttttag 6480
aattgtgtct tcaagttctg tgaagaatgg tggtatttta atggggattg cattgaattt 6540
gtagattgct tttggcagtc attttcacaa tattgaatct acccatgcat gagcatggga 6600
tgtgtttcca tttgtgtcgt ctatgatttc tttcagcagt gttttgtagt tttccttgta 6660
cagattcttt cacctccttg gttaggtata ttcctaagca ttttatttca tcttttgcag 6720
ctatcataaa agaggttgag ttcttgattt gattctcagc ttggtca,ctg ttggtgtata 6780
gaagagctac tgatttgtgt acattaatct tgtatccgaa actttgctga attcttttat 6840
cagttctagg agctttctgg aggagtcttt agggtttttg aggtaaacaa tcatattgtc 6900
agcaaacagc gacaatttca cttcctcttc gtcaatttgg atgcccttta tttctttctc 6960
ttgtctgttt gctctagcta ggatttccac tactatgttg aagaggagtg gtgagaatgg 7020
ccatccttgt cttgtttcag ttctcagagg gaatcctttc aacttttccc cattcagtat 7080
tatgttgcct gtgggtttgt catatatggc ttttattata ttgaggtatg tcccttgaat 7140
gatgattttg ctgagagttt ttatcataaa gggatactgg attttgtcaa atgctttttc 7200
tgcatctgtt gagatgatca tatgattttt gtttttaatt ctgtttatgt ggtgtatcac 7260
atttattgac tcgtgtatgt taaaccatcc ctgcatccct ggtatgaaac ccacttgatc 7320
atggtgaatt atctttttga tatgttgttg gattcagtta gctagtattt tgttaaggat 7380
tttagcatct atgttcgtca gggatattgg tctgtagttt tctggttatg tcctttcctg 7440
gttttggtat taaagtaatg ctgacttcat agaatgaatt agggatggct ctttctttct 7500
ctattttgtg gaatagtgtc aataggattg ctaccaattc ttctttgaat gtctggtaga 7560
attctgctgt gaatctgtct ggtcctggac ttgtttctgt tggtaatttt taaattacca 7620
tttcaatctc actgcttgtt attggtctgt tcggggtatc taattcttct tgatttaagc 7680
taggaggttt gtatctttcc aggaatttat ccatctcttc taagttttct actttatgtg 7740
cataaaggtg ttcatagtag gcttgaatga tcttttgtat ttctgcagtg tcagttgtaa 7800
tatctcccat ttcatttctt attgaggtta tttggatttt ttctcttctt ttgttggtta 7860
atcttgctaa tcgtctatca gctttattta tcttttcaag gagccagctt tttgtttcac 7920
ttatcttttg tatttttttg ttgttgtttc aatttcattt agttctgctc tgatcttggt 7980
tatttccttt cttctgctgg ggttgggttg ggtttgttct tgtttctcta gttccttgag 8040
atgtgacctt agaatgtcag tttgtgttct ttcagtcttt ttgatgtgga tgtttaggga 8100
tatgaacttt cctcttagca ccgcctttgc tgtatcccag aggttttgat aggttgtgtc 8160
actattgtcg ttccgttcaa ataatttttt gatttccatc cgatttcgtt tttgacccaa 8220
tgatcattca ggagtaggtt atttaatatc catgtctttg catggtttca aatgttcctt 8280
ttggagtcta tttccagttt tactccactc tggtctgaca gagtgcttga tataatttca 8340
gttttcttat atttatggag gcttgtttat gacatatcat atggtctatc ttggagaaag 8400
ttccatgcac tgttgaatag aatatgtatt ttgtggttgt tggatggaat gttctgtgta 8460
tatctgttaa gttcatttgt tccaaggtat agtttaaatc cattgcttct ttgttgactt 8520
tccatcttga tgatctgtct agtgctctca gtggagtatc gaagtccccc agtattattg 8580
tgttgctatc tatctcattt cttaggtcta ttagtagttg ttttataaat ttgggagctc 8640
cagtgttaga tgcatatata ttttcctgat ggacaaggtc ttttaccatt atatactatc 8700
cctctttgtc ttttttaact gctgttgctt taaagtttgt tttgtctgat ataaaaatag 8760
ctacccctac tcacttttgg tgtccatttg catgaaatgt ctttttccac cccttacttt 8820
aagtttatgt gagtccttat gtgttaggtg agtctcttga aggcaacaga tagttggttg 8880
gtgaattctt atccattctg cagttctgta tcttttaagt ggagcattga ggccatttac 8940
attcaatgtt agtattgaaa tgtgaggtac cattgcattc atcatgctct ttgttgactg 9000
tgtaccttgg ttttttgttt ttaaattgca tttttatttt ataggtcctg tgttatgctt 9060
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
taaagaggtt tctgttttga tgtgtttcca ggaattgttt caagatttag ggctcctttt 9120
agcagttctt gtagtggtgg cttggtagtg gcaaattctc tcatcatttg tttgtctgag 9180
aaagactgta tctttccttc atatgtgatg cttagtttca ctggatacaa aattcttggc 9240
tgataattgt tttgtttgag gaagctaaag atagggcccc aatcccttct agtttgtagg 9300
gtttctgctg agagatatat ctgctgttaa tctgataggt tttcctgtat agattacctg 9360
gtgcttttgt ctcacagctc.ttaagattat ttcctttgtc ttaactttag ataacctgat 9420
gacaatgtgc ctaggtgatg gtctttttgc aatgaatttc ccagttgttc tttgtgcttc 9480
ttgtatttgc atgtctaggt ctgtagcaag gctggggaag ttttcctcta ttattccccc 9540
aaatatgttt tccaaacttt tagaattctc ttcttcctca ggaacatcaa ttattcttag 9600
gtttggtcat tcaacataat ctcagacttc ttggaggctt tgttaatatt ttcttattct 9660
gtttcctttg tctttgttgg attgggttaa tttgaagacc ttgtctttga actctgaatt 9720
tctttcttct actgttcaat tctattgctg agactttcca gagcatttta catttctata 9780
agtgtgtcca gtgtttcctg cagttttgat tgttttttct ttatgctatc tatttccttg 9840
attatttctc ccttcgcttc ttctattgtt ttttggattt ccttgcactg gggtttggct 9900
ttctctggtg cctctgatta gctgaataac tagccttctg aactcttttt tcaggtaaat 9960
cagggatttc ttctcagttt agatccattg ctggtgagct agtatgattt ttttgggggt 10020
gttaaagagc cttgttttgt catattatca gatttggttt tctggttcct tctcatttgg 10080
gtagcctctg tcagagggaa gttctatggc tgaaggctgt tgttcgtatt cttttatccc 10140
acgaggtgtt cccttgatgt agtactctct cccttttcct atggatgtgg cttcttgaga 10200
gccgaactgt agtaatggtt atctctcttc caggtctagc cactcagcaa gtctaccagg 10260
ctgtgagctg gtattgcggg ttgttggcac tgagttctgt ggtgtgaact gtctgtgtgt 10320
ctctccgcca tggacacctg cacctgttat gggggaggtg gtagaggggt gaaacggatc 10380
cctggttctt agctttggtg gtttaatgct ctatttttgt gctggttggc cttctgccgg 10440
gaggtggcgc tttgcagaca gcatcagcta tggtagtgtg gagagggact ggcagtgggc 10500
ggggtcctag agctcccaag aatatatgcc ctttgtcttc agctactagg gagggtaggg 10560
aaggaccatc aggtgggggc agggctaggc ctgatctgag ctcagaccct ccttggatag 10620
gtcttgctgt ggctgctgtg aggggatggg agtgaggttc ccaggtcaat ggaattgtgt 10680
acctaggagg attacggctc cctctgcgga gtcatgcagg ttgtcaggga agtgggagaa 10740
agccaacagt caccagcctc acccagctcc tgcgcaatcc aaaggggtgg tctcacgccc 10800
actgtgtccc cgctaacaac tctgagtctg tttccaggca gggggtaagc agggctgaga 10860
acttgccgca gtctgcccac ctcccagtgg caaaagaaaa gggctttagt tcttccccag 10920
cctgtggagt ctgcacgcag gattcgcacc ctcccccgtg ttatggccag gaggcttctt 10980
gaccggttca aattgttaca aagttcagct ggagacttcc ttcttcctgt ggtgtttccc 11040
ccgtgcctct ggccaccctc ctgaaggatc cttgtgatgc caggcaggag tggcctgctt 11100
ggggacccag cgagctcccc aggcctttcc agctgcttcc tctatccctg tgttttgctt 11160
gtctatctaa attgactcag ctccagataa ggtcagaatc ttctcctgca aactagaact 11220
tcagtttccc cataggaggt gtgcgttcca gggcggagga tctccctttc ccacttccgc 11280
agttggggca ctcacataat ttggggtgtc tcctgggtcc agcaggagca gtccgcttcc 11340
ttcagagggt ctgtgggtcc tcctgggatt cctggtttat tcctgcagtt gttctggagc 11400
tgaaattcac aatgtgagcc tctgcacgct gttctgtgcg tccgagtcga agctgccatc 11460
tagttttgcc tcccatccgt ggtgatgatc tatgatctct acaaggatac atttgctaga 11520
aatatttgtt ctctctggcc gggcgcggtg gctcacgctt gtaatcccag cattttggga 11580
ggccgaggca ggtggatcac gaggtcagga gatcgagacc atcttggcta acacggtgaa 11640
accccgtctc tactaaaaaa tataaaaaat tagctgggcg tggtggcggg cgcctgtagt 11700
cccagctact caggaggctg aggcaggaga atggcgtgaa cccgggaggc ggagtttgca 11760
gtgagccgag atcgcgccac tgcactccag cctgcgcaac agagcgagac tctgtctcaa 11820
aaaaaaaaaa aaaaaaaaaa agaaatattt gttctcccta ccctaaaagg gatataattg 11880
aaatacaaaa aaacaatatg gagaggtaat ttctttcttt ctttttcttt ttcttttttt 11940
tttctttttg gagacagggt cttgttctgt tgcccaggct gaatgcagtg ggacaatcac 12000
agctcactgc agccttgacc tcctgggctc aaatgatcct cccaccttag cttcctgagt 12060
agctgggact acagatacgc accaccacac cagctaaggt ttaaaattgt ttttaatagt 12120
gagagaattt cacaattttg ccaggctggt ctcgaactcc tgggctcaag caatctgccc 12180
acctcggcct cccaaagtgc tgggattata ggcatgaacc actgcaccgg aaccttggag 12240
aggtaatttt taacaaggcc atcttttctc taacagagga gcactaagaa gtcagatttc 12300
atcctggcat gtgactgtca cacaagcaaa tgactgtgct gattagaaag cttgtgtagc 12360
tcagaaatat cacataatat gcagtctccg ttgagcaaca ttgcagctta tgttcattag 12420
gtaaaaccat agtaatctga aaatatttta ggtatatctg ccattatttt atgactaaac 12480
aaggagatga ttttagtatt gattactttc atgcacatat tttaaaaact cctgattttt 12540
tatgttggaa acattccagt tctttttttt tttttttttt tttttttgag accggagtct 12600
cgctctgtcg cccaggctgg agtgcagtgg cgggatctcg gctcactgca agctccgcct 12660
cccgggttca cgccattctc ctgcctcagc ctccccagtt cttttcttat ctagctattt 12720
4
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tgaactatac atttgattgt attccaaaaa tacgtacaac tattatgtat caataaaatg 12780
tcctaacttt tttgcatagt gaaaggtttg ttcaggttat agtatgagtt gcagtcatcc 12840
tgtttttggc atgggaggga gatgtttcta aactagccag ttataggtgt cacctaccaa 12900
tgttctacaa aatgtggacc aggcagagag aattacagat gctgggtgga aactttggtt 12960
ctgggcctga ttctgcccct aacttggcgt gaagcctcag tttcttctta ctacagcagg 13020
aaaaataata cttgctttat ctgtttcatg tgtctgctat gatgataaca aatataatgt 13080
atatgagaca atttaaaaac ttaaagcatt ttaagttcct tggtctttat gggagaggga 13140
ggaccatcat ttctttctct tttttctttt tcttcttctc ctcccctttc ctcctctttt 13200
tttcattcct tctttttctc cttatctttc tcctcctccc tctcctcctt cttcttcctc 13260
CtCCaaCCtC C'tCCttCtCC tCgCttCttC CCttCtaCtt ttaCttCCtt CttttCtcct 13320
tCt CCtCCat tCtCtttCtC C'tCCt CCttC atCCaCtCCt tCttCttCtt ccttttgaga 13380
tggaatcttg ctctgtcacc caggctggag tgcagtggca tgatcttggc tcactgcagc 13440
ctccacctcc cagattcaag tgattctcgt gcctcagcct ccctagtagc tgggattaca 13500
ggtgtatgcc accacaccca gctaattttt tttttttttt tttttttttt gagacactat 13560
ttcactcttg tcacccagac tggagtgcag tggtgtgatc ttggctcact gcaaactcca 13620
cctcccagat tcaagcaatt cccctgcctc agcctcctga gtagctggga ttacaggtgt 13680
gcaccaccat gtctggctaa ttttgtattt ttagtagaga tggggtttcc ccatgttggc 13740
caggctggtc ttgaactcct gacctcaagt gatccacctg cctcggcctc ccaaagtact 13800
gggattacag gtgtgagtca ccgcacccgg tcctttcctt cttcttcctc ttcttcttct 13860
tcttccttct tttctctgtc tccttctcct ttttttcctc cttgtccttc ttctgtctga 13920
tgcatagtca agggtttgat aagtgtctgc tctgtgctga cagtttcagg agcagtacag 13980
aaactcctat tttgtactcc aaataatcca caagaattaa ttggatcacc tcgaaggagg 14040
aaagagaagc tcaaagagat caggtaagtt gcacaagctc tgaatcccag cacaccgtga 14100
aaacgggctt caaatctggt ctttctgatt ccaaagtcta tagtcttacc tgtgattcac 14160
tttcctgatt tgttaaaaaa aaaaaaaaaa aaaaaaggat gcttcatttg cttaagtaaa 14220
attccaggga attttcagca gaagttttaa atgttggtag agaattttct tgaggcaaaa 14280
ctgataatca taaagcttgt ctggctacca aaattgatct ggtagtcaaa acttcttggt 14340
aaagttatca gtatagagac ccaagagaaa caaataagaa gaatctgcta ctaaattttg 14400
gcggagttga gaaatttttt aatttgagct ttcactctaa gagataagag tctgtgacca 14460
attgtattgt gtgttttgca ttgctatgaa ggaatgcctg aggctgggta gtttataaag 14520
aaaagaggtg tatttggctc agagttctgc agcctataca agcagggcag cagcttctgc 14580
ttggcttctg gggaggcttc aggaagcttt tgctcatggc agaaggcaaa gagggagcag 14640
gcatgtcaca tgagagggag caagagtggg ggaggaggtg ccaggctcct ttaagcaacc 14700
agctcttgca tgaactaata gagtgagaac tgaatcatta ccatgaggag gacaccaact 14760
cattcatgag agatccgccc ccatgaccca aacacctccc accaggcccc acctccaaca 14820
ctggggatga catgtcaaca caagatttgg acgggacaaa tattccaact attcacccat 14880
gttccctaac ttgaagggag ttcacattag gacaagttca ctgaaatctt tgttttggaa 14940
tggggatgga taagacatca tttattaagt tatggttttt agtttctggc tttggctaac 15000
tcaaacaaaa agggaatatt tcagactggt gcttggtaaa tcatagaatg acaaacaatt 15060
ggaagaccag gttaaaatga acttggagga cattaagtga attaagccag gcacagaaag 15120
acaaatactg caaattctca cttatatgtg gaatctaaaa aaagttgagc ttatacaaac 15180
agagagtaga atggtggtca ccagaggctg gggaaggagg agttgaggag atatcggtca 15240
aagcatacaa aatttcagtt aggcaggagg aataaattca agagatctat tgtacaacat 15300
ggtgactgta gttaataaca ttgtgactgt attgaattct tgaaagttgc taagagagta 15360
gattttaagt gttctcactt aaaaaaataa gtatgtgaga taatgcgtat gttagttagc 15420
tctatttagc catttcacaa tgtgtatgta gtccaaaatc atgttgtaca tgattcataa 15480
atacattttt atttgtcaat taaaaatacc ctggaatttg ggcaacaaaa gctatctgcc 15540
caggtgggaa caaatcgcct ctgagcatct ttccttcatt gcatctctaa tcaagataga 15600
aagtccctgg agagagggtc tgattggaca agcttgagtc cgatccctat actttggcta 15660
tgagaggaat attcttgctg aagtcgtctg tgatagaccc tgtggatgca tttggcttgg 15720
aaatacgaaa gcgccttgat ttagaatccc ctcaagtctg tctgttcaca gtgggataat 15780
ttttattctc ttcctctcca gaaggaatca aggggtgtca taaaggaggt atgtctgcta 15840
agcagaacta cctcccctcc ccaaagaaag tctgttacca tgtatacttt taaacatttt 15900
attttaaaat aaaattagac tcacaagaag ttacaaaaac agtacagaat tgccatgtaa 15960
cttttaccca gctccccaca atgataccat cttatataac tctagtacat tattaaaata 16020
tggacattga caccggtaaa atactattaa cagaaccaca tactttattc tgcttttgct 16080
ttttatttta ttttattatt ttattatttt ttgagacaga atctcgctct gtcacccaag 16140
ctggagtgca gtggtgccat tgcaacctct acctcctggg ttcaagcaat tctcctatct 16200
cagcctccca tgtagctggg attataggtg cccaccacca tgcctggctg atttctgtat 16260
ttttagtaga gatggggtgt caccatgttg gccaggctgg tctcgaacgc ctgacctcaa 16320
gtgatctgcc cgcctctgcc tcccaaagtg ctaggattac aggtgtgaga caccacgccc 16380
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
agcctgtttg gcattttttt aatacgtgct ctataatatt gatttttgtg taaacatgtg 16440
tttgtatata tctataacga gaactcaagt catactgtaa tcctattttg taaactgact 16500
tttttccttt atcagtatat caagattatt ttcccacatc atttgacatt ttttctacag 16560
tgtaatttaa tggctacatt gttttctatc ctatgaatat atcaaaccta tttcttaaaa 16620
accctactca gggattttaa aaaataaaaa cgatgtttta atattataaa gattcagtga 16680
ggtatattct tatacgtaca catttctaag gtttgagttc ttacaagatg ctgaactagc 16740
taagactact ggttctcatc tgtcacatag ggaaaaatta tagaaggaaa acatcaagat 16800
ttggaaaaat ctgtgagaat tgttttgcat tagtgtgtag gtgtgtgtgt tggggtggtg 16860
gctgcagctt ggggcagagg cctcaggtgt ggctgtggag tgatcagata gagtttttgg 16920
agttcggctt ttgccccagg acacttggtg cctgccccca gagctgcagc ccagaaggcc 16980
gttctcagag gtgaagtcca ggcagtgagg agctgtctgc cagtaggcag ttgaagaaaa 17040
aaaatgagct agaggaaaaa aacaaaaaaa caaaatctcc ttctaatgct gccaggctgc 17100
cgggagctgg aaatgaagca ctgacaggag tgggtatttc atggtgaagg gaataatcaa 17160
ctggtttttt tggtacccaa gactttccac cttcacacac acacatgaga tgctttgaaa 17220
taaagatagt cacttgactt agtaaagttt gttgacataa aaatatgaga aataccaaag 17280
aatacaaaaa ggaaaacttc gttaatatta ttcagactta aaattccaga ttgtatcaac 17340
attaaggggg ttgatgaaaa catgggagaa agccaaggga cgtgagatcg ggctcaattc 17400
ttgacttgct gggggaaggt atcaacacag aacttttaag aattagaagg cattaaaaag 17460
aaatagaaat cctgaatcaa attgaaacag taaaataaaa tagtccaaag atgtgtaaat 17520
atatcactat cacaataact ataaataggt taaatttgcc agttgaaaga aaggaactat 17580
taaatgagat tttaaaaatt tggatatatg cttttcatgt gaacatacct aaagcatata 17640
cacaaaacca gaaaataaaa agatggaaat atccacagag tgacaaagga aagctggtgc 17700
atttgtatta gtatcagata aagctcacat ttagataaaa aacattatag taatagagaa 17760
agtcacaagg ttaaagtttc aattcaccaa gaaatatcca ttctaaacat gtatacatac 17820
ccaattaagc tgcctcaaaa tatatatgac aaaaattggg agaactataa agtcagatat 17880
aaggattgaa aagaaagaaa tgaaactaat tattttcaga tgatatacac gtttacatga 17940
aaaaactcca aagaatcttc aggcaaatta ttagaaattg taggagagct ccgcaagagg 18000
gctggatata aaattaatat acaaaagtca atgtcatttc actataccag aaaaaagaca 18060
ataacattag aaaataaatc taacataaga tgtagaaaaa cttcttagag gaaaaatttt 18120
cttgggaaat attaaagaag atctaaataa gtagaattac ataatattca tgcataagaa 18180
ggcaacattt tgaagacgtc ttgttataca taggcctagg aataatatag ttttaagcta 18240
tattattttg aactgtagat gaagaaaagc tctttttttc cttgagtatt ttaagatttt 18300
gaataaagtc atattgctct aggaatattt tatacttctg ccagcagtgt ttgagaatgc 18360
ctacttccta cattatcacc accataaatg tttaaaacct gatagcacac agtttaaaaa 18420
atttgtaatt ctccaattaa cagtgacctt taaaaattat gtttactgat ctctattatt 18480
ttgtcctttg taaatctttt attagttttt atgttcacat gttccgtttt aaaatagact 18540
tttaagagct ctttgtatta agaatattaa ggctttgtcc atataattag tatttttcag 18600
aatacccttt ctaggtacag tttttcagtt ccagtgcaca gaatggaaac ttgctacctg 18660
ct acaccaca ttttcactag tatgtgatgt attcatcaca aacaacagta ttggccaaca 18720
ttttccctca ctgtgaagtg cacatttgac atcctttaga aaaattactg acggttttga 18780
gacgattgtt ctgtgctttc tttcagtcag cataattttc ccgaaagcag agatgactct 18840
tccagacttg ctaccaatgc ttgaacaaac tgtgtaagct tagtccaaaa aaaatatttg 18900
attaatagat tttattttgg tagattctaa ggttccaagc agtcagagaa ataatcgcag 18960
agcctcaaat atctccaaaa tctgatacca atccttttga ttgtgaatta tattctgtag 19020
ctaccaaaga aggtaagttt ttattttttc tactctatta actttccctt ggacaactga 19080
atattaagat gactatgtaa ggaggttatc agaccaaggc ctcacacatc aggataaaag 19140
cacatgccat agaaagaaca tttgtgtctc aaaaggtgat accaagacaa ggctgtggga 19200
tatatatggg cacaatggtt gataccttca aagacttcat acatggtgtg gaggtttttg 19260
gagattttaa tttataatga caatctttcc agttaggaga atttttggac tgtaaagtta 19320
gccaaacaac ttttcaatga taataaatgt ctatatctta,cacaggggga atacagtttt 19380
tgtttgtttt agttttttct ctgtctattc atataggggc atcatatgtc tttatcatta 19440
aaaactgatt tagataggca gttgtagaga aatttaatgt gtgggaattt aaagttttaa 19500
aaagatgtag caaaatatag atacatttaa gacccactgc accaatgaaa aagggaaatt 19560
aattaaacta gacaactttt atgggtacta accattaaaa ttaaaatttt agtcattgta 19620
aattacatta cattataata gttttcaatc tattgttaag ttaaatattt tgggtaacaa 19680
ttgtatttca cagttgttca cactttgcat aattttctaa ggaaaatgag tcccttaggg 19740
agaaaattgt tcttaaattt tattgttgga taatgttgct gtactaacat ggtttactga 19800
agtggatcta ccatgggtgt ttaggttttt gttctttaca aaatgtattg ggtgaaattt 19860
tccatatcac tggtgaactt ttcatgctaa ttttccagtc ccttagttta aatattatgc 19920
attttttcct gcaaatctat cttgaatctg aaaaggcccc agaaggaatt agcgtgagtc 19980
cagagtagat ggactgcaaa tgttacacat atttcaatat gtatccagct ttcaaaaata 20040
6
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gcttattgaa atcaaggttg aaccacatga aattttgggt ttttttggat gtaaaaaatg 20100
gttatatatt ggcattttca tatcatccaa tctaatatct tcctctagtg aggttctggc 20160
aaaaaaaaag tatgatgacc agagttgttc actcttttaa gctttatgtt tcaaaatatt 20220
tttaaaattt aaaaccatct aagtgcatcc caaaaaacat tggaaaattt tgtaggctag 20280
ttttgtttaa tgatttttct tctatagatt tatttttatg ctatgcctta ctctccaatt 20340
agattttagc catccaagaa aggtaccttg tacttctaag cgattctccc atcacctgga 20400
cgttaactgc agcccacact gcagtgtctt gactgcagta ggcactcagt aaatatttat 20460
tgatggtcct gattatggga tgatgaaata tgctaaaggt aacttaaact tttgtcaata 20520
aaaccgagtt tcaggttagt ttgacctttt ccgtatctct aaatattttc tttcatgtca 20580
tttttgtgaa atagctcacg aaagtactta ttgattctga aatccttttc ccctctggta 20640
ttcctgagct atcctcactc acacacagca caccagtgct attgtttgct gttttgttaa 20700
aatcattctc attaatattc ctcattcaat aaaaatagtt gattcccact tatgcaccaa 20760
actctattct aaagactgct gtttatttta tggagtcaat atcatcattt tgttttccat 20820
tccacataat agttggatgc caatatgaag tgtatattta taaataatat gtgctttttt 20880
tatttgttta tttttatttt actttaagtt ctgggattaa tatgtgcttt taacattatt 20940
gtttaaaaat aacaggagat atcatatctt aagcaccttc tatattctgg gcactgttct 21000
aaatgtatca aagttatcat ctcatttaat ccctccacac acctgaggga agagagtatt 21060
attccttatt tacagataag gaagctgagg cttggaagat tcatatatct aagatcacaa 21120
agctagtaaa gcagccaagt ttgagtctaa atccaggttt taaatatcat attgcatgtg 21180
ggcatagatg agcaagaaca ggttttcctg aagatggcca gtctaaggct tagaagaagg 22240
aagctcgggg agcctaaacc aagatatgct aaggcaagtt tttttgctcg tttgtttttg 21300
agatggagtt tcgatcttgt tgcccaggct ggagtgcagt agtgtgatct cggctcaccg 21360
caacctccgc ctcctgggtt caagtgattc tcctgcctca gcctcctgag tagctgggat 21420
tacagtcatg tgccaccatg cccagctaat tttgtatttt tagtagagat ggtgtttcac 21480
tatgttagCC aggCtggtgt CaaaCtCCtg aCCtCaggtg atCCgCCCr'3C CtCagCCtCC 21540
cagagtgctg ggattacagg cgtgagccac tgtgcccggc ctgctaaggc aagtattgac 21600
cattagagga gatgactagt cccagtggca ggcctttcct actgggagtc agccaagagc 21660
tCCCCdCtCt tCtggttCCa ttgttcctcc tgcaaagttc cattcataaa gtggtttccc 21720
atttgattgt ccaatgatgc aaatctccag tcctttttag cactgagttt ctcatagcct 21780
tttaccattg agtttctcat ggctaatgaa tgctaatgaa ttggcattcc gatttatcta 21840
taggattcca tgagtcagcc tcatgaaaga aggttccact ccctcactgt gggtaccgtc 21900
tgggaattag acccttaata ggagtaattc agcaggcaat gtcttctcta ataacactcc 21960
agtctcactg agagcttcta ttcaaaacaa caatctaaag gtctacagtg tgactttcaa 22020
ctaaactgaa aaaagaatag aaaatgaatg tatgtgatgt acacattcat tcaaatgttt 22080
atccctaaaa ttcatagcag attatgactg atcattaaag ccaaattaag ggggcaaaat 22140
gtataaaaac aaaaggaact cttaggcata atagtcttta aagtaaaaca ttactactga 22200
cagttgcttg tgtgaaagat atctttattt aatatggtaa aaagaacaca ggaattgcta 22260
gcacttaccg tatgtccatt ttatgtccac cttaaaatag atatgtctgt atagtcatca 22320
gattagcact ttagaattca ataatttcaa agaaatcaga atggacattc attacatgtg 22380
cttatctggc aggagaattg aacaaatcct ttctatagga aaatgtaaaa ttcctaataa 22440
ctccacagga ttgtaagact tgggctggta acttcagtga atacagcaga gtttgggcga 22500
tgggaaaagg tacagttgtg ttcctaaact cttaactttg tgaggcagtg actttatttc 22560
ttcttcatga ttttgcagta agttcagtac agtggttagt ttcagtatag ttcagtggct 22620
aagcttttga gagggacagt tctatgttct aactcaactt ctgccacttg ttagaaagtg 22680
actcttgtca aactattggc cctttcaaac ctcagtttct tcatctgcaa aactttattc 22740
atggggttgt tgtgagggtt aaatgaaaaa tatgtaaaac tcatcaaaat tttaageaca 22800
aaataccaag tctcagcaga acacatacag taggagtcca gccattaaaa tttgaaacag 22860
gcagaggcaa aaatattttg tttagaagta cttgcatttt ctagctcttt ggctgagtgg 22920
acaacatttt ggtgttcttt ttcttattgt tattttttaa agcatacgta tatgttatgt 22980
agactctttt gtatgtatat ttaactcaca ataaatattt ataaatagaa agaaagatat 23040
cacatatatg tgcacataca ctggtaagcc ccaatacact gcctcatttc taaatgactc 23100
tagcatttgt aggacagtgc ttttaaacct ttcgcactca cgagatactc tggggagctt 23160
taaaatatat gctgatgctt gggctccact tccacatatt ctgatttaat tgattagggg 23220
ttcggctcag gcatcagtat ttgtaaataa aagcttccca gctgattcta atgtgaagtt 23280
aaaattgacg gatactgata ccgataaaag agtgagtgca atagacacaa aaca.aaatag 23340
gagatgtgtc tcaaCaatgg taagattgtt ttaaaaatta tagtacaatt aaaaaaataa 23400
tgtaatgcaa ttatttagaa aattcttaca attttgtatt ttgaaagcac catgtggata 23460
tcatggggaa aaccagaact ttgttggatt tccttaacaa agattttgca gcttggtatc 23520
atttccattt tgtagtattt tgatatccag gagatgaaag tgggaagtgg acaattgcct 23580
ataaggccat gctttgcacc agggtgtcca gatgagaggc aagtggaggg taaagtttag 23640
cctgcattct gttccctaag gtacatctcc tggtgagggg tggcttctaa tcaggggaag 23700
7
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
aagtcctatg tcttgtttcc taatgcacgc acaggttcca caagccctca ctttgttctc 23760
aagagcatag catttatttt ggtgcttaag actgctgaat gtcacaaaat aatttttccc 23820
agcacaaaca aatattcaaa atagttatgt gcacagcctg tttgagcacc aataagtttt 23880
ggctctgtgg cctgtttggg cactgacatg gtttggctct gtgtccctac ccaaatctta 23940
tcttgaattg tgatccccac atgtccaggg agcgacctga tgggaagtga ttggatcatg 24000
ggtgcagttt ctcccatgct gttctcatga cagagagtaa gttctcagga gagctgatgg 24060
tttaaaagtc tttggcagtt tccctttctc tccctctc'tc tcctgctgct atgtaagacg 24120
tgccttgttt cccctttgcc ttccgccatg attgttttaa gtttcctgag gccttcccag 24180
ccatgtggaa atatgagtca attaaacctc ttttctttat aaattaccaa gtctcaggca 24240
cctaaaccaa ttagaaggtg tgccattggc acacagcagg gtcctggtgt ctcccccacc 24300
atccagccac cactctgcca ggtgtgaatg tattaactat tgctggagtg aggtgaaagg 24360
aggcagtcct gcagaagggc cactgccact gggatggcac aggagggcgc tcgagagact 24420
caccttagtg actctatcaa ctggtgaaaa tatttagata ttttcacaat caatatggcc 24480
ttgcttgtat atacagggtg attataaact ctcttgccac ttatcacaga agtcgaagtt 24540
tcatcatttc ttttcctgta tttggtttat gtgcaacaat ataggtttat tttccagttc 24600
tggaaaataa tcatggttaa tactgactga gaactgatca tttcctttcc tctttatacc 24660
aaccaatggg gcaggtacca ttattaaagg gggaggaaat agaggttaaa taacatgccc 24720
ccaatcagta gtggggaaat gaaagaatca ggattcaaag ccaggtttgt ctgggtcttg 24780
ggaccagctc agcgtctgtg ctgtactgcc cgggactcct gctgccaatt ctttctacct 24840
cattatccct caaccctgca ccagcaaatc cacagggcgt gagatgaaga gaagagagga 24900
ccacaggcga gaaagtggca gcagcaagag aagatgtacc atgaggaagt tctgggaggt 24960
tctgcccgtc tttctgagaa caggggagag acagagctga gttacaactg cactgcttct 25020
tagcttctta gtttctcttc agaattagtg gcaaagaaga gttttcgaag tctttagcat 25080
gtattaaacg aagaattttg tttataagaa aaaattgtgg atcgttccca tgtttgtctg 25140
gaaaactctt gttaaacttt tgtgcagcta gtaaattaag tcactgttta ttctgtgtag 25200
tggaaagcat gcttaaactc taactcagga gacctgattc caggaatagt taagcctgag 25260
ttcattataa accacttaag ttatctgtgt cattattcta gtctgttaaa tggagggctt 25320
gagctggttt cttgtaaggt gggatttggc taagtgctct tggatacagt tgctcacctc 25380
tttgagcctc agctttcttt ttggtgatta tttaatcgca tgtgataaca aatacagggt 25440
gttttgtgta atgcctggaa tggcactgag attgtctcca ctacagtaag gaggtggttt 25500
agaaattagc taatttatta attaatggcc tatagagctt catgtaggtt ggtacttcaa 25560
agtcccattc atatggatca tgttcatatt tatatattca tcacttttat ttcaaaatct 25620
ctttttctgc tgagatcaac tgagatttct agaaagcagt cctattgtca gcactttgcc 25680
cagtacattt agtaagaact tgactagcat tgactcaaac agttctctta gaagggctgg 25740
caccttttgt ttcaattttt ttaaacatta actgcccata ataattgaag catgaatgca 25800
ctttctttgg attatgaaac aaatcaatca cagacatggg aattaggtgt gttctcttgc 25860
tttgttcaat atcatgcatt ttttttgtct gagctttcac tgtgtcccca gaactgtgct 25920
tggtgctaac agtggcccca cagagtacgg ctttatattc aaggagatga caatcttgtt 25980
ggaggaaaaa ccttatacat agaacaatta aggaacaatg caagggaaac acacattgca 26040
agttttgatt gtacctattt tatggctatg gtataaaaca aagcacctgt tgttcctgag 26100
agtgaaggga taagacaata actacaaaaa ggtgaaatga gttaattcaa aagggaacat 26160
tgagcatgtc attttcctat tgaagtgcta ttatttggta tcggcttcct ttggtggtgt 26220
tggtttttga ttccctctgc cccggactct gttgtttaaa gatgttcttt ctatgaggga 26280
tcttggatgc attttagcag tgtttccact gccctttgtt ttatattctt tgatgccatc 26340
ccaggtacat cacattcttg ctagatgagt aaaggtaagc atacttagaa gtcaaaaaga 26400
aaaggctgaa gtggtgactt agacttgaga aattatagat tccatggaga aaactgtgtt 26460
taaatcacag gacaggctga aaactcacat taccacctga tggaagtgaa ctctactttt 26520
ataggttact aggagaaggt cagccttctg taaaagcaga taaacaagga taccattacc 26580
agagtttcaa gtaatttaaa ttaagaactg aacattgata ctgatatgat ttctagttta 26640
ttatctgtga cagaacccag tagcttattg aaaaactatc atggaagaaa taactaagaa 26700
ataaccattt aaaatatatc aggatataat gaggatgaag ctttagataa cacaaaaagg 26760
caatttctct ttaggctgaa aaataccaga cacagatata tcgacagagt gacctgccag 26820
aatccctact ttccagccca tctgataaag gtcaacgatt gaacacccaa acacgttgat 26880
acacacagca cctgcctgat gaaaaccgtt aacagtgttt ttctcagccc agagtgcact 26940
gttttcttaa agttttgaaa acagtaatct aaatttccct attccatgag taaagttcta 27000
cttttttctt tttcacacta aacagcattc gatgttttag ctgaaagtca attaagaaaa 27060
atgtattgtg tctgtgtttt tcttgctttc ttttaagcac ctctaaaaga acttgttctt 27120
cttcctgaat tgagaacgag gtaggaatga aagactgaaa cggtaactct catcataatt 27180
ttattattat gacaagttgg gtttatgaag tatttttcca attactgcct ccaattgtta 27240
aataggtaga taacatgcca gctttaactg ccaaaaactt gtagtcctta aaatattttt 27300
tgtagtatta ctattagtat catgaacaga aatagcagtg ataaaaatca aatcaagttt 27360
g
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tgtgaacacc aaaattccat ttgcctgtgt gtggagggtg gtttaggatt ggtagaatta 27420
atattctttg caaacggctg cacctagcat ggtcgccttg aagccctggg agttctctaa 27480
ttttcctggc tcgagagact tccattaaac aagaaaatga ggtgggaaag gtcagaggat 27540
tcacagggta acaggaactg gacctgaacc tgagcttcat gcagtccgca gattttttaa 27600
gtggtttgtt ttttagaagt gtttgtcacg acctctaaat cattgttaat ttcatcgtta 27660
aactggcctc agagagattt tgttttaaag agacaatgca gttagaggat cgtgatctct 27720
gaactcagaa gcccagaact ccaaagctgg aagccaccag atcctagcaa gtgaagctct 27780
gtcaatctgg agccgcagat tttgaccacg tgtgcacagc ctcccatctg ggcaagccct 27840
tttctctcca ccactccact ccacagcttc tgtttctttt cttttctttt tttttcgctg 27900
aattcatcat ccctcccttt cccatgccga gacttaaaag gtttcaaata cttcaaaaat 27960
caatgatttc taaatcacct cagatgactt acatacaatg ttttattaca ttttcccaga 28020
gcagaatggc atattaagaa atggttttat tttcaactat attttctctt aggaatatag 28080
agacattatc tcaaattatt acctcgaaga gacagagaca agaattttgc accattctag 28140
ttctcaaatc attttaggta ttttatttca ttttgcctaa atctcttaga cggttatttc 28200
ctcgtatcac ttaaaaatta cattttactt gggcagggcc taaagaatta cattgaaaaa 28260
ctaagaaatt attgggaaaa aattccatta gcacaactat catgatcaga agaaattggc 28320
taatttcagt gtcttttctt tgggctcttc atagaaaatt gttgaaatgt gtctttcata 28380
agtaactggc attctgaaat tgatttaaag ctgtagaggg gaagaaaagc tacattggaa 28440
aaattaaatc ttaggtttgg agatatttta aaaaactcaa caagttccat gcccagagga 28500
gtgcagacac tgaccctctt tttcagctat tagaggtgag gaaaaaaagt tgtgtggttg 28560
gtgtggagag agagagacac acgcacttcc tttagccatc atcctactaa caccttcaca 28620
gtacattttc ttgctaataa tcccaaccat ttctacaggg aaaagtgcat gttcctgttc 28680
tctggtagaa gggccaccca aggaattcag gttcctggtg agtaagaatg acagaagtac 28740
ccacagctcc tgggccattg gtctcctcta tccagcctcc actgaccttg ctgggtccac 28800
tgcagttttc ttcttgattt aactctatga gctctctgtt ccttcaaagt actggagctt 28860
ctggccttag cacatctgtt tctgcagcca gagcaccttc actgagaagc agacctctac 28920
ttggctgggt tcttactcac Cctattggtg cctcttcccc atccccctcc.tcctcctcct 28980
cctcctcctc ctcctcctcc tcctcctcct cctccaggga acatatagtt ggcagcaagg 29040
gttgcagaac gaatgaaggc atgcatgaat gcacatgttg gaggacgaag gttctgtttt 29100
tactctcagt gcaccaaaac ccagcagagt taaatagtgg aaggttctta agtgctcaag 29160
tgagtagatg gaggtcataa ggcaagcaga gtgggaaggg ctagaaggag aagaaaggag 29220
aaagggaagg caggagagga gagaggtggg gaaaatggaa gggtagttga atgtcatagc 29280
aaattagagt tagaagagga gaattagtag aaaacagagc tagagtcaaa aacagagtga 29340
gacagacaga aattcataga tttgctgtct ggcccagatc tcattggata actagagcct 29400
cccttcttcc tttgggttga atggtcttta ctcattcttt atgtagacca tcctttactt 29460
ccacatggag tttgtatgtt cccatagaca ccaatacttt acatatcaga acacttgtca 29520
ttttattaaa aattgttttt tattagtttc ttttcccact agacagtcaa tgtcatggat 29580
gcaggactat agggtcttat Ctttttcatc acagtagccc tcgaacctag cacagtgaaa 29640
gttgcccata atacattact aaatatttgt tgaaagccta aagcactggg caaatcattt 29700
tgactttcca gacttcagga tccccatttg tgagggagct ggtctatttg atacctaaga 29760
ctcccctcca gcacaggtct tctataattt tgtatctaca tggcttcctg cctgatgcca 29820
ggaacttaag atttaactca agaagacagg gatgttgctt gcaaagaccc tgaagatctt 29880
gtcatccaaa ctgtgactgc Ctggagactg tttatacagg atcttgaact gggctaggag 29940
agtgcaatgg atggtagtcc Cagtccttgt ttgcagggag aggaagacag cgacaaagca 30000
tttctatgga aagaaggagt tgctcataag tctactatgg acatcaaaat atgctgatga 30060
gccacagcaa gttcattaca aagggatttc agatagaagc ctcctccttc agagtgagga 30120
ggaagaatca tccaggaaag agagaaatta tgtgtatttc atatattgct gtatgtacat 30180
attaatcagc cagcaaatat taagtgcatt catgggcaaa atgccaaaga gatgaagaga 30240
aaaatcagac tccaaggatc atataatctg attgtggaag aaaggcatat tcatcatgaa 30300
aatgtagcaa agatgttaag tgagtgtctt agtctattct gtgctgctat aaaaaatacc 30360
tgagactggg taatttacaa aacaatttat ttctcgtggt tctggtgact aggaagtcca 30420
agatcaaggc accagcagat tggttgtcgg atgaaagttc agtttctgct tcatgcatgg 30480
tgcctccaga ggacaggaac actgtgtcct catatggcag aaggtagaag ggcaaaagag 30540
gaaaaaccct ttttttttct ttttttttga gatagagtct cgctctgtca cccaggctgg 30600
agtgcagtgg ctcgatcttg gctcactgca agctccgcct cctgggttca tgccattctc 30660
ctgcctcagc ctcctgagta gctgggacta caggtgcccg cccgccacca tgcctggcta 30720
attttttgta ttttttagta gagacggggt ttcaccgtgt tagccaggat ggtcttgatc 30780
tcctgacctc gtgatctgcc tgccttggcc tcctaaagtg ttgggattac aggcgtgagc 30840
cactgcaccc ggccagaaaa actctatcag ttccctttat aagggcacct aatttcattc 30900
atgagggaag ggccctcatg cctaatcacc tcttaaagcc ctgcctgtta atactatcgc 30960
actggcaact cctgagtttt ggagggtgca cattcaaacc atagaagtgg gataagccag 31020
9
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
acact.tgggt ttcctatggg tcctctccat ttggttttcc tgttaaagat ttaaaagagc 31080
agaaacacta ctttattaga gaaagggcat ttgaacttgg cctttgaaca tggcaggatt 31240
tggccactta gagattgggg gtgccattcc aggtagagag aagagcaagg agaatggaga 31200
gcacttggca tttatgagaa tagtgagggt tcatgtcagg ttacatgaag ctgactcatg 31260
acaaattaat ttggaaaggc aggttgtgac caggctaaag gcatctggac tttgctctag 31320
aggaaatgtg aaaccattgc agatttctga gcaagctgtt ggccagagcc gtgcttcggg 31380
gcgactcaca acagtggtag gaagctcttt gggagctggg agagagagag agagagagag 31440
agagagagag agagagagag atgggaatcc aggggagaac agaacaagtg agaaagcagc 31500
tgcattgcgg cccaggctgg ggttgctggt ttctggaaag ggggtagtgt tgggggagtg 31560
gggagagggg ttaaatgtga gcttctgagg aagtacagga ggggtgaatt ccaccatgga 31620
gaaagtattc aataacaagc ctacagagaa gttgaggaag gtggaggagt aaaggacaat 31680
gatgtcctcg agaaacctgc tcatgaaacc tgctcaagta aacctgagga ggcaaaagcc 31740
tgattctaaa gtgtgagaga gcaacagcac aacctgggga ggtggggtat caagtccgaa 31800
ccaagggtga agggcaggga ctcaggtgct ggagtgtttc aatgtggatc ttggggttgg 31860
cacttgcttg ctgagttacc ttgggcaagt tactatgtgg tcttagtttc tgtaaaatgg 31920
agatcatgat gtaaccactt ggtagggctg ttggaaggat ggaaggagtt cagaaacaga 31980
aagctcccag cacagaacct ggcccgtaat aaacagtcta tgtgtttgct atcacgaggg 32040
tacttttaaa gaaatttagt gcagatgagt ataaatgaga cgtggagtga gtagcagaat 32100
caacacaagg tttttcttat aatggatgag agattgtaaa acacatttgc attggggaga 32160
aggacacatg ggagagggaa gaaatggaag acacggaaga tttgttggag gcaaatttag 32220
atccacgaca aaagtacggg agtaagtgca tggggaaaac ttagtattgg agggaggaaa 32280
aatggcctca ctttgcactt cgaataacat ctactttctt tacctggtcc tccaaaggcc 32340
accagggcca gcctctggcc tgtttcttta gccgtaactc ctccattctc ccccgctgcc 32400
atttgcacat cttgcatttt ctcagagctg ccaagatggt cgtggccggg ccttcctcta 32460
gctagcctat cttcctgcag agcccttccc tcagcttctt acttgg.ctga atctgttgtc 32520
ttacccagct ctcactttaa attccgaagt ccttccctga ccgtcaggtc caaagtagcc 32580
attcaacatt ccttacatta cccgtttttc catctttaca tggcattgat cttcacttgg 32640
tgattccttg tttatttatt tattggtgta ctgcctgcct ctcttcacca acgtataagc 32700
ttcattacag cagagacctc ttgcctggtc atcacagtat ccttggctcc tggcacatgg 32760
taggagccca gttaaacgtt tgttgaataa ataaatgaat acatccttct gtaatatgtg 32820
agaaaagtgg gaggcaagtc taggtgaaga aggcacttaa aaaaaaattt ttttttgaga 32880
cagtcttgct ctgtcaccca gactggagtg cagtggcacg atcttggctc actgcagcct 32940
ccacctcccg gaatcaagtg attctcatgg ctcagtctcc tgagtaactg ggattacagg 33000
cttgcgccgt tacacccagc taatttttgt tttcgttttt tttttttttt ttttttttga 33060
gacggagttt cactcttgtc gcccaggctg gagtgcagtg gcgcaatctc ggctcactcc 33120
aatatccgcc tcccgggttc aagcaattct cctgcctcag cttcccgagt agctgggatt 33180
acaggcctgc aacaccatac ctggataatt ttgtattctt agtagagatg gggtttcacc 33240
gtgttgacca ggctggtctc gaactcctgg ccccaagtga tctgcctgcc tcggcctcca 33300
aaagtgctgt gattataggc atgagccact gcacctggcC ggaagacaga ttttgaagtg 33360
gagaggagtt agaggaaatt gagtcatact taattttatc tgaaaatcat gaagtaaaat 33420
aatacataga aagtgaaggg gtgaacttct gggtgtatat attcaatgga aataaaatca 33480
gtgtcaaagg tttctctgca cccccatgtt cactgtagca ttatgcacaa tagtcaagat 33540
atggaatcga cctgagtgtc catcaacaga tgaatggata aagcaaatgt ggtatgtata 33600
cactgtggaa tactattcag ccttaaacaa gaagaaaatt ctatcacttg tgacaacgta 33660
gatgaacctg gaggacatcg tgctaagtga aaggagccag gcacagaaag acaaattgtg 33720
catgatctca cttacatgtg gaatccaaaa aagttgaact cgtagacaca gagaggagaa 33780
tggtgggttg ctggggagga aatggaatgc ggcagaaagg ggagatattg gtcaaagggc 33840
acaaagtttt agttagatag gaggagtaag ttctggagac ctattgtgca gcatggtgac 33900
tgtagttaat aatgatgcac tgtataccta aaaattgctg agcacagtag aacttaaaag 33960
ttctttttaa aatttttatt ttaggccagg tgtggtggct tatgcctgta atcccagcac 34020
tttgggaggc cgagatgggc agatcacctg aggtcaggag ttcaagatca gcctggccaa 34080
catagtgaaa cctcgtctct actaaaaata caaaaattgg ccaggcatgg tggtgggtgc 34140
ctgtaatccc agctacatgg gaggctgaga caggggaatt gctcgaaccc aggagatgga 34200
ggttgcagtg agcctagatc atggcactgc actccagcct gggtgacaga gtgagactct 34260
caaaaaatat tattttaatt tttataaata aagacaggtt ctccctatgt tgcccaggct 34320
ggtctcagac tcctgggctc aagcggtcct cccacctcgg cctcccaaag cgctgggatt 34380
gcaggcgtga gccactgcac ctggacaact tcgaagttct taccacaaaa aaatgataag 34440
tatgtgaggt ggtagatatg ttaattagct tgatttaatc atttcacatt gtatgtgtgt 34500
atcaaaatgc cacattgtac ccaaaaatat atgcggtttt tatttgtcaa ttaaaaaaaa 34560
gagaggggac tataggcaca caccaccatg ccaggctaat ttttttgtat ttgtattttt 34620
ttttttttga gacggagtct tgctctgttg cccaggctgg agtgcagtgg caccatcttg 34680
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gctcactgta gcctctgcct tccaggttcc agcgattctc ctgcctcagc ctcctaggta 34740
gctgggatta caggcacatg ccaccgtgcc cagctaattt ttgtattgtt agcagagtcg 34800
gggtttcgcc atgttggcca ggctggtctc aaacttctga cctcaggtga tccacctgcc 34860
tcggcctccc aaagtgctgg gataacaggc gtgagccact gcgccaggtc atttttttgt 34920
atttttaata gagacgaggt ttcaccatgt tggccatcct ggtcttgaac tcctgacctc 34980
aggtgatcca cccacctcgg cctcccagag tgctgggatt acaggcgtga gccaccatgc 35040
ccgccctaaa ccttttttaa aaatatgttt taacattctt tgtgctcaaa ttcatgatca 35100
attttttttt tttttttttt tgagatggag tctcactctg tcacccaggc tggagtccag 35160
tagcacgatc tcggctcact gcaagctctg cctcccgggt tcacgccatt ctcctgcctc 35220
agcctcccga gtagctggga ctacaggccc ccgccaccac gcccagctat ttttttttgt 35280
atttttagta cagagtttca ccgtattagc cagaatggtc tcaatcttct gacctcgtga 35340
tccgcccgcc tcagcctcca aaagtgctgg gattacaggc atgagccacg gcgcccggct 35400
tcatgatcaa attttgtaaa tggttgatgg atagatgaaa aaaattctct aattgaaaga 35460
cataaggatc actgtatgat cagcaaatgt agataaatga atataatatt gattcacttc 35520
taaaagaaat atattgatgt ctcccactat aattaaattt taatcaagtt cttggacttc 35580
taaatagttt ttgccttata tatttggctg ttttcacgtt tggacgcttc actttattaa 35640
ttattgtatc tcctttgtaa gagtgtacca ttcatattac ataatctctc tatcttgttt 35700
ggtcaggttt tccacaacta atcaaaatgc cttggtatta acgtgactct ttttcaaagt 35760
agcgtggaca attttgctgt catcatgtag tcctgggtct ttgggtttta tctttctaag 35820
actgtagatc tcaatcttga gtttatcaat ataatctata aaaaattcca aattaagcca 35880
ggcatggtgg ctcatgcctg taatcccagc actttgggag gccgaggtgg gagaatcact 35940
taaggccaga aatttgagat cagcttgggc aacatagtga gaccctatct caacaacaaa 36000
ttaaaaaact gctggatgtg gtagcgtgca aatgtattgc cagctactca ggaggatgag 36060
gtgggaggat cacttgagcc caggaaattg aggttgcagt gagccatgat tatggcattg 36120
tactccaggt tggagtacaa actttcagct tgtcactgaa aaaaaggaca ctccatatca 36180
ctttttgcca ttttgtgtgt gtttacacat ctatctatcc acattgtgct taatttggac 36240
tttacaacca agtgattttt ctccattata aaagaaattg catcattttc ttttttttaa 36300
aattttactt taagttctgg gatacatgtg gggaatgtgc aggtttgtta cataggtata 36360
catgtgccat ggttgtttgc cgcacccaac aacctgtcat ctaggtttta agccttgcat 36420
gcattaggta tttgtcctaa tgctctccct ccccttgtcc cccaccaccc aacaggccct 36480
ggtgtgggat gttcccctcc ctgtgtccat gtgttctcat tgttcaactc ccatttatga 36540
gtgagaacat gcagtggttg gttttctgtt cctgtgttag tttgctgaga atgacggttt 36600
ccagcttcat tcatgtccct gcaaaggaca ggaactcatt cttttttatg gttgcatagt 36660
attccatggt gtatatgtgc cacatttcct ttatccagtc tatcattgat gggcatttgg 36720
gttggttcca agtctttgct gttgtaaata gtgctgcaat aaacatgcgt gtgcatgtat 36780
ctttatagaa taatttataa tccttttagt atatacccag taatgggatt gctgggtcaa 36840
atggtgtttc tggttctaga tccttgagga attgccacag agtcttccac aatggttgaa 36900
ctaatttaca ctcccaccaa cagtataaaa gtgttcctat ttctccatat catctccagc 36960
atctgttgtt tcctgacttt ttaatgatcg ccattctaac tggcgtgaga cggtatttca 37020
ttgtggtttt gatttgcaag gaaattgcat cattttccac tgaacctaag ttgcagttcc 37080
attctgccta agaccaccaa actcacctgc cccactgtta taccttctgg atgtcagtga 37140
aagttcatgg acaagagaat atttgtaaaa ctgcattgga tttctgttga gaaatgctat 37200
gttttcaaaa ggtgaaaaaa tgtagacatg tattttcaga ccttttattt ttcaatcata 37260
gcagtggaat tccttgatgg tttatgaaaa taaatgtttt tctcactcct aggccattta 37320
aaaatatata atatggagtt gaagttatta atagaaataa ctaagggtga gagagaatgg 37380
cacttgtact attgagtaca atattagaag caagtgctgt tatattgcca gactatataa 37440
aataacaagt gtttctagtg cactgagtga atgtatggtt tagaaaacat tactaattac 37500
gtgcgtattc attgatttat tcactaagta ctcactgagg gtctactgtg tacctgagtc 37560
tagccagagg cttgtggtgg agagctgagc aggtcaggtc caaacttatg ttcttgctat 37620
ttctttgggt gtgggtggtt ggatggttag ctcagtggtc tcggatgctg gaatttgttc 37680
taataagttt ctgagctgct tcataaacca agagggttag gggaactata gctgagtcat 37740
ctccttttcc tcctcttcct ccttcttccc ctcctcccca ccgtctgtta ctactattat 37800
aggaaatttg aactggaatg aaaaaaaaat cagtgttaca aaaatggtca cattttggaa 37860
taactctaca cttacatagt gtgttctagt gattagaaac aaaaaagcca tcattttagg 37920
ctagattttt cagaatgatc acaatgctac cactgttttg cacttacctt aaaaaataaa 37980
gtgcttcccc taagtttgat catttgcttg ttagcataat ttggccatta aacattaagc 38040
attgtttgag acccgtaagt caagccaggc tatggtgaaa caaaattagc aaaattcgaa 38100
ttgatgccgg aaactggtga agccgccata gatttaagga ccaatttgcc aggttaccgt 38160
ctgcaggttc tgctatggac caggtggggg cagcagagag ctggctgtgg tctccagaag 38220
ggaaggccag cacctgcctg cagattccaa ggcacaggtg gaggtggtaa tgagttacga 38280
ggtagagtca aggtttggac tgcatctgag aagggaggaa agcaagagag ttagaaacac 38340
11
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
cataaagatg agactgcaga gcaagccaga atggaagtag gacaaagaac tggtgtaagt 38400
caaagagcaa aggtgcaggg gtcacaggga ggagaggttg ggtgggcaga caggaggtgc 38460
ccgaaggagg ccagcctgct tcactagtgc cccttccagt accttcccaa ctcggtgagc 38520
caggtccata cttggttctg tttggtcttc caagggctat gaagggacag ggatgtgaga 38580
gacaccagcc atctctctct cctgagctat taataatgaa agttcctgtt ttatgaacaa 38640
atactgaaat gaatggagaa cactcaacaa tttggtagca atcagggtgt ggtagtgaag 38700
cattgcctgg gcttttcctt ctggttcctg caaaggacta aggtcctcag cagcctctgt 38760
ccatcttttc ggagattttt cacaatcacc aaggaaatat agttcagtgc tcctgtttac 38820
ttaatggtcg gctacgcttg aaatatcatg ctctccctgt gtggtcttgt cataattatt 38880
ttcaaatggt gctaattagc agacccaaca catgggcagc cttccttccc cagacttggc 38940
accctcactc gctgcattta gcacccctcg tgggaaggca tcctggagat cccttatctg 39000
caccctgtct ccatctaccc cttcccactc gcggaagctg cctcaccaga gaaactgcta 39060
tctgataaag aacatcaaca agtcctagca gatggctgct tatctcaaga cacatatatt 39120
caccaaaatc ctagcagaag aaaaagctgt gtttggatgg tcc~ctgagag ctaactataa 39180
catgttcaaa ctgtgtaacg cagtttggag atggagacag agtatggaga aagaaagaca 39240
aagggagaat acccaaaaga ggttttggaa aagaagaaaa atttgttctt tatacatata 39300
tatccataaa gatgagggtc tcactctgtc atccaggctg atctcaaact cctgaactga 39360
agggatcctc ctgcctcagc ctctccagta gctgcaacta caggtaccaa gctgagcaag 39420
aagaaaaatt tgagttaggc tttagaacat caaactaaga ctctgatttt cttgagaaag 39480
tggatagaaa atttgtggtt agagatgaca ccagtaacga taggtttcta ctcttagcta 39540
tgcctggggc agcttgaccg ccactttgtt gatcacatta atttacctct tcctgccttt 39600
atttcccttt ctgtaaaatg ggaattaatg tgcttgatga caatatctcc aaatgatttt 39660
taaggcaaga agagagaatg ttactgacag gcccatggtt ctctgggtga gagggtcact 39720
gtgaatgaat gtacacacag agccttttat tagtgaggct tagggtgtcc ggtttttctt 39780
ggcggagtaa acatccaccc agtagtattc actcagtttg cattgttctg tcgcattgtt 39840
tgtaaatctt ttgagtgatt acgcagcatt tgttccctat tgttcataat actctttaaa 39900
aagctgacta taggactcca gtccccactg gtttgttctt tgccacttgg caaaggttga 39960
ttgattttat ttttcctttg gcctgtgctt cttagtggct tgaaatgaac acggcttttt 40020
ttcctgttta cccctttgcc cacattgtca ataatagagt cgccctggga agcagagttt 40080
gcaaagggag gagggtttgg tataaatttg gaagattgta ttgtttcaga tttattttct 40140
caaatgctga aactgcttct caggggttat acttctttac tcatgaaaac tcacacattc 40200
tcttaggtgg tactgttaaa catgttacat ctgtaaaaaa attaataaaa cgtaatgaaa 40260
gaagcaggaa gcaagtgtat acacatggtg gcctgagcaa ttggctgtca tggtttggtt 40320
tgattatagg tgtgtgaggc acatgtatgg tgttgcgtgg aacagatgga tagaagtggt 40380
aaaaaagatg aatccaacct agtgcttttc aattctcctt gcacatgaga atcacctgga 40440
gaattaaaaa aaatacattg atgccgactg ggcacagtgg ctcatgccta taatcccagc 40500
actttgggaa gctgaggcag gtggatcact tgaggtcagg agtacgagac cagccgggcc 40560
aacatggtga aaccctgtct ctactaaaaa tacaaaaatt agccaggtgt ggtggtacac 40620
gcctataatc ccagctactt gggaggctga ggcaggcaaa tctcttgaac ccgggaggca 40680
gaggttgcac tcaaccgaga ttgtgccact gcactccagc ctgggcaaca aagcgagact 40740
ccatattaaa aaaaaaaaaa aaatttgatg cctgagtctc tccccaaaaa tcggaacatc 40800
tgtgggtgtg ggttcggcat ggatatttgt aaagtctccg tagctgcaaa gccaagttgg 40860
gaaccactga taaccaacag aaaaatgctt ctggaagtgt ttccggggaa ggagtcctag 40920
cctaggatca gacacctgtc tgggctcaat acaaaccact ggtttttttt ttttttttct 40980
gagatggagt cttactccgt tgcctgggct ggagtacagt ggcgcaatct cagctcactg 41040
caacctccac ctcctgggtt caagcgattc ccctgcctca gcctccagag cagctgggac 41100
cacaggtgca tgccaccact cctggctaat ttttgcattt ttagtagaga cagggtttca 41160
cactgttggc caggatggtc ttgatctcct gaccttgtga tccacccgcc tcggcctccc 41220
aaagtgctgg aattacaggc atgagccacc acacccagcc accactgggt tttataaact 41280
ctcagtaggc ctcctcttct ggcctggtcc catgctatct gacccttctt gacattcaaa 41340
aaaagtattt ttctttagtt gaactccagg aacatgaagt ggcattaaac agaagtatga 41400
attgccttta ttaaaattgc agtggtcttt ttcttaccaa aggtcctgac ccagttgtgg 41460
aaaaattgtt tcttgaatgt gggtgacaca tctgtttcat atctccaagg caatgcctca 41520
gagccaactc ctcccccgtg tgactcaagg atgccacgtg tcccacatgt ggcctgtttt 41580
cttctcttaa catggcctaa aaggccctta ttgaactccc gttagcttta tttatttatt 41640
tttgagatga attcttgctc cgtcacccag gctggtgtgt ggtggcgcaa tctcggctca 41700
ccgcaacctc cgtctcccag gttcgagcaa atctcctgcc tcagcctccc aagtagctgg 41760
gactacaggc gccttccacc acacccagct aatttttgta tttttagtag agacagggtt 41820
tcaccatgtc ggccaggcca ggctactctc aaattcccga cctcaggcga tctgcctgcc 41880
tcagcctccc aagagctctc cttagctttg aaagtaaaag ccaacccctt ttggctggcc 41940
catgaggccc cacacacctt agcattcctg ttacctctac cacctcctct cctaactctg 42000
12
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ccctttgctg gtgccaattt gactgcacta gtgtcctttt tgtgactgca gctgtgcctg 42060
ggacactccg gtctttgctc ttgctactgt tctgagctgt ttatgtccag aatgctcttc 42120
cagcagttag ctacttgttt cctctgagtc ttcaggtagc tgctcaatat cagcttctca 42180
gtcaccctgt ctgatcacct ggcttataag tccagtccct acccttgtac tccccatctc 42240
taatccctgc ttaatcatcg ccttagcact gtcaccatct gactttcttt ctatatatat 42300
tttatttatt ggttagctcg gctgcttcaa tagataccat aaactgggtg gcttaaaatc 42360
agacatttat ttcccacagt tctggagggt ggaaatctga gatcagggtg ccagcatggt 42420
ctggttctgg tgagggcctc ttccaggtgc agacagccac cttgcttttt ttcttttctc 42480
tttttttttt ttttttttga gttggagtct cgctctgtca cccaggctgg aatgcagtgg 42540
tgccatctcg actcattgca atctccacct tccaggttca agtgagtctc ctgcctcagc 42600
ctcccgagta gctgggacta caggtgcaca ccaccacgcc cagctaattt ttatattttt 42660
agtagagacg gggttttgcc atgttggcca ggctggtctt gaactcctga cctcaagtga 42720
tccacctacc tcgacctccc aaaatgctgg ggggtcgtga gccaccacgc ccggccagat 42780
ggccaccttc tccctgtgtc ctcatgtagc agaaagagat caaagagctc ttttgtttct 42840
tttatgagag cactaatccc atcacaaggc cctgacctca caacctaatc accttccaaa 42900
ggccccactt cctgtcgcca tcatattggg ggtttggatt tcagcatatg gattttgggg 42960
ggacacaaat ctttcagtcc gtaatagttg gcctcctccc ttgttccact agaatataag 43020
cttcaggagg tcagggatct ttgtctcttt tgtttacagc tatgttccta acacctacaa 43080
caatgcctgg cacatggtag gtgctcagga gataattatt ggatgaaaaa aaatgaaccg 43140
gtctcctcct taacccctga aatcctgttc gagtcgctgg gtttgccttg ctccactggg 43200
atgaagtcct ggcttggtgt ccttgtctcc caggggtaga cgccccgtct ctgggaggac 43260
ttgaggctct cctggcctgc tgcttggcct ccttacctgt tctgcccact cagagccctg 43320
ccagctgcct gggatggctg ccgggcacgt ccttgttcct gctcagtcaa ccagttgggg 43380
ccttggtttg gaccttcact tattcttctg tgaacctacc tctctggtcc ccagctcgtc 43440
ttctgaaatt ttgatgtgtt ggtcaagccc agtcttgttt gcacatccct gtgaatgatt 43500
cttaattata tttctggctg gctctgtgca gtagaccata gaaataacga ttgtttctgg 43560
ggttgcgctg gagtgtgaac aggtggggaa aatgcctcag gacgattgga ccgaggagac 43620
tctgagatga ctgatgaaag cgacagcaag agctttccac gctcctgatg gcaggagggg 43680
acggcggtgc tgaggggtgg gggaggctca gggggagctg ttgagggtcc cgtgctcgtc 43740
aattctctag cttctcaggc gccttgatct tgtcatttag aagcctctgg aagcacaggg 43800
actgtggaaa ctggaagctg ttcttggact atttcgcaac acttttctcc aggaaaaaga 43860
aaaaataaaa aaaagcctca ttctcttcgt ccccaatgtt acataatcga acatttcccg 43920
tcctggttga aatgaatatc ctctttgcct gaataaataa tgcacagatt cttcgggaca 43980
ggctgcttcc tccaggccgc cgcttccaag ggatccggtc gctttgtggg tttagtggtg 44040
gcccacagct ggacgcgggg tccagcttgg ggtgggggag gcggtgcttt ctgccaaaat 44100
gtcttttaaa cgtctcaaca agtagcaaac aaggccccac ctgcgacagt tgtagtgatt 44160
ccggaagacc tgctcaccac gaggtgctgg ggtcgcttgc agctggcagt ctccggtggc 44220
tgcagtttaa ataaatctcc taagtgcaga atcaccacac agggcgcgga gaaactgaaa 44280
agttaaaaca tctggagtta caaacactca caggcctatc agctgtctga gtccccgtag 44340
gaaaactgtt tatcggatgc tttagtattc aaccttttat ttcctagcac aggttttttg 44400
attttcacat ggagtgtttg attattttcc catgcccaag tcactgtttt catagcctgt 44460
tgtttaatct gtgtgcacct ttgttttcac tctatttcct ttgctttcct atatgagaaa 44520
aataaatggc accattgaat tgcacggtag aggctgatgc tattccaggt gctcaggttg 44580
gctttcccat ctttcgtttc ctcctgtagg aagttttttt tggtataaag ggaaggacag 44640
aattggatct ccctggaggg agtttcatgt gtttcttatt ctgagctgcc gggagctggt 44700
tcacagcaca acttgataat tgctgagtag acctaaagtt ttgaaaatca agatctcttt 44760
ggagttttac aagtaaaatt tcaaaaatga gaaatgacta tcccaattta ttttagaaga 44820
aaggtgcagc ttgtaaactt tcatgaattt ggtaaaaggg ggctaatttg aaaaggaaaa 44880
ctaataggca atatttacaa attgtgaaaa atatcagaat agtatacgtg gaagagttat 44940
tagacattcc atttgcagtg gtaaacccat tcctttgatt ctgaatcttg tttaggtttc 45000
cttaagaatt tgatgaagtt ttcagactct tccttcagaa aaatgcacat attcttatgt 45060
acctaaatgt ttggatatga tttcagggga ttccaaatcc cctggggacc ccccatgtgg 45120
atgtttgtga tgcagaatgg ggtaagaaaa ccaggagagc ctacaaaaat tttatgaaat 45180
agaaatatga acatacagta ctgagccaaa atttagttgt gaggaaaatg atgttaaatg 45240
cattcatttt ctaaatgatg acagaaaatt agactcatat tactatccgg gtgaagcata 45300
ttttgtactt atggtgacct agtgatccaa atgcctgctc tttggtctta tcctcttatc 45360
ttccttatgt caatactggg ctgcttaaat atgtactgtc tccgatgtca ttatctagtt 45420
ttgttctttg ttttctatgt tttatctttt acttcttgtt cctatttcaa atactttgac 45480
ggtattggga cttggggaca tgtcctttcc agtacagatt ttggtattgt agagggaggt 45540
ttacaagccc aggtgggtgt acttggggac tgaggctgct cagtagccct gtaaatggtc 45600
agagtctgct gtttctgttg cttggagagc aaggtgaatg caggtctctt tggatattgg 45660
13
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ggatgataga gggatgtgga ttggagagga acaggacttc ctgccccctc aatttaaatg 45720
gagattcatt tgatcaaaaa aaaaaaaaaa agcacatata ttcaccaggc cctgtgtgaa 45780
ctaccacctt ggatgtaggt ggagtaagcc atattcccag gtagcctgca atcaactgca 45840
atccattggt ggtaggaggc atgggagata cagaagtaac tcaggactag attgaattgg 45900
ccacttatct aagagtgtta tcaagtgttc tgtaaatgtg tgaattctga ttagttatca 45960
ggttgtcata catttttttt tctttttttt tttgagatag agtctcactc tgtcgcccag 46020
gctagagtgc agaggtgcta tctcaggtca ctgaaacctc cacctcccag gttcaagcaa 46080
ttctctcacc tcagcctcct aagtagctgg gattacaagc atgtgccacc acgtctggct 46140
attttttttt tttttttttt tgtagtttta gtagagatgg gatttcacca tgtggccagg 46200
ctggtttcga actcctgagc tcaactcatc agcccacccc tgcctcaaaa agtgctggga 46260
ttacaggcgt gagccaccac acctggctac gtgtcataca attcatttgt ctcccttcct 46320
agacacaagc tcctcaggat catatgtgtt cttccttgct ggcacagagg agatgcttca 46380
gtagtgcttg ttgctagagg agaagggtac aagtggcatg tggagagatt cagagaaggg 46440
tagaata'gga tgatgttggg ccatcaggaa ggtctccatg gagaaggtgt gctttgagat 46500
gaacactgag gaagtggtgg gatcacacct gacctagata gagaaggggc tgaaatccaa 46560
gcataggatg gtgggagcag ggaaagagag gttgactgaa gttgaaggct ggagaggttg 46620
gctggagacg ggtgatcagg gatatggtaa gtggtttgtg cttaatttaa tcttgcagta 46680
acacggtgag gatgattaat cgggaacata atctggtgaa ggtatgttgg acggattcga 46740
aatggtagag gctgtcggca accagaccaa ttaggacacc attgcaaaag tccagctgag 46800
agctgaagag gatctgactt gtgacaggga gtaggacaaa caagggatgg aggctggagg 46860
tattttggag atacagcctg cagttcttat aatccaaact tccccagaat atctcagccc 46920
aggaataaaa ataggatgaa aacaacaata acacaataat attttatctc tgctttctat 46980
caactgtttg caacctgcaa ttctttctgg ttcttccttc ctgcggggcc aggtgaacag 47040
gcaggtgctg aatatcactg ctgggctcac agaagccccc agtgctgggg ggccaaggct 47100
gcggctgctg gtgccaatca aaggcaccca taggcaggac cctcttccac taggtttcat 47160
tgcaaacggg aagcctcaag gcaggcgctt tccactgcta atcggtacct ggtacaggaa 47220
ttaaggcttc actttgtttg ttctgagggg tttacagaga tttttcttct gtaaagccac 47280
tgctcctttc actaaaattc cggagtttgt gcaagctggg aagttaaact tagcaacaga 47340
gtctctgctg tatttaaata tcatttttgt ctgacactgg cctccttttt tttttttttt 47400
tttttttttt tttttttttt gagacggagt ctcgctctgt cgcccaggcc ggactgcgga 47460
ctgcagtggc gcaatctcgg ctcactgcaa gctccgcttc ccgggttcac gccattctcc 47520
tgcctcagcc tcccgagtag ctgggactac aggcgcccgc caccgcgccc ggctaatttt 47580
ttgtattttt agtagagacg gggtttcacc ttgttagcca ggatggtctc gatctcctga 47640
cctcatgatc cacccgcctc ggcctcccaa agtgctggga ttacaggcgt gagccaccgc 47700
gcccggccac tggcctcttg tccttagagg aaatatgtga atttctcctt tctgctcaga 47760
agtacacctt agtagttgac aaacgtaaac tacccgaagg gccagccttc tctggatcct 47820
acttgagacc ttgcttcctg ctgagaagtg tgtgcatttg tgtatctggt gatcgagatg 47880
tctggaagag tggggagaag actgaggggc agatggggag taagaagggt cagaaagcta 47940
ttttggttca gcagtatcaa taatgttttt gctttaaatc attgtcttct tcaatgttgc 48000
ttcctttgtc actcctgtaa atatgatagc ccatttattc ttctaataga aaatttttca 48060
taattatttc ctcacataag atgtttatgg ctttatatat atgtgtgtat ataaagagga 48120
ggcacataat ttatgaaagc agattttaaa agcctttcta cagatgaaat gtaaagttca 48180
attgcatttt ttcttttgga gatgggtctt actctgtcac tcaggcaaaa gtgcagcggc 48240
acgaacgtgg ctcactgcaa cctcaaacag ttctcccacc acagcctcca ggtagctggg 48300
accacagaca tatgccatca catccagcta attaaaacaa tttttttttt tttttttttt 48360
ttttatttag agacggggtc tttctacatt gctcaggcta gtcttgaact tctaggctca 48420
aatttcttga tttcttccaa aagtattttc tgcttgacat tgtcatttga agaaagatag 48480
ttttaaaaaa atttgaagaa agagactatt tttatcccta taagcttgaa ctagggcttt 48540
catactgagt aaaagacagt atacagtgtc attgaggatg ggtcatatta tggctccgtt 48600
gtcgaacact ctagatctgg acactgaaaa gtggactact gatggatttt atgcctctgc 48660
tataaaaacc agcacctggg gctggacgca gtggctcacg cctgtaatcc cagcattttg 48720
ggaggccgag gcggccggat cacgaggtca gcagatcgag accatcccgg ctaacatggt 48780
gaaaccccgt ctctactaaa aatacaaaaa gaaattagcc gggcgtggcg gcgggcacct 48840
gtagtcccag ctactcagaa ggctgaggca ggagaatggc gtgaacccga gaggcggagc 48900
ttgcagtgag ccgagatggc gccactgcac tccagcctgg gtgacagagc aagactccat 48960
ctcaaaacca accaaccaac caaccaacca accaaccaac caaccaacca gcacctaggc 49020
cctggatgcg tgtttaaggt agctaaacac tcttaggtta cactattctg atgggaaaga 49080
ccaccagagg tgcccttgga tacctggtaa taagggctat agaagaaatt atggaaattc 49140
tacaaccctg tcagtgacta tagccaacca tgcggctata gccagaccct gcaatgtgct 49200
catgggtcca gagcccccta tgtgttatct cagctcatgg gctttctctg ttcctgcata 49260
acttcacttg ctaggaggct ttccttactt tggcctccat gccaccctga gacatgccct 49320
14
CA 02426405 2003-04-17
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tgtcctttgc ggctcatgac ctcagtgcag gtttccaaat tcataccctc agagcttgaa 49380
tgattggtcc agttcatctt tttcacattt ggtcatgtcc taggtcactg gccagtctat 49440
agtttggctg atctttggtt g,ggtgtctca ccatggtcca gttagctgtg atctgaagtg 49500
ggcgtagggt ggggaggttg tatgaacttg agttggttgt tcaagtaaca ggagctgaga 49560
gcatggcaat tttccttaga acgatagtga gtgagtggtc aggtactgat tgatatctcc 49620
aggtaagcag agtttcaatt ttggttgctc ttcacgagga aagccagaag cccagagctg 49680
ttttgctaga gtgatagaac tgagatagtg ttttgagcag tgcccagtgg gaacatcttt 49740
gctgagaaga acgaataaag aattttggca attaactatg taactgagtc ccagactctg 49800
ctatcatctg gggtggcaga taaaaacaca cagtccaaat aaaaaacctg attttttatt 49860
ttagcctgaa tcacccagat cacagcagga ttttgcttga acaacccaga cagattgcat 49920
tcattttctg ctttactgtg cttgtggaag ccaggctgtt agtggtttct tctggaatgg 49980
gagaatgtat cacaaaaagg ttggaacctg aaaaatttct agaatttcat tgttctgtgc 50040
ttcttaataa acaatgtgac actatcaagg aatgtgtgtt gaccctcttt ttttaaaaaa 50100
ataaagatgt agtggatagc acaattttga tgaaatgtca ggctttattt ttcatttgaa 50160
aaatgtgtgt gagggaatca ggtgtaatgg catgatacat ctctttaaat tatacttacg 50220
agattaaatt tgtcctgtgt ttcaattaca ctgtattata ctgcttcat't taaattgttg 50280
ttttcttctt ttttaattgt tcaacctaat tgtctaatag tgatgaatgc aatttaatta 50340
gacacttttc cttgaaggat atatatatat tttccctata ataaagcaca gaatagttta 50400
aaaaatgtat tggtccaagc acacattttt atttttagtg atttcattag aacaataaac 50460
ttcaaaatga ttcataacaa cctttctgga ttgatttgat ggaactgttt ttacccattc 50520
actgataaac ctgtcaacag tttcctctca tgacacatac aaagcacgtg tgttcccata 50580
gtgtgtcctt gtgtgtaatt cccttgtgct ggttcagatt ctgaaatgga gctttaaaag 50640
catggaggct tgagttggtc catgtgagtt tgaaccctgg ccgcagctgg tatgggtact 50700
taatctcagt atcccacggt ttcctcaact gcaaaatggg tttttagtag tacttacctc 50760
actgggttgc tacaaagatg cttaaactag tatctgacat ctagtacagc cagccctcca 50820
tatctgtggg ttccacatct gaggattcaa tcaacctctg gttggataaa aaatatctag 50880
gaaaatagct gcatactagg ggaaaaaaaa aagaaaaaaa tatccaggaa aaaaattgtg 50940
ccagtactga acatgacttt gctcttttca ttctctaaac aatatagtat aacacatatt 51000
tacttcacat ttacattgtt ttaggtatta taagtaatct atggattatt taaagtatac 51060
aggaggatgt gcataggata tatgtaaata ctatgtgatt ttatatcagg gacttgtcct 51120
ggaaccaata tcccaaccct aatactaagg gatgactata tatgctcaga agacatttgt 51180
tgtcattttt attctcttgc actcaagaaa gcacatattg gaatgcaaac gaatatcaat 51240
aatagttttt taaaggataa ttaagttaat ttataattta catacaatat acattgtaca 51300
tttatatttt ctaatgaaaa ggaaataatc tataaccttc agttcagaat tcattagctg 51360
tcctattttg agaactgttg ctctatgtaa ttttcgtctc tgtattgatg tgtaaaactg 51420
gttttaacag gtagctaaat gctgtttgaa aagcatactt cacccattct ggcaactaaa 51480
ataattgaaa gatttaatta atttagaaaa aaatttcgct ttcaaaacac ttgaactgtt 51540
cagagcatgt tattcaataa tctacctttc accagaaatc ataataaaca caataaaaat 51600
gcttacagaa cccccacaat gcgttagtat acatgattat tccttgtgta agtgaatctt 51660
gttgagattt tatgctcagt Caattgcaat taaatacttt atatattaac taaaatgtgt 51720
cctgctctat gtattctgga gaagttactc tcagacaaat ttacatattt aaattatttt 51780
atgggctaac tgataagtat agagaagact gaagacagtt aagatcattg atttcaaaat 51840
gttttaaagt gttgattatt tattttggtt ttctttcttt cccatgccag ttttgagatg 51900
cacctcttac ttggcaggtg ttcctctgta ctgggtactg ggacagagag aaatacagta 51960
gcaagaggga gatcctgcct ccgccccatt ctaccattct cactgccaga aagccagcct 52020
tttttcaagg cttgtagaga agaaaaagag aaaatatttt taaaaattca tttaaagtac 52080
ctactgcata aaccacacca gacatgatga gatattaaaa tgtcaatatt attaaaaatt 52140
tttaatatga ttttacagcc cctttgctac tttaaaatgt ttatcttagt gttaaacaaa 52200
caatcaataa cctcataaac ttaaaaattg ctgcaggaaa taccggacag tttatggaag 52260
gatcatatga cagaaggaag ggctgaagag tgtgagaagc tagacctctg caggttaccg 52320
aagtcaagaa cctcattaat cggtaacaag aagtgcagag cgggcttttg agtccatgcc 52380
tgagtaagaa agtcccaaaa aacactcaca gaagatattt ccttgcccct gcttttagtt 52440
tagctgtagc taactttgga ttaacaaaat ttatgtgctg aatgatgttt tatttttttt 52500
tccaactcca catgcctgtc tagacttcaa gctttattac gaataaagag aaaatcggct 52560
ggatggcata aaaaatattt caggcagatt aacacatgat ttacctcttc ttgaacatcc 52620
atcttaatgg aagtgctaag aaagttagat tcgggcctgg cttggcaaaa gcaaggccac 52680
cccctcctct attttttcaa tgagattttc caatcctagt caaatggtgg tgctagttct 52740
ttatttttga gttactgcat ttcctaattt catggtcata acagcctcct gtctaccgac 52800
tcagaacgga ttttaccaaa actgaaaatg caggctccat gctcagaagc tctttaacag 52860
gctcgaaagg tccatgctcc tttctcctgc ccattctata gcataagaag acagtctctg 52920
agtgataatc ttctcttcaa gtaggtactc ctatttcttc tcaatttatt ttttcctttt 52980
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tgatataatg tgctactgtt tacaagcata ttgtaacttc agagcttacc tctcatcttt 53040
aaaaaatgtt catttttttg tctttctgct ccaaggatat tttgcaaagt tactggcaag 53100
tattcctggg atgataaaat gtgaaatcta aacttggtac agtggaaatt cacttctaga 53160
ataatattta gctgaggcag agggcaatcc gactaccctt ttcttagtac agcacacaca 53220
ggctgcctgt ctgttccaga taacataaat gtattggatc tagcactagc taggagacac 53280
tgtattgttg aactgtgtta gaattttata agctcttaat tggacaaatc tcagagtagc 53340
atgaacacac tacctgtttt ctgaatcttt ggagccataa cttacgtgag tttgaactaa 53400
gcgatgtgaa taagccatta tttgtttcct aaaggcagtc aagttttctg aaaagctaca 53460
catttagcag caaaagaacg agcccctctg tcttgaaatg ggcctctgat tttaagcaag 53520
ctcttttgag tcctggtgtc ccattttctc agttcctttt tgcctcacaa tggcacatac 53580
ataatgactc caccacatat agcagtgggc tactcgggta atgatgtggc agtcacaaga 53640
cagggcagaa tactttcatt ttggttagag gaatgccaca tgtcttagga aatgctcgct 53700
gaactgtaag tttcatactt tgtcaagaag ataaccagta ttctctcaaa caagtccgta 53760
ggagccaaca tgattaaaag attttaaagc aatttactcg atagaagggt tgggcttaat 53820
caggacttgt gatcatggca atggttcctg cttaaaggtg cccagatttt taatgccttt 53880
ttgtgccaga tctaataggc ttacagagca actccatgta tatgaggttg ctgggaaact 53940
catctggttt tgaatgtggt atatacatat tttaatattg agagtaaact taggaagacc 54000
aggtagaagt atttgaactg aattctgaaa cgtacagaga acttaaattg gatgagaatg 54060
tttgagaacc atggatggtt cagggtccat ttgtataccg taaaatccct tcctatttct 54120
caaaagcaaa tgttttcttt gattttgtta atatcctgtg atgactgccc actaggcctt 54180
ggaatgcatg cagataatgc tgtagcagtt ggataaaata ctctagaatg tcagattttc 54240
aaggaaatta caaataaaaa caatgtaggt aaaagatacg acatgtagga aaaaagcaaa 54300
attttcctta agaatacaag cgtcgtattt acgagtagaa gatttttctt ggacatttgg 54360
agatacttgt ttcattttat tgcttgtgac agtcaaggaa aggaataaag ctcttgtgtc 54420
ttaaacttgc agcaagaaca aagtccaact atctttcgtt tctgataact ctgtgtcttt 54480
ttgttcaata ttgggtttag agctagctac catctacctt cccttcaaac actcactcta 54540
aacctccaca cagtgtaagt atttacatca ggcatctgct aaacattttc acatggttat 54600
ctgcaggtct tctctgagtc tgtctgcatt catttatcct agttgctcag aacaatcgct 54660
tgggctgacg gcctggtggt tgagtttact ttgctttgaa tagggaacag ctgtgctcca 54720
ggactgcaga ttggctattc ggaaaaaagg gcaaggaaga gagtgaccca gctctgggta 54780
gaccatccac actgtaaaaa aaaaagtcat agcatagtct tcatctatgg cagtggagat 54840
atggtcctgt ccatccacct ctatcaggag agggtctcca ttgttaatct ctgagaaaga 54900
ggctccatct gtgaaacctc ctgcatattg tctaatgaag tgctattttg aaaggcgtgc 54960
actgtacagg taagagtgat gatggtgtgc ctgccttctg ggcaacatct cagtagactt 55020
cctctgaatc attcccactg gacccaacag caaaagcgta cacatcattg agttttatcg 55080
ttctatctaa ggcgtataac atttttctct ctgaaagtct gtgattcttt cggagaatga 55140
aggggcttac cctatccatc tgcccctaaa aatattcgct ggaaagctga tacctctgct 55200
caggttttcc acagcagatc actcttcagt aagaattctg atattaagta gtttaattca 55260
gatccatgga aaatgactga gtaccagcca tagctcccac cactctctag ctgtgcaatt 55320
tagaggcaga ttatttaacc tcatgccttg aatttctcat ctgcaaagtg ggagtactaa 55380
cagtagctac cagatatatt atatggaata aatgacatta agccactcat taaactcctt 55440
gcagtttcca agcattagaa actcagtatg aggaagttat ttctattcta agcctagcac 55500
agtgcctggt actcaataca tgttggttga atcagtgaaa taattcaagg tcagcaccaa 55560
agctgctagg aatttatgaa catctgatca taactggaaa cttgatctaa aaagcaaagg 55620
gcagtcaatc caatcaactg agcgtaccat ctgttgaaat gctgctgctt ctgtaatgag 55680
tataaagtgt tggaagagaa agtccaggaa cctccatcat tcttccttcc atcattcctc 55740
tcctttgtga ctatctttgt gatgagaagg gtaacaaaaa aatcttgctg agatgagcgt 55800
gtcaaaaacg tgttacaaat gcttcacatt ccctttcaca tcaacagaag catgttgctt 55860
cattgttggg caatgtctta gtccatacac acatagagct ctatgctgat ttttttttga 55920
gatggagtct cgctctttca ccgaggctgg actgcagtgg tgctttctca gctcactgca 55980
acctccgcct cccaggttca agcaattctc ctgcctcagc ctccagagta gctgggatta 56040
caggcatgtg ccaccatggc cagctaattt tcatattttt agtagagacg gggttttacc 56100
atgttggcca ggctggtctc aaactcctga ccttaagtga tccactcgcc ttggcctccc 56160
aaactgctgg gattacagac gtcagccagc atacccggtt gtatgctgat gttctaattc 56220
aatgtgatac caaagacctg agatagtctc tcccactctg gccccataac atatgtccac 56280
gaggtggtaa taataacaac tatagtagca cctaaggttg gggcagctct tactttgtgc 56340
gatgcttttt atagtgttat tacgtgtgat tctcacagca accccaggtg gtgaacaacg 56400
ttatgattcc tgttgtacaa atgaggaaac taaggctttg caaagctagg taacatgccc 56460
aatattacac agcttcaaaa gtgacagccc taggacttga agataaactc atctaattcc 56520
aaagctcatg cttttagcca ttacttgaga cagtattaac ttttaaagtt tgtaatcaat 56580
atgaatttgg ccttgggaaa gcaggttaag catctggggt tgatgggaga taacattaca 56640
16
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ccctctctta gcctcagcaa cttcatctgt aaaatgggaa taattacatc cgagtcacag 56700
aagttttgtg gctcttcatg aggattaaat aaagtaatgc atgtaaaaga gttttgtaca 56760
aagttcactt ttataaaatg caagttgtgg ccgggattgg tggttcacgc ctataatccc 56820
agcactttgg ggggctgagg tgggtggatc acctgaggtc aagagttcgt gaccagcctg 56880
gccaacacgg tgaaacccgt ctccactaaa aatacaaaaa ttagccagga gtggtggcat 56940
gggcctgtaa tctcagctac ttgggaggct gagactggag aatcgcttga acccgcgaag 57000
tggaggttgc agtgagccga gattgtgcca ttgaactccc acctgggcaa cagagtgaaa 57060
ctgcatctaa aaaaagacaa aaaaaaaaaa aagtaagttg ttatatgcaa tgcataaatt 57120
attacttagt tccatgtaaa atcttcccac taagtgaatg agggttcacc tggctgtagt 57180
gctatgagat agatatgagg ggcagattgg tttatgcttc tcaaaaacag aaagtgtgcc 57240
agggtggaag tgtgggtggg gagtctccgc ctcccagcca tgtggcaaag ctggaatgtg 57300
agtacagcag cagtatggat gcggttttga ggggatggtg gtaatcctct tctggcggca 57360
cccctccagt attgtgggat gctctctgat ttcttttgag aagacaagta gctaggagct 57420
tccctagcct ttctgttgta aaaaccatca agatccctgt tgaatgcata cctggagctt 57480
ggtttcccta agcacagact ttaataactt catttggttt tagtctccta tttaaagctg 57540
ccacccactc tcaatttttt gggttttcct actaagaatg gatataacat gggcagtctt 57600
ccagttctcc tttcttgctg ccttgaagac aacacacagg ccaatcacaa ggaggcagag 57660
acaggcccca acaagttgac aatcctagag agcttagtgt gagtagactt gctgaggttc 57720
ctgacttttg ctggaatagg agagtgccac tggctttttg acatttcttt ttccaactgt 57780
ttccttgtca aaatgaccag cagctcagct cccctaaaca tacctcctcc cctagattgg 57840
ttcagaggaa gccatcaagg tccttttgca aacggatgat ctgcattttt gagatccttc 57900
tttcctctgc tgttcataga aatggtctca ttggaataat tccttttgga atgttactaa 57960
ggacaccaag aaatcaacaa gaaaatttga gtgtatctga cagaagaaat ttggcttttg 58020
tactctaata attatttatt agaagcaata actggtcaga atttatttgc ttaaaaccat 58080
gtaaagaaag gtgcttaata aagataattg catcacatat agtaatccgt tttagtatct 58140
ttcaccttaa aactatgtga caaataaaga cacaaattgc tctttctttc taataagcaa 58200
ttttggaaat tccttattgg gaaattccaa attttacaaa atttacaaaa tttaaaattt 58260
tggaaatcgt acctgcatca agttttctga aagaatattt aaggattaag gttacttaga 58320
atccaatata tgcatagttt aatttaactc atattgttaa attctttttc taattttatt 58380
taagaaatga gtaatattga caagggcctt gctgtggttt attatggctt gtcctagagt 58440
ctctattccc agctagatta aaagtgcctc agggctgggc atggtggctc atgtctgtaa 58500
tcccaatatt ttgggaggct gaggccagtg aatcagttga ggccaggagt ttgagaccag 58560
cctggccaac atagtgaaat gctatctcta ctaaaaatac aaaaaattag ccggacatgg 58620
tggtgcatgc ctgtaatacc agctacttgg gaggctgagg caggagattc gcttgaacct 58680
gggaggcgga ggttgcagtg agctgagata acaccactgc actccagcct gggagacata 58740
gagagactcc atctcaaata aataaataaa taaataaata aataaataaa taaataaata 58800
aataagtagt gcctcgggtg catagatggg gttgttcagg tttctaccct gtgccttggg 58860
aagtgcctgg tacacactgg tgtttggcac ataattgtag agtgagattg agcctggcat 58920
gttccttgat ccctagacaa tctctatcag gtgtgatcag taaggcacat aatatgatat 58980
gtgactatta cagagtagca cactacaata tgtgcctaaa gccataacat caactaatac 59040
aattcagcag agtagaatgt gaagagtgct tgcagagtgc tgagcaccac ggtgaggaag 59100
tgtaaagaga agaaggtatt tctgggttgg tgcaggatgg ttagggatag ctttgggtag 59160
gaagcgactc ttgaccatga ccttaaagga caggtaatgt ttacatggga aaatacaagg 59220
aaaaggaggt gcataatgaa aggcatgggg gaggtggttt tgggaaacca tcagtctgac 59280
agaaacatag ttaagaaaag tgcaaggtgg tggtaggagg taatttagaa gtggagagtc 59340
agatgtccta ttaaggagct tgaactttat cttgtaggca ttaaagatgt tggtgtagga 59400
ttggaatgaa ataaagactt aaccttagaa aaatactgtg tggattgaag ttttcagatg 59460
aagagtgggt acatcaattc ggaggtgagg gaaatagttc aagggaggtg tcacaccatt 59520
aaaaaaaatc ttttaggact tgttttttgc aatcatgatt gtttatggtt gtaaagattt 59580
tgtttcagaa atgattggtg gagaaagaag tgtattgaga atcaaaagat gggactgtgc 59640
cactgatgtg cgcagtgaga agctgcaagc ttggtgcccc atcttcctaa ctgtaaaatg 59700
ggcataacaa ctaccagaca gccgtcaaaa cattatacta gtgatacaat gaagactaag 59760
tgatataatt ttgaaaggca gtatgcctta tatgtgtaaa atgctgttta cttggaatat 59820
ttttatagta aaattatttt ctttggacaa gatatagatg cagaagaaaa tgatcatatt 59880
tctgtgagat taggattcag accatttgaa ttttttatat ttattaaata ggtactttat 59940
gttgggtact gaataagtct tttattttta acacctcatt tccctcacaa aatggatggc 60000
atctttggac taggggaaat gtgtggtccc tgcagctgta gtattttatg attctatagc 60060
ttttgccttt agcaaacttc tcttagaata gtgatttaag ggctgggtgt ggtggcttac 60120
acctgtaatc ccagcacttt gggaggctga ggcaggcaga tcacctgagg tcaggcattc 60180
gagaccagcc tggccaacat ggtgaaaccc cttctttact aaaaataaaa aattagcccc 60240
gtgtggcagc atgcgcctgt agtcccagct actagggagg ctgaggcaag agaatcgctt 60300
17
CA 02426405 2003-04-17
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gaaccgggag gtggaggttg cagtgagcca atattgtacc actgcactcc agcctgggcg 60360
acagaacatt taatgctggt ggctcacacc tgtaatccta gcactttggg aggccgaggt 60420
gggtgaattg cttttgctca ggagtttgag agcagtctgg gcaacatggc gaaaccccat 60480
ctctataaaa aatacaaaaa ttagccaggt gtggtggtgc acgcctgtag tcccagctac 60540
ttgagaggct gaggtgagag gatgacttaa gcccaggaga tccaggctgc agtgagctga 60600
catagcgcca ctgcacactg cattccagcc tgggcaacag agcaagatct tgtcttaaaa 60660
aaaaaaaaaa gtgacttaag atactgacag tataaacaca accaaaccca tgggcatctg 60720
tgctgggaat aaaagacaga catgttttca ttgcactgat ttaggattct gcttggaaag 60780
gaaaactgtg atctctcctg cagttgccta aaatgcttta cagttatggg aatggaaaag 60840
ctaaattctg tgatttgtgg gtagagggaa ggaggacgag tgtcctttct gatttcctct 60900
ttttccttct cttccaaggg gaaataaaag gctagagcaa caatttaaaa agaaaaggca 60960
aggagctact gggggtagag tcgggaggga aaaaggccaa acccactaaa taatttcact 61020
tcagttacag taaatctcaa atgatgatgc tacactcctg agaatgttcc atggtggaaa 61080
tgcctgggct ttgaattttg agcagcgaag taccaggaga gggtgacatg ataacattca 61140
acaggaagaa cactgctctt gtccgtttga cggtcctatt cctccggatc actcaatctt 61200
cacaaatcaa gcatatagct ccttcacatg tcatttgtga agggaaagac tcctaggaaa 61260
atgttttcta ggaaagggaa aaaagcagaa agcaaaggtc tcctgcttac tacagcattc 61320
gtgttgcata agcagtatta atgtagtgga gtattaatca cttagaacag ttcacgtatt 61380
attcctatct gggctctgca gggtcctttc ttcacttctt tctcgacatt tggattctgt 61440
ccattttact cctccctctg cacttggaat agaagtgaaa tttgttgtgc caattctctg 61500
cttgttagaa gccatggtaa tgtttagtag gggaaaagct ttgtactgct acatagaagg 61560
aggttttggg attatttaag actttacttt gttgatggga ttcctagaat ctactattac 61620
tgggtatact agacaagttt gtagatttac aaaagtgtgg ataacatggg ttgcacttga 61680
tttctttatc cagctctttg gttctaaatt tattgccaat tttatttatc aaaactattc 61740
tcagcggagt agtattttct gtggacacaa ggaaacatct gtgagcttaa accttagagg 61800
cagatagcca gttagaacat ttggcatatg aagcttagat agcagaagag aaaaattaac 61860
caaggcaacc ctcaaaaata ttgagaaggc aactaagaaa aatttcttat cactgacaga 61920
ctgcagtatt gagttcgtgt taatgaagaa atgtcagaat acataatgaa tcaataagga 61980
gtgtcatatt atggcaagtt tcaatgttgg tgtcaatctc gactgccagg atttatggta 62040
gattatataa tggaatcctg agttctgaga gatcaaagga aaatgctggc tctttcttca 62100
tccattctct taggtcaagc ctatgcagca agaagccaag ttgagaattg agcaattatc 62160
tgaagtgggc agtggagacg gccaaaccag ataatatata accagaaagt caccgtggag 62220
ggaaaatgtg gactgaaaat aggataaggg gtggaggtag aatgtcaagc catttggtca 62280
gtgtccacag tccaaattta ctgaataaca gccaattcct tacttcatgt ggttatttag 62340
agcgagacta gaggacaagt gaaaaaaaaa aaaaagagtt cattcctaag gttgttgcat 62400
gtttgtgcaa aatttcttca aatctctgtt attatctgtt acatgtctaa ttctgagtac 62460
ttccagagat tgcatttcat tactttagat tagtgggttg aagtggtgga ggaagcccat 62520
ataatctgac ttacatggag aaaacaagtc tttttttata gtttagttga gtgttatatt 62580
taattagcct ttttttccct ccataatgca tgcttatgaa ttttccactt aaaattctga 62640
ggctctgacc tttatcattt cctcatggag caatttctgt acctccttaa ctttagtaga 62700
acatagcaat gaaatataca agtcccctag aatagaattt gtgtgaattt ggttttctaa 62760
aaacacaact accaaagtct gaggaccagt gtggtatttt tttcttctat ttgatatgga 62820
aaccataaac tacttacttt gagcagatgt ttcccagtcc taaaatacag ctatcagtcc 62880
actggcccct ataaatctgt tggagtgcac ctgctaattc tgaagcctcc ctaatacaat 62940
gttaaacttt cctttttttt tttttttttt tgagaaaaaa attgtaaatt aggttcactg 63000
ttgcttggaa ttaggaaaaa ataaaaacac aggcatacta atatttcaga tggaaaaaca 63060
aagttaagaa ttcaacaagt ttttttcccc cactctatca tgtcttgcac atttaaagct 63120
gttatacaac attttaaaaa caaaccaaaa aaacccaggg cctttttcca acagcttagg 63180
ctgatgaccc acagtaaaaa agtgccccat gggatattct taaagcaccc caagggagtc 63240
tattgaaata acttaaagta aaaattcaga agaattttac atgtaattaa aaattaagaa 63300
cgttgtttta taagcaatag ggaaaagctg tattaagttg cattgctcaa tttctcactt 63360
gctctgtgca gtgactgctt tttcaaccat gtaacaacgt ctgaatcttc gtggtaaaat 63420
catacctatc acagccacag caggttttgt tctgctgctg cacatgtgat ttgagatact 63480
gtgggctggg agtttttttt ttttttaatt tctaatggca aaatggatct atagaaatgg 63540
aagtcatctg taatctcagc actttgagag gctgaggtgg gtggatcacc ggaggtcagg 63600
aattggagac cagcccagcc aacatggtga aacccatctc tactaaaaag ataaaaaatt 63660
agctggcggg cgtggtggtg tgcgcctgta gtcccagcta cttgggaggc tgaggcagaa 63720
gaaatgcttg aacccaggag gtggaggttg cagtgagccg agaccgcacc gttgcactcc 63780
aatctgggtg gcaagagcga cactacatct caaaaaaaaa aaaaaaagaa gaagaagaaa 63840
tggaagtcat cccgtgggcc tgagttggtg tagtggatta tggcctgtgc gtgaatgaag 63900
aaatacttgc caatggcatc agtggtaact agcttaagcc ctactcagct ttgtaaaata 63960
Ig
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
atgtaatcaa ggaatttgat ctgaacaggt aagccaaaca ttgattcttc agtgcctatt 64020
gataagtgag actacttttc tttttaacag ccttatttca cttaagtggg gagtcaaact 64080
agctttaatt aaggaaatct gtagaaatca cccacatctc cctttccttc tctgttaaaa 64140
aaacaaaagg aagaagaaaa ctaggaagga gtaagcacaa agatctcttc acattctccg 64200
ggactgcggt accaaatatc agcacagcac ttcttgaaaa aggatgtaga ttttaatctg 64260
aactttgaac catcactgag gtatgtgtga acatactagt ttcctctttc tctctcctga 64320
ctttgtccgt aaattgataa gatctaattt ggtcatcagt ttggagaacg atttttcatt 64380
taatttcttt cattatcaag tgtgtattgt caggggctta gcagtacacc tactatctga 64440
tgggcactct acatgcgttg cttaggttga aattaaggat acaatctgtg cactaccacc 64500
atttaaaaaa atccccaagt ctactgtgtg ggtgaggttt ctttgcatag tatcagagag 64560
gttaaccaat ttatttacat actcaatagt ccactctaag tagggaaaat ccaagctttt 64620
tttttcttaa gaaagagctt ttcattcttt tttccctcag agctttacca tagtttccag 64680
caagtgaaaa catttcttga tttgaatttc acaacctcct tctcctcttg ccagttgtat 64740
ggtgctaata ggaagcaaaa tgtgagtgtg cttttaattt aaccctaaaa taggggaata 64800
tcttcagaat ttagacttta catattcagt gacctaccta aaaatagaga catagttcta 64860
accttctcaa tcattaagaa acatttctat tgaatttaat tattcaaaac aacaggtagc 64920
agtttcacaa gggaaaagac aagccatgcc acttgtattt gtggtcacca agtaattaca 64980
ttatttttta tttaaaatta agataaaata acttactgac tgtcaagtcc atttctcatt 65040
tcctccatag aacattttaa aactagttca caaacctctt gaaaagtcat gcctctagaa 65100
agtgcaaatt gtcaccattg cctagaagcc aacttgagag gctgtgtatc tatgcagcat 65160
tttgcaaatc cagtagcagg catgtgatat aaaagattaa atgcacccct gatttgtgaa 65220
tactatccta gccttcaaaa tgttcaaaag cacaggaagt ctgcactttt aaaaatataa 65280
cctgcccaaa ttgcaaggga ggggttgggt gtaggaccta ggtctgtctg ccaatcagct 65340
tgagatgcca gtggacgaaa cctgacttca ctaaaaacca gactggcaaa tattactcag 65400
cgtggtaatt tcctaattgt agaactggcc tgtttggtga agtatttcag gaaaattttt 65460
agctggacct tttctaccct actgcataag aaatgaaggt ttctaggcaa agactttact 65520
tagtgactaa ccaaaaatgg taaataaagt caccgcttcc aggcttagct actgtcctca 65580
aaacagctgc aggactggtc aggccagtct tctgaggctg gaggtgcatg tggaaccccc 65640
agagccttgt ctgcaagggc atggctgact gcaggctgtt tagaagcacc ccgccccgtg 65700
aaactcctct ggcttaggaa ttttaaacag ttctagttct aatctctctg ctcagagtct 65760
gagcagctgt gaatgagctc tcctgtgaat cacagaaatg ttaatgggtg agctgctcta 65820
gcttcttact tccaagtgga aggcgcctgt agctctttgc cagcttgatg cagtgagttt 65880
gattcctctt ttgggcagca gggagagata atgaaggagg gggaaaaaag attttaatat 65940
agaaacgagt cttccatctg gctgaggctg aacaaagtag aagaaccagt gcaagtcact 66000
gggggtatgg atctcatacc attttcagca tatacctccc tttctctctt tttgattcta 66060
cacatgtcag tccctgagta gtcttgcatt gctttcccca ctttgaagtc ttagatccaa 66120
aactctgatt cCagaaaggt ctaaggtgct gttgctgaga ttttgaaaga gacctgagac 66180
aaactgttgg gattctagac gctattgcgc atctgcctgg gtaactgtgt cacttaggtt 66240
gggtcaccag aataattctc ctccattttt gctgcctttc caatttataa acaacacaga 66300
acatcagtgg ttctcccata atcaaatata tttggctcta ttaatattaa aatttgatct 66360
tgagtagaaa gattctaagg gctaaaaaat aaaagatgta aaatgtatgt tgataggtta 66420
gtgtagaagc cacccatggg gttgccccca ctcccactct ttcatatttt ttttaagaaa 66480
caacactcaa gttacaaagt cgattctttt tttgttttgt tttatttgag actgagtctc 66540
actctgtcac cacccaggct ggagtgcagt ggtgcgatct tggctcactg caacctctgc 66600
ctccccggtt caagcgattt ttcctgcctc agcctcccaa gtagctggga ttacaggtgc 66660
ccgccaccac acccagctaa tttttgtatt tttagtagag atagagacag ggtttcacta 66720
tgtttcacca tgttgaccag gctggtcttg aactcctgac ctcaggtgat ccacccgcct 66780
cagcctccca aagtgttggg attacaggcg tgagccaacg cccctggcca caaaagtcaa 66840
ttcttaactt aaaacataaa agttccattt cttttatggt ctacttagtc atgtctggag 66900
tcagtgagct cagtcaagta gtttgcagaa tgacagttgt gatacctatt catttaccca 66960
ccagattatt ttctgctctc ccatggcact ttatagaaaa cagtttattc ggtcattaca 67020
acagctctag gagggggttt cattaaaccc actttctagg aaagcgaact aaggcttaga 67080
aaaatcaagt aatttgctaa agactaccca gctggcaatg atatgacagg acatgaactt 67140
aggacaataa ctcaaggtct tggtccctgt aaatatgggt ttccaggtta tgtatgcagg 67200
cagagggctt agatcctgaa gtttccttca gaaacttcag gatctaagcc ctctatatag 67260
gagcagtata aaaaggaagg atctcttccc atagggagct tgtcatccat tgaatgagga 67320
actcagactt ccactgtgaa atgatatttg tatccccatt gtgtgcgaga tatggggact 67380
ctgatcatca taagagcaca tttttcctgc ctataaatga tacttaatag agctgacaga 67440
ttatatatat ctggaacact tttacctagc agaaagacaa caggctagga ttagctgact 67500
aataatttta tttatcaagc tcaattccca tgctgacttc tcttcctcta gtgaaaatgt 67560
gtcatcagat ttggtcccaa actggagagg tgaaaggatc ctttgaccag tataatagcc 67620
19
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
atgccatcag ttttgctttc ctaattaagt tttatatggg ttaatgatct atatcattat 67680
tttgggggtt tctaaacaca tatgaactaa agatggaaaa gatgatggaa aagatggaaa 67740
gaagatgact cagatgtaca aaggcttgca gagagaagga taagccaaaa aattggtaaa 67800
tcacacatga ataatcaaga actgactaca atataataat atgtgtccat ttccactaat 67860
gaataagctg ccattatgtc tcttcattct ctatttagga caaattactt ctctgctgta 67920
tttccattct tacaggtacc tatctgctgt gatttttccc agttttgact ttatcttgtt 67980
gctttaatct tgtctctaag taagctgcaa cccagtaaat atattccagt attgtttatt 68040
gtaattcctg cctttatgtc aggtggcaag aggaagggac tggttttatt aatttatcag 68100
tctgggtgtg tgctaagagg atccttagta catgctttga ttatggtaga ttgagtctaa 68160
aagattcagc tggtttattc catttatttt ggtctgtcta cctaacaagg tcacacagtg 68220
gattatacta gttttctatg tgtcatattg ttggcctgac acataatagc aaataagagg 68280
taccagaatt ttctgtacag tctgaagctg tgtgtgtaca acaaccagtg aaaaatctta 68340
gttatttgga cttttgggtt ccatgatgcc agagaaagcc agacaccagc agctggaatc 68400
agctaagacc taagaccctg catgcacata tagatgttta cattttcttc ctattgcgac 68460
attcagccat tgctttggcg cctatttcaa taatatattg ctgctcatca aagtggaaat 68520
aatgttttgt tactagctga gtattgaaaa gctcttcata gttttgtgat tttgactcag 68580
ctccaacatg caggacccat ttcttcaact gactttggca acaggagaga ttgactagtg 68640
ggcttgaaag tgatccactg ctgtttctgt ttaactttct tcaatcctac tgggtcttgg 68700
gaagaagagg tagcgggcat ccttgtttgc ctcaaccagg aagcacaagg ccatcccagg 68760
gcggggcagg agagaggtgg gagggaagaa gcaggctcca cagggccatt gtttaccttg 68820
ttggcgggtc aggtcttctc agggtagggt tcctgggata agagcaaagc ttattggttt 68880
tccttgctgt gccacgagag cacaccagat cacccctgca gccttgcttg ccttcccaca 68940
gcctgccctt gcctagggtt tcagctgata tcctttctac tcaggaggag aaaccacaga 69000
acacatggag gaagtgtttc cagtgttaag actttagacc aaactataga aatctgttct 69060
acctggaaac ctgaagaaat aaatcatgac tgctactcag tagaagtaaa ataaaaaaac 69120
agctttactg gtttggaatc ataggaaggc tttctgtata gcctctctga gagctgccta 69180
ctggaaggat ttgtcctcaa aacgtgagga tttgtggtgt tccagggttt atatgacact 69240
ggcaggatag tttgctagag ggctgtgctt cgacctttat ccaagggatg taagccgtgt 69300
gtttaggtta gtgagcgtct agcacaaagc tctaatgttg aaggagcatt ggaggcaggc 69360
tgtgcctctg aacatgtaga attgactaga aatgccaatg ttcatttcaa aatgaaatca 69420
ttatctttct tatgcttcca tttaaaaatg attattacat ttttgcatat ggttgaatgc 69480
atattaattt tagcaagttt agaaaagaga taagcataaa gacatacata aaaatcactt 69540
attctcatca gctatagata atcactaaca atattttagg acattttctt ttcatctttt 69600
tcttagcaat atgtatgtgt gtgggtatac atatttaagt gtgtatatat gtaaattaaa 69660
aaacataaaa tattcccaca atataattaa taaaaatcta agatacaaca caatttccgt 69720
ttgtaatatg tagtgtatat atgtatatat acacattata tgtatatata aaatacatgc 69780
ataaaataga tacacaggta tatattttgc aaattgaaat gatgttgtat cttgtagatt 69840
ttatttaaca ttagaattta tttacactac ttaggtgttt taacaaggat tgtggtccac 69900
catttatttc cttaagagta attccaaaaa gtggaaatag aatgtcaagg ggcaaagttc 69960
tttataaagt ccttaaggag tattgccaga tatatttttt tttacttcct tttaaaacat 70020
gattgtattg tagaagttct ctttaaaaat tccaagcaaa aatttttcaa aatcccatct 70080
agaaatcaaa tcatgatttt atttggctat gcctcttgta gtccttgtct atgaacttat 70140
tctattatta aatataatag gtaatttcca ctaatttgac agatagaatt ttatttttta 70200
cattttctct tgttacagtg ccatgcatat ttctattatg ttacagagat cttgggggtc 70260
ttttttcctc cctttttcct ttctcttttc ttgttctgta ccccttcaca gaaaccaaca 70320
aatacaggtt gatgtgtatc ctctactctt ttctccatgc tcacacaacc caatatttac 70380
acatgcactg atttttcagg gcaatggtcc ttctttatca taaattgtgg gataaggtta 70440
tatacataat atatgtgtgt gtgtattact ctgaatcttg gttttgtcac tttgcaatat 70500
gtcttaaaga ttctgataaa tcttatagat ctatctcatt cttttcagta gttgcatgca 70560
gtataaattt actataactt attcaagtaa tctgctttca gctgatactc tgttgtgaac 70620
agttttcaac atataaaaaa gtgctgtcat tacaaatatt cttagatata tattcttagt 70680
aattgggggt tttattttta tggtgtaagt cccaggagta gaattgctgg tttaaaaggt 70740
atgtgtattt ttacatttct attggttttt tcatattatt ttctaaaaat attatagcaa 70800
atcacagtcc cactagtgat gttggagagt atcattttcc tcactagtac tcctatttcc 70860
ctgctttcta atctttcctg atctaatgag taagcattgt taattttctt tteattttct 70920
tgacttctaa tgagcttaag catcttttca cattattgtt gttcctttgg attttcttat 70980
ctgtcaatta ccaatggata tccttgacct atttctccct tatatggttg cttttctctt 71040
attaaaaatt tgtaaaagtt ctttgactat tacagatttt aaaaactggc agataaagtt 71100
gtatgattta ttgtgtataa tatgatattt tgagatatac atatatcttg atatatcaat 71160
atcgagatat atatatcaca cgttgtggaa tggctaaata tagctaatta acatgtgcgt 71220
tacctcatga agttatcatt tttgtggtga gaacacttaa aacctctcag catttttcaa 71280
2~
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gaatataata tattgttatt aactatagtc accatgttgt acagtggatc tcttgcactt 71340
acttttccga tttaactgaa gttttgcatc ctttgaccaa tgtctttcca accctcacct 71400
cccacccctc tgcccgacac tgccccagcc ccggtaacca ccattctact ctctatgtct 71460
atgagatcaa cctttttaga ctctacatat aagtgagatc ttttggtatt tgtctttctg 71520
tgcctggctt atttcactta atataatgtg ctccaggttc atccgtgttg ttgcaaatga 71580
caatattttt ctcttttttt aaggctgaat ggtattccac tgtgaacata taccatattt 71640
tctttatcca ttcatctgtt gatggatact tagattgatt ctacatcttg gctattatga 71700
ataatgctgt aataaacatg ggagtgcaga tatggctttg acatactgaa tacattcgct 71760
ttgggcatat acccagtagt gggactgctg agtcattcgg taattgtatg attactgttt 71820
tccatagtgg ctgtactaac ataccttccc actaacagtg tgcaagggtt ctctttactc 71880
cgcatccttg ccaacacttt taatcttttg tccttttcat aatacccatt ctaacaggtg 71940
tgagatgata tctctttgtg gttttaattt ccattttctg atgattatag tgatgctgag 72000
cattttttct atagattttt tttttttggt cagtggattg ctaaatctta ccccgtcaat 72060
aatttctcct ttgattttac ttttataatt ttctgctaca aaattaaaaa ataattgtat 72120
gaaataaaat ttttcttcct atacgtattc tgaatttcct atcttacttc aaagagtctt 72180
cccacctcct attttctaaa attttcttct aaaaatttct atgttttatt ttattatttt 72240
taatatttag tattttttac atctggaatt tttttatata aaagtggaag gctcaactgc 72300
atctcttttt atataaagaa cgaattgttt aaacatcaca tgttaaataa tcttttctcc 72360
aataaattaa attatattag catcaattta aagatttttt ttctctaaac cactaatcta 72420
tttatttgtt gccaggcctg agacgtattg ctttgattat aatagctgta tagtctcttt 72480
taacatttgg caagtttgat gctccctact cattaatatt atttataatg ttagcctggt 72540
tttccttttt ttttttcagt ccaaatagga tttagtcaga agaaagatac gtggattaca 72600
tttttaaaat actgatcaaa atgaagatgc tccaaccgta taaatggcag atgaaataga 7260
ctttaaagta aaaaatattt atcacacaat atatcagaaa aatataacaa acccgaacca 72720
acaaacatca gcaacgtagc tccaaaatat tagcttgaaa catgaaattg ccaatagttg 72780
accacttttt gacctacaaa agcaacaatt tatataaaga aaaggtcaat aaaattatgg 72840
taaattgaat ttttttttat tattacactt taagttctgt gatacatgtg cagaacgtgc 72900
aggtttgtta cacaggtata cacatgccat ggtggtttgc tgcacccatc aacccgtcat 72960
ctacattaag tatttctcct attgctatcc ctcccctagc cccccaccct ctgacaggcc 73020
ccagtgtgtg atgttcccct ccctgtgtcc ttaggttccc acttatgagt gtggcgtttg 73080
gtttgatgtt cctgtgttag tttgctgaga atgatgattg ccagcttcat ccatgtccct 73140
acaaaggaca tgaactcatc ctttttaatg gctgcatagt attccatggt gtatatgtgc 73200
cacattttct taatccagtc tatcattgat gggcatttgg gttggttcca agtctttgct 73260
attgtgaata atgctgcaat aaacatacat gtgcatgtgt ctttatagta gaatgactta 73320
taatcctttg ggtatatacc cagtaatggg attgctgggt caaacggtat ttctagttct 73380
agatccttga gaaattgcca cactgtcttc cacaatggtt gaactaattt acactcccac 73440
caacagtgta aaagcattct tatttctcca catcctcccc agcatctgtt gtttcctgac 73500
tttttttttt tttttgagat ggagtctcac tctgttgccc aggctggagt gcagtggtgc 73560
aatCttggCt cactgcaagc tCCdCCtCCC gggttcatgc cattctcctg cttcagcctc 73620
ccaagtagct gggactacag gcgcccgcca tcatgcccag ctaatttttt gtatttttag 73680
tagagacggg gtttcactgt gttagccagg atggtctcga tcttctgacc tcgtgatcca 73740
cctgccttgg cctcccaaag tgctaggatt acaggcgtga gccaccgcac ctggcctgtt 73800
tccagacttt ttaatgatca ccattctaac tggtgtgaga tggtatctca ttgtggtttt 73860
gatttgcatt tctctaatga ccagtgatga tgagcttttt ttcatatgtt tgttggccgc 73920
ataaatgact tcctttgaga agtgtctgtt catatccttc acccactttt tgatggggtt 73980
gtttgttttc ttgtatattt gtttaagttc ttgtagatat tagccctttg tcagatggag 74040
agattacgaa atttttcccc cattctgtag gttgcctgtt catgctgatg atagtttctt 74100
ttgctatgca gaagctgttt agtttaatta gatcccattc gtcaattttg ccttttgttg 74160
ccattgcttt tggtgtttta gtcatgaagt ctttgtccat gcctgtgtcc taaatggtat 74220
tgcgttggtt ttcttctagg gtttttatgg tttcgggtct tacatttaag tttttaatct 74280
tgagttaatt tttgtataag gtgtaaggaa gggatccagt ttcagttttc tgcatatggc 74340
tcgcCagttt tcccatcacc atttattaaa tagggaatcc tttccccatt gcttgttttt 74400
gtcaggtttg ccaaagatca gatggttgta gatgtgtggc gttatttctg aggcctctgt 74460
tctgttccac tggtttatat atctgttttg gtaccagtac catgctgttt tggttaccgt 74520
agccttgtag tatagtttga agttaggtag catgatccct ccagctttct tttagcatag 74580
gattttcttg gctatacggg cttttttttg gttccatatg aaatttaaag tagttttttc 74640
taattctatg aagaaagtca atggtagcct gatggggata gcattgaatc tattaattac 74700
ttttggcagt gtggccattt tcatgatatt gattcttcct atccaagagc atcgaatgtt 74760
tttccatttc tttgtgtcct ctcttttttc cttgagcagt ggtttgtagt tctccttgaa 74820
gaggtccttc acttcccttg taagttgtct tcctacatgt tttattctct ttgtagcaat 74880
tgtgaatgga agtgcactca tgatttggct ctctgtttgt tattactgta taggaattct 74940
21
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tgtgattttt gcacattgat tttgtatcct gagactttgc tgaagttgct tttcagatta 75000
aggagatttt gggttgagat gatggggttt tctaaatata caatcatgtc atctgcaaac 75060
agagacaatt taacttcctc tcttcctatt tgaataccct caatttcttt cttttgcctg 75120
attgccctgg ccagaacttc caatactatg ttgaatagga gtggtgaaag aggatatcct 75180
tgtctggtgc tggttttcaa agagaattct tccagctttt gcccattcag tatagtatta 75240
gctgtgggct tgtcatgaat atctcttatt attttgaggt atgttccatc aatgcctact 75300
ttgttgagag tttttagcac gaaggggtgt tgaattttat tgaaggcctt tttttcatct 75360
attgagataa tcatgtggtt tttgtcattg gttctgttta tgtgatggat tacatttact 75420
gatttgtgta tgttgaacca gccttgcatc ccagggatga agctgacttg attgtggtgg 75480
acaagctttt tgatgtgctg ctgggttcag tttgccagta ttttatcgag gatttttgca 75540
tcaatgttca tcagagatat tggcctgaaa ttttcttttt ttgttgtgtc tctgccaagt 75600
tttggtatca ggatgatgct ggcctcataa aatgagttag ggaggagtcc ctctttttct 75660
attgtttgga ataatttcag aaggaatggt accagctcct ctttgtacct ctggtagaat 75720
tcggatgtga atccatcttg tcctgggctt tttttggttg gtaggctatt aattcctgcc 75780
tcaatttcag aacttgttat tggtctgttc agggatttga cttcttcctg gtttagtctt 75840
gggagggcgt atgtgtccag gaatttatcc atttcttctg gattttctag tttatttgcg 75900
cagaggtgtt tatagtattc tctgatggta gtttgtattt ctgtgggatt gctggtgata 75960
ttccctttat catattttag tgtgtctatt tgatttttct cttttcttct ttattagtct 76020
ggctagcagt ctatctattt tgttaatctt ttcaaaaaac cagctcctgt gttcattgat 76080
ttttttttga agtttatttt gtgtctctgt ctccttcagt tctgctctga tcttagttat 76140
ttcttgtctt ctgctagctt ttgaatgtgt ttgctcttgc ttctctagtt cttttaattg 76200
tgatgttagg gtgtcagttt gagatctttc ctgctttctc ttgtgggcat ttagtgctat 76260
aaatttccct ctaaacactg ctttagctgt gtcccagaga ttctggtatg ttctgtcttt 76320
gttctcattg gtttcaaaga acttatttat ttctgcctta attctgtcat ttacacagta 76380
gtcattcagg agcaggttat tcactttcca tgtagttgtg cagttttgag tgagtttctt 76440
aatcctgagt tctaatttga ttgcagtgtg gtctgagaga ctgttaggat ttccattctt 76500
ttgcatttgc tgaggagtgt tttacttcta attatgtggt caattttaga ataagtgtga 76560
tgtggtgcta afiaagaatgt atgttctctt ggtttggggt ggagacttct atagatgtct 76620
attaggtctg cttggtccag aggtgagttc aagtcctgaa tatccttgtt aattttctgt 76680
ctcattgatc tgtttaatat tgacagtggg gtgttaaagt ctcccgctat tattgtgtga 76740
gaatctaagt ctctttgtag gtctctaaga acttgcttta tgaatctggg tgctgctgta 76800
ttgggtgcat atatatttag gatagttagc tcttctcgtt gcattgatac ctttaccatt 76860
atgtaatgcc cttctttgtc ttttttgatc tttgttggtt taaagtctgt tttatcagag 76920
actaggactg caacccctgc tttttttttg ctctccattt gcttggtaaa tcttccgcca 76980
ttcctttatt ttgagcctat gtgtatcttc tgcatgtgat atgggtctcc tgaatacagc 77040
acaccaatgg gtcttgactc tttatccagt ttgccagtct gtgtctttta actggggcat 77100
ttaacctgtt tacatttaag attaatattt ttatgtgtga atttgatcct gtcattatga 77160
tgctagctgg ttattttgcc cattagttga tgcagtttct cgtagtgttg atggtcttta 77220
caatttggta tgtttttgca gtggttggta ccagttttac ctttccatat ttagtgtttc 77280
ttttaggagc tcttgtaagg caggcctggt ggtgagaaaa tctctcagca tttgcttgtc 77340
tgtaaaggat cttatttctc tttcacttat gaagcttagt ttggctggat atgaaattct 77400
aggttaaaaa ttcttttctt taagaatgtt gaatattggc ccccactctc ttctggcttg 77460
caaggtttct gcagagtgat ccactgttag tctgatgggc ttccctttgt gggtaacacg 77520
acctttctct ctggctgcac ttaacatttt ttccttcatt tcaaccttgg tgaatctgac 77580
aattatgtgt cttggggttg ctcttctcga gagtatcttt gtgatgttct ctgtatttcc 77640
tgaatttgaa tgttggcctg tcttgctagg ttggggaagt tctcctggat aatatcctga 77700
aaagtgtttt ccaacttggt tccattcttt ctgtcacttt caggtacatc atcaaatata 77760
ggtttggtct tttcacatag tcccatattt cttggaggct ttgttcattc cttttcactc 77820
tttcttctct aatcttgtct tcatgcttta tttcaagttg atcttcaatc tctgatatcc 77880
tttcttttgc ttgattgatt cagctattga tacttgtgta tgcttcataa agttcttgtg 77940
ctgtgtttct cagctccatc aggtcattta tgttctgctc taaactggtt attgtagtta 78000
gcaattcctc tatccttttt tcaaggttct tagcttcctt gccttgggtt agaacatgct 78060
tcttcagctc agaggagttt gttattactc accttctgaa gccggcttct gtcaattcat 78120
caaactcatt ctccatccaa ttttgttccc ttgctggcaa ggagttgtga tcctttggag 78180
gagaagaggt gttttggttt ttggaattgt cagccttttt gtactggttt attctcatct 78240
tcatggattt atctaccttt ggtctttgat gttggtgacc tttggatggg gtttctgtgt 78300
ggatgtcctt tttgttgata ttaatgctat tcctttctgt ttgttagttt tccttctaac 78360
agtcaggccc ctctgctgca ggtctgctgg agtttgctgg aggtctactc caaaccctgt 78420
ttgtctgggt atggaggctg caaaacagca aagattgctg cctgttcctt cctctggaag 78480
ctttgtccca gaggggcacc caccagatgc cagccagagc tctcctgtat gaggtgtctg 78540
tcaacccctg ctgggaggtg tctcccagtc aggaggcaca ggagtctggg acccacttga 78600
22
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gcaggtagtc tgtcccttag cagagctcaa atattgtgct gggggatccg tttctctctt 78660
cagagccagc aggcaggaat gtttaaatct gctgaagctg tgctcacagc cgccgcttcc 78720
cccaggtgct ctgtcccagg gagatgggag ttttatctat aagcccctga ctgggactgc 78780
tgcctttctt~tcagtgatgc ccttcccaga gagcaggaat ctagagagac agtctggcta 78840
cagcagcttt gctgagctgc gatgtgcttc acccagtttg aacttcctgg tggctttgtt 78900
tacactgtga caggaaaact gcctactcaa gcctcagtaa tggcggatgc ccctcccccc 78960
accaagcttg agcatcccag gtcaagttct gactgctgtg ctggcagcga gaatttcaag 79020
ctcatggatc ttagcttgct gggctctgtg ggggtgggat ccactgagct agaacattgg 79080
ctccctggct tcagccccct tttctgggga gtgaatggtt ctgtctcgct ggcattccag 79140
gagccactag ggtatgaaaa acaaaaactc ctgtagctag ttcggtgtct gaccaaatgg 79200
ctgcccagtt tttgcttgaa acccagggcc ctggaggcat aggcacccaa gggagtctcc 79260
tggtctgcac ccaagggaat ctcctggtct gtgtgttgca aagaccatgg gaaaagtgta 79320
gtatctgggc aggagtgcac cgttccttag ggcacagtcc ctcagggctt cccttggcta 79380
ggggagggag ttccctgacc ccttgggatt cccaggtgag gcgatgcccc accctgcttt 79440
ggctcaccct ctgtgggctg cacccactgt ctaaccagtc ccaatgagat gagctgggta 79500
cctcagttgg aaatgcagaa atcacctgtc ttctgcgtta atctcactgg gagctgcaga 79560
ctggagctgt tcctatttgg ccatcttgcc ccttggtctg gttttcaacc ttcagtcttc 79620
catatttatt ttgaatgaat tttctgcagc tttattaaaa aagaatagaa acaagtaaga 79680
gcaaagcata gttggtttat ggttgtaata aacttatatg tatgtcctaa tgatttgaca 79740
gctttgtgat agtatcttgt aatccaagta catgatatat ttctacatta tttagatctt 79800
gtgttaggtt tttccataag attaattttc ttcatattgg ctttcttgct atgtttcttt 79860
ttagcataaa gctaatccag gaaaaggaat aaaactggaa ggaaaaaatg tcttaaacca 79920
ttaatattgg ctgaccccgg tggtagggtt atgaatgaaa catttttgct tcttccactt 79980
ttttatattt tccaaattgt ccatattaat catgtatgat ttttataata ataaattaat 80040
gaaatttaag aattagataa ttgattgaat tggataattg aattaataaa atttaagaat 80100
gagaatagga ataattgtgc tttgaaaagt catatacaca agagttttag atggaattca 80160
atactaaatt tatatgctat actaaatcag taattctcaa ggagcaaagg tgctggggag 80220
tgtggaggag ctctttgttg gtgttgcaca tacaatttaa gacaacattt tccttattcc 80280
tcaccatttt aaccatatca cctaaccagc ctctggtagc actcaataga catctgatga 80340
atgaatgaat aagtgaatga aaacattgtg acaaaatggt ataacatttt gtatttgaaa 80400
aatatatgaa aatctattct tttcaaatat aaaatgggaa aataaaattc aataaaaata 80460
tcttggttgg tgagaataca caaaagatat accttcttgt ctatgaatta gtaataagaa 80520
attgtcttga ggaagtcaac tacatctgga aggttctctc tggacaagga gcataagtga 80580
aaaacagtgc actaaattat aaccaagagt tgcaacttac cattttaatg cttcagcaca 80640
ggcacagaga ctaacattta ctaagcaaac aagaagtctt ggcaagttaa ttaaataatg 80700
aattattttt ggtgaccaag gagttgggct tctcatttta aaaccatgca tgagattttt 80760
ccctttctac ccattactaa aatatcgtat tagtgtgaaa aattatacca ggactgggag 80820
aaaaagaaat cacatctgtc cttgacaatg ggctgaatga agaggtgaag gagtggtttt 80880
actatctaag tgactgaaaa ataggttatg gtgccccagc aaatccttgt tgtttgctga 80940
caattagtga tgtctgttta aatcatgcag ttttattagg ccttaaaaat atcttttagt 81000
tagtttcaat ttcatcaagg gaaaaggaga gcagagtaga gtggaactct gctcagagtc 81060
cggttggaag ccttcaactt tgttctccct gttttcagat gagtgtctat ttgtggctct 81120
accttttctc tttcttctct taccatgaca ctcccctctt ctctcttatc ttagctgttc 81180
ttttcttctt ccgcatatta ggcagtggga gaaacaccct aaatcagttg gaggtgagga 81240
aagaagaaaa gcacccctat cttggtagtt cctcattctt cccttcgtca cgtccatgtc 81300
atcaggctct gccttcatct gcgatctgga tacaatccaa tttatagcat ccattcaacc 81360
aaaaaatatt gagctcttac tatgtcaaag tagtgttctg gatgctcggc tccatcagta 81420
aacaacctag actaacatct tgccgttgtt tacatctcgt ggtgtagagt ttacaccttg 81480
tggtctagaa tttacatctt gtggtggagg caggcagatg attaacaata aacttaagta 81540
ggtctagatg tcaaaaggtg gtaaatgcta caggaaagag caaaggtcga gccaggtaag 81600
gcagattggc tgtgtgggtg tggaggaagg gtgcaagagt actgtcaaga taagccttcc 81660
tgagaacatc tgaaccagga catgaaggac atgaggaagt gagacagtcg ctatccaggg 81720
aaggaatttc caggcagaag aaagagccag tgttacacct taaggtggga gcatttctgc 81780
gagactggag aatcactgga gtccattgta cttggagccc agcaagggag aaaagattgg 81840
aggactcagg aggtgctggg gcaggtgaac tgctttttga ttggggagtt cagagggtaa 81900
tgctttggat aaatgtaact gaaaactttc tcagaagtgt tttcatacta tctctacaat 81960
tcattttcat gtgaaaactt aattggcgag cagattaata tggtgatctt cccttagatc 82020
actaggaaaa tcttgtttta tgaatttttc ttcccttttc attcactagc agagaaaaga 82080
gttgtaaagg agccgcagaa aattatagta ggtttctccc tactactgag ctactgagac 82140
tggaagatgc tcacgttagc aactgagtat atttatgtat ttccctttaa tgtttgaagg 82200
gtcaggaata tttgacttag gatactagtc tgtttagaaa catgattcaa ctagctacat 82260
23
CA 02426405 2003-04-17
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gactaaacta gcagctgtca gagagaatgc aaggtcaaaa cttagtagtt gataataata 82320
aagaaagggc agagtgttat gaaatgttat gatctgggta atccattggc tcactttttt 82380
ttgtcagcct aaggttacaa gatgataaat taagttgcta atattctata tctaccattt 82440
acttttcctt tatcatgtgt ctggcaatat gctgagtgtt ctacctctag cattttattc 82500
aaactgtgca atctgcctgc tgaaacaagt atcattaact tcatttccta aggtgagaaa 82560
attgaggccc agagaggtta aataagttta ggatcatatg catagctggt aagtactata 82620
ctttaatatc cctttgcctt catgctttgc tctcactcca tgtttaaatg agcagagaga 82680
cttatcttta aacagatata tagcaagtag tattttccaa atgaattcca caagatgctc 82740
cattgcaaaa gttcaaataa gtttagaaaa atgctgcaaa ctttgtgctt cttaagagat 82800
ttacagtgca gattagcaca ttaaagcctt tgggaaattt gtattagaaa aacctttatt 82860
aacttattta ccccaatttt tccaagcttt ttgatcacga aactctttaa aaaacaacaa 82920
gtataattgc ttttatagta ttctttggga tacacttgga gaagtgttac atgaaaagat 82980
atgattggat aaatttaaat ataggaagaa ttatttaatc attttttgga ataaaacacc 83040
aattttaggt tgtctaacat acatttgagc caagacatga aggacatgag gacataattt 83100
acttttgtcc ttgtaaggac ataatgcact tttagtggtt tgcattgttt attttctttt 83160
gaatttcatg ttactttata aaggtaatta tttaatcaaa ccatttgtta agtgtcagac 83220
actatggtag gtgctggtaa tataaagaga atatgtaaac atcaacacaa catatctcct 83280
agtatgggct tacagtacag tgagagacac aaacaaataa tttgtaggat tgaaataagt 83340
cttacatttg ccacatcaat aaagcactat ggaaacaaag gcacaagaac ttaactttgt 83400
ccaatgaagt ctttcaggag gaggtgatat tggagctgaa ttttaaagga ttcatagatg 83460
tttatctgaa ggactaatgc aacatgttgg aggtgagtct tcaggaaaga ggcaacaaga 83520
accatttggg taacaagata ggacttggca agttagggga gtcgtaagtg gttcattacg 83580
gctagaatcc agggctctct ggagagattg ggagtacaca gatcactcaa gggtttggta 83640
tgaactgtca ggctactaag acagaaataa caaaaatcag atgtgggttt agaaagagca 83700
ttttggctgt aatacagaac atgatggata attgatggag cgagattcct ggggagatag 83760
aagaggatag ggccatgtaa gtacatctgc tggtatttta aaattagaaa aagaaatttt 83820
tggtagcaaa atcagaacag acccaccaac tctttgcaaa tcatgggact agaatgtttg 83880
gaaaggaaga tgctaacgat tttcattcat ttgtttatca tctatgttga gtgtcttctt 83940
gggcctaggc agcatgccca aagctgggag aataagatac tgtatgagat gctagaaaga 84000
tccccacctc tcctttccag aaattcagta tatcagacta attggtttac agttgtgacc 84060
atgggctttt ggcatagctg ttcaacaaga tttcattctt tttcaaaagc aattcattca 84120
tccaccaaat atttgttaaa caaatgtacg ttgcattgta gtgggtcctc agggagctgg 84180
atgtacatgc caaatatgtt tcattttatt tgaagcaagt ccacagacaa gtaaactagt 84240
caagtgatac caggcaaagt gatttgcttt ccaacagatg gtgacagatt aatttcctaa 84300
gagactgatc tgccccagag gcactgggaa agtcttgtta gggaggtaga ttatagtcag 84360
gaccttggaa aattgttggg aataattgag gtcaggaagg gtatacttag gtggatgggg 84420
acagcccctg agcgagggat cagtcctttt ggagtgagca cggaatattc aggtgcctgg 84480
gaggagtgaa ggcttgtgct tcagcactga ttgtgtgcac cgatggtgga acatacctgc 84540
ctgctcagaa gctttggctt ctctctgtag gtgagagaca gccattagaa gtccttgaac 84600
agggaagaaa cacggtgaaa gcaaggattt cattgagaag tccctcatgg aagaagaaga 84660
ttacattgga aagagcctgg cttagggagg gagcagtgac aatcagagaa aaaggcagat 84720
aggggcaaag atactggaag aagaggaaaa actgtccaaa gctttgtcct tgtgtgggaa 84780
agctggtgct gttggcgtga aagaggaagc aagaacatgt gcactgacac ggctgagagt 84840
ctccaaaacc attgtctttc cttaaaacag taatgatcac aagcagctta caactttgca 84900
tatagccact ggggcaaaat cctattaaaa gctaattcat tatctgagcc agtgcatgat 84960
aatgcgatgt aaaggcgtgt tgggaggcag atgatcagaa cttttaagca aactaaattt 85020
cataacattt attagaagcc tgtctctatt tccagaaaac gcctataaat gtggctgtaa 85080
tgtaggctac aggtcatcac actgaagtag aagcaatgta caatacctga aaggttagag 85140
aagttcaggg tctgggctta taaaaaactt cattattcat ttgaaagata ttgttttgta 85200
tcccccaatt gtggttttca atgtatataa aagcaggata tcatactttt tgatctatgg 85260
atttggaagg ggataatggt gtggtgggca ctgagcatat ggaattattt aattagagag 85320
atgcccttta gattactata aaatataacc agaatctcct gtttagactt ctaaaatcta 85380
cttctttgaa aacactacta aaatgaccac aaagacctgt cctcacaagt gggagctatt 85440
aatcaatagt gtgtacacat ggacatagag agcagaataa taaacactgg agactctgag 85500
gggtgggagg ggaagaggga ggtgagggat gagaaattac ttgatgggta caatctacac 85560
tattctggtg attgatttct ctctgtttcc tcttcagaaa ctgagaggaa atttagtttc 85620
ctcagtcacc actcctccaa actcctgcgt gggtgataca agacttgctg tcatcttgag 85680
gcagaagggg ttaggggatt tccccattga acctgatagc cttcatttca tttctgtctt 85740
ctcagggaaa catttacccc tctttactaa atggaagaag gtttgtaaac taggagggta 85800
tctatggatc tgattgctcc ttcaccactc tgctatatat ccatgtaaca aaacagcgct 85860
tgtggccgga tacagtggct cacacctgta atcccagcac tttgggaggc cgaggtggtc 85920
24
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ggatcacctg aggtcaggag ttcgagacca gtctggccaa tacggtgaaa ccctgtctct 85980
actaaaaata caaaaattag ctgggcgtgg tggagcattc ctgtaatcct tagctactcg 86040
ggaggctgag gcaggagaat cgcttgaacc cgggaggccg aggttgcagt gagccgagat 86100
catgccactg cactccagcc tgggtgacag agcaagactc catcgtggga aaacaaacaa 86160
acaaaagaac agtgctggta ccccctaaat ctataaaatt ttctaaaaaa taaaatgaca 86220
ataaaggaat gaaaaaggca taggtacaag cagatgggat aggacactaa agcaagctgg 86280
agtaatactg gaattctaga aggtagaagg cttagcagag cagttcaggt ggaacccacg 86340
cctgtggggg caggggcatg agcagtgagc ccatctaact acgggacccc agataggctt 86400
gggatctaga agcgacagat gcctctaaag gctgggggta ggctgggact gaaagcagaa 86460
ttggtgtaaa gtctttaaaa ggagcaatta gatccacaaa taccttccta gtttctaatt 86520
attctaccgc ttaggagaga ggggtaaatg actccctgaa aacagagaaa tgaagtgaag 86580
gctatcatgt taaatgggga caacacctag cccctccttc ctcaagactg acaggaaagc 86640
tcctacaacc cacgaaggag tttggagggg tgttgtctga ggaaactaat aagtccaaga 86700
gaaagaacct tcagaaacgg acatttaaag gattaggtcc ccacccgatt accctagaga 86760
tacacataca gaaatgtgat tggacagtca aggatcaccg tatgatgctt ctaacctgaa 86820
caatagacac ctagtcacac acccaaacaa tcacacacac acatacacac acacacacac 86880
ttacttcact tctgctggag gaatttacaa gatgaagaac atcttgtatc tcttttgggc 86940
tactgtttgt gaaaggaatg gttgcatgtg ctcttggcta agccaactcc atcctgaaga 87000
cagatttttg tgaggtgggg gaaattcgcc cagcgttaat agtgttagtg gttgtcctgg 87060
gtccatcctg gtctgtattc ctgctttttc attttcagat ttaaatccag agttattaca 87120
gatggtaaca tctgatgcca atttatggat ctttttcata attcacctgc taggaatctc 87180
aggtaaccta taaaatatgc ttttatttgg tcattttaag agttacgttt ctgaatttca 87240
ggtattttat cctgtattgt cagcacatta aattagggaa cacattcatt gacattctat 87300
gtattttcct ttgtatttca aagtcagagt caagtattta aaaagataag atctttcatt 87360
ttgtgtgtga tcccacggaa tactttctac tgtagattta ttaaaattct cccacctctg 87420
gcctctgatt aaggaattgc agagtattct ctatgacaac tcattaaacc tattattccc 87480
cccagggcgg tttagtatat cactaaatat acttttagtg atatttgttg attggagcat 87540
agcttttgtg tttgccaaac atcattgatg tgttttgagg tcatgtggtt gtggggggca 87600
gggggtggtt gtaaatgtaa tagtgtccct ctagtattgt aatacttcaa ggacatagaa 87660
tttatttttt aaagtcttaa atctttttgt ttgtttttct aggaaatctt gagtctatgt 87720
tctttgattt gagactatag agtttcttgg taaagtctcc aattattggt tttctgagta 87780
aattcttgag aattggtgag gctcccagga ttattgtttg tcatcctgtt ctaattaata 87840
gagaaaaagc atataaatct tagatgtctt agatctggga ctattgcatc tacttggctt 87900
gagccaaagt gtcatctaat ttttatccag taattgtggc aacatattgc ttccaaaaca 87960
aatcacattt gtaaatgcat attgagcatt ttctacatga agggcattac cagggagtga 88020
aagaaatata aggtctgaat tttgtcctct gggagagaac attctagtgg gagagatgag 88080
ttgtgaaaag ttaaataaca aatatttata gatggtcaat ataggaactt gcaaatatta 88140
ttaagattaa ttacatgtga aaaattgtta ttgaattcaa ggcaaaagaa gtgaacttaa 88200
actgagttgc acaggaagaa ctcataaaaa ggtgagcttg tgttggatga gtggatttgg 88260
gcagataaag aaagacagga gcaaaaataa agaggtggaa aaccacaggg gtgtttgatg 88320
tatgcagggc acggaaatca gttgtatggt ggggggtacc ttcaacttaa aacctctgta 88380
ccagttaggg tgcttgagtt gtaagaagcc gaaaccaatt ctggctcatt taggcggaga 88440
aagaatttac aatccatgac taggatatat ccctccatct atttaatccc tgtttaactt 88500
ttctttattt tttatagttt gtatagtttt ctatgcagaa gacttgcaca tctttcgtta 88560
catttgttca taagtatttg acacttttat gttattatta aagattttct tttttttttt 88620
ttgagacgga gtctcactct gtcgcccagg ctggagtgca gtggcgcaat ctcggctcac 88680
tgcaagctcc gcctcccggg ttcacaccat tctcctgcct cagcctcccg agtagctggg 88740
actacaggcg cctgccacca cttccggcta atttttgtgt gtgtgttttt agtagagacg 88800
gggtttcacc gtattagcca ggatggtctt gatctcctga tttcgtgatc caaccgcctc 88860
ggcctcccaa agtgctggga ttacaggcgc gagccacagc gcccggtcaa gagttttaaa 88920
aaaatttcag tttctaactg ttgacactac atagaaatac aatagatttt tgcatattgt 88980
ccatgtatct gccaaacttg ctaatttaac ttattaatta taataatttt atctatggat 89040
tcttttggat tttccaaata tacaacatgc catatatgag tagtgacatt tttatttctt 89100
cttcctagct ccgtaacttt attctatttt cttgacctac tgcattgact aggatccttt 89160
actacaatgg gaagaaaaag tgatggtggg cattcttttc tcactcctga tcgcagggca 89220
gcatttaact tttcaccatt atgaatgatg tttgctctac agatttctgt agaaccattt 89280
atcagattca ggtagttaat cctaacttgg ctaacagcaa ttaaaaaaat gaagtaatat 89340
aaaaattaag aaattaatat gctgctaatg atatgttgtt gagtaacata aatataccaa 89400
tttttctata tctactgaga tgatcatatg aatattgttc tttatttact atggtgaatt 89460
gcattcatta attttctttt cttttttttt ttgagacaga gtcttgctct gtcacccagg 89520
ctggagtgca gtggtgcagt ctgagttcac tgtaaccttc acctcctggg tccaagtgat 89580
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tctcctgcct cagtctcccg agtagctggg attataggtg tgcaccatca cgcccggcta 89640
atttttatat ttttagtaga gatggggttt ccccatgttg gccaggctga tcttgaactc 89700
ctgacgtcaa gtgatctgcc tgtctcggcc tcccaaagtg ctgggattac aggtgtgagc 89760
cactatgcct ggctggattc attaattttc aaatgcattt taaaatttct gaactaaatc 89820
caacttgatt ataatatact atcttttttt aagggaaaag tagatgaatc agactcagca 89880
aaaataggag ccagaatagc aactgatacg gtttgtctat attcccaccc aaatctcatc 89940
ttgaattgta atctccataa cccccacttg tctagggaga gatctggtgg gaggtgatgg 90000
gatcatggtg gcagtttccc tcttgctgtt ctcgtgatag tgaattctca tgagatctga 90060
tagttttata agggcctctt cccccttcgc tactcactct gtctctcacc tgccaccatg 90120
taagacgtgc cttggctact cctttgccat ctgccataat tatctgagat ctccccagcc 90180
atttggaact gtgagtcagt taaacctctt ttctttataa attacccagt ctcaggcagt 90240
tcttcatagc agcgtgaaaa ttaactaata cagcaaccat ggcaggggaa ggccaagcac 90300
cttgactgag tatatccaat gggagaggag atttttttct cacagccaaa tcaggacact 90360
cacagctttg tgtttaaaag cttgggctct ggactcaggc tgcctggttt gaagtgccag 90420
tcctccctct tatgtggcag gggaccttag ctctgagtat ccttctctat aaaggaggat 90480
gatgttctat ttacccaata agattctaag gattaaatga tacattaaag tgcacaggtc 90540
agatcactct cagcccatag aagtaattat aattccagct attattattg ttatttgtga 90600
atatgagaaa gaagaaagtt cactctgaca tcctgtaaat ggaaaattca actgaacatt 90660
gaaaaatgtt taaatctgtc tatcagaaag tttttcatca aaagaaaaca ctgagtagtc 90720
tagtgttgta gcttgatcca aaaccttgaa taattttcaa actcatttat gatatctgaa 90780
atattcaatg acttatacct ttgaattttt tggcagcttt gtggaggtat agctgacata 90840
taagaaactg cagatattca aaatgtacag ttttataagt tttgatgtat gtatacaacc 90900
attaaaccac taccacaata acataaggaa catacctgcc ccccatccac acatttgatg 90960
cgcctccttt taaaattctc tttcctaccc tccacccctc actgtttacc aaaaagaatg 91020
tctgatggtg ccctgggcag tcccactctg cctagaaaac accatagaaa aagacagcaa 91080
aagtgctttc tcactctgga gttctacttg attttaatgg acatagatta gtgtgaacca 91140
cataaaccag tactaaaata caggatttga tctagaaaag gtgatgctaa aaatgcatgt 91200
agataaaacc taattttttt cagacaccaa aatgaaaaat tattagtatg ccatgacaca 91260
tgaacacttt tatattccac aaccactgtg ctctcctttt ggtgttcatt tgcaatggat 91320
ggaatgttta tgtcccttcc aaatttgtat gttgaaatgc taactctcaa gatgatggta 91380
ttaggaggag aggctgttga gaggtgatta ggccatgagg gtggaaccct caagaaaagg 91440
attagtgccc tcagcaaaga ggcctaggag agctagcttg ctcttcccag catttaggga 91500
cacagcaaga gggtgccgtc tgtgaactag aaagcaggcc ctcaccagat accaaatttg 91560
ccaatgcctt ggccttggac ttcccagcct ccagaaccat gagaagtaaa tttctgttgt 91620
ttataagcca cctagtctat agtgtgtttt gttttagcag gctgaatgga ctaaggcatt 91680
atttattgtg agttctattc accatggagc atatgtggcc tatgtgtccc tggcactgag 91740
gcaggaactg agcagagtac gcaggggaat taataatgct tggacctatc tttaaaacac 91800
ctagagttta gtaggaatca actggaagta gtagggtaaa ggaaagtagg tgacttttgt 91860
tgagccctgc catgtgctag agactgtgct aaagtgattt acccacatta tcttatttga 91920
acctcatggc aagcctgtgt ggtaggtcct attcctctat ttacagatgg ggaaactgaa 91980
gctcagagac attaagtaat ttgcccaagg ttatagaatt atcagcaaca aagctgaaag 92040
tggcaaaggg ctctttctag tcaggaggaa ttaagagagc ttgggtgcag tggctcacat 92100
ctgtaatcct agcattttgg gaggccaagg tgggaggatc agttgagccc aggagtttga 92160
gatcagcctg ggcaacatag tgagacttcg tctgtacaga aaaaaagaaa aaagaaaaaa 92220
agagcttggg atcgtgcctc ctgtgactca gcatcacctt agtcttggtc tgcctccatt 92280
ctgaattgtg ccctaaagct agtcattgct tccttcttgg tttctgctac aagtttctgc 92340
ctctcccact ggcccatttc cggggttcct gttcctgtta tgcacatcaa tccctagatt 92400
tctgaggtcc cagagggtgg gcttctgctt agtccctgtt tgtcttccca gggctaggca 92460
tcctggtcct tagccctggc actggggctt ctctccctgc tgccttcgac cccccggggc 92520
tgaccatctg ctgctctatc cctgcatcct gccagctttc acatcccctg tctcgagctc 92580
tgcttgccct ttactcttga ggggaactcc ctgcctccac ctgttggact ggtctggtcc 92640
cttcactggt cctgcccttt ctgaccatct tctactctgg tctggcctcc cattttccag 92700
agctcatctg tctccatgtg tgtcctgctt ctcagagggt cttgagttcc agcttttcca 92760
ggtctggctg gtgccatggc caaaacctgt cccacctctc ccattcgagt tcctcactag 92820
ctcctttttg acagttcttt cttttttggg gtctagcttt ggccttgctg catgaatcat 92880
taacacataa atatgtgtct tcacaattaa ttgtttccat ttggtgtttg ctctagtcaa 92940
ggaggatgga gagggagcaa catcttgtac tgaatgtctt gacatcacta gaaactagac 93000
tgcttgtgct tcccgggcat gctgaggtct caagaataaa gagtatccct gaagacattc 93060
ttatcagtct tcccctggtg aaacattcat cctaattttt cct tttagct ttgagaccac 93120
ttttgcatga tttttaatat gtcattaaat taaatagata taattttctc tgtctagcca 93180
agctgctgtt agaagaatct ttgcatacaa ctaatcataa aaaagacatt cttcttgcct 93240
26
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ctttggaaag gagcctgtgt cacctaagag tgaggagtac actcattctt ttgtgccttg 93300
ttcatctgct caggggatta ttgattagca gatagaatgt gggtgcaggc tgggcgcagt 93360
ggccatgtct gtaatccagc actttgggag gccgagatgg gtggattact tgaggtcagg 93420
agtttgagac cagcttgtcc aacatatagc gaaacccccg tgtctactaa aaatataaaa 93480
ttagctgggc gtggtggtgc atgcctgtag tcccagctac ttgggaagct gaggcaggag 93540
aatcgcttga actccggagg tggaggttgc agtgagctga gatcgcgcca ctgtacacca 93600
gcctaggtga cacagtgaga ctccatctct caagaaaaaa aaaaaagaaa tgtgggggca 93660
gataagtttt ttggggggtt tgcttttaat tctttggaag aactgggctt ggctggctgg 93720
gcacctagag caatgtggat atgggcagct gcttgtccca tggatgccag ggacagagtc 93780
acaagagaga tggttagaaa tggtgccagg ttctcgctgc ctcgtgccag gtcagctccc 93840
aacaaagcct ttgtacaaga cacatataaa ccctcagaga gtttatgcta acccagtgtc 93900
ttggccatgg cttactcatg atggaaaact gatcatattt tattctggcc acatggaata 93960
atagacatgt aatcactatg agatttgagt tgcagggtct ttggtttcta ataaccttta 94020
taattttctc cctcatcagg gagacagaat aaggtgttta cattactact ttcattttgc 94080
aagaataaga tcgaggttaa atctacagtt atgtcttgat agactgcagc agatttctgc 94140
atcagtagaa agtgctgttt tcccactaat cagaagaaga aagtgctagc cataatgata 94200
tgggtccact gtgaagtaga agacaagaaa cagagcagga cgtggaattg ggagcaatga 94260
gaaaaggtgc ctagagttgc tcttggcacc ctgcacctta gatcaccctt attaactgcc 94320
tgctgtttac tctgaaaatc tttctgtcat ttttgagaga taaaatctga aaatgcagtt 94380
tcttcaagtt agaaatgata atttttataa tagagtttaa gaaagccatg cttcttttct 94440
cttctatgag aacattttta tttcaattat aaaattgcca ctataaatag ccagtcaagt 94500
tcatagggca tgagtctcat caggcggata atttacatta tataaaaaaa gtatgagtta 94560
tttaactaaa ctaaaaaagc aaccagtatc ttgtggtcac atactgtatg tgatcccttt 94620
tacttgcaag gtaaaaagtg gtttcataac cttgccaata taattccaaa gaactaagga 94680
cttagtgatc gttgctaatt gaagttattc tgtttatgag caagcaacac tatttctttg 94740
atgaaaacca gaaaggattt acgtgtcggt aaatagggtt cctttatgtt tgtgtatgtg 94800
tgtgtgtttg tgtgtgtgtg tgtgtgtgtg tgattttatg aggtttgtct cattcttcta 94860
tgctagtgag tgttgattag ttggattgcc ttttcagttg acctattgct ttttaagagc 94920
atttttggat atagtccctt aacccagaat taacttctat gataaaaacg.ctttttgggt 94980
tgtcagagag gctaataggg gatatatggg cagggagttt tttaccagcc gtcagatctc 95040
atcttgcaga ctgtaactac tgtaaccatg ccccatgaag ggtagtacaa atcatgctat 95100
tgaaattgag agagatggct gccttttgga caggaagaga actagaagtt tttgactttg 95160
tgaatctaac ctctgcagct gcatccccca gggctgctgt ccacataccc tgtgctccac 95220
tccctctcat gatttctctc accaccgtca ttctttgttt ctcttgttcc tttatcctga 95280
agctctcaac ctatgaacct gtgaaaagcc cagataacag taacagatta catttattta 95340
tggaacattt attatagatg gtgtcatttt ctaagtactt taaccatatt gattccttta 95400
atctttgcaa tcatgcagtg aaacaggtga ttctcatact cccattttac agttgaggaa 95460
actgaggcac tgaggggtga aatgacttgt ctgggaccac atagtacgta gtcgagctag 95520
tatttggacc cagactgtct aactcaagag cccaagttat tggccaccat actctatagc 95580
acctctaacc cagatcaaat atacacagca ccatcacata gtgaaattaa tcagtgtcat 95640
gtccattccc tctgcttaat tgtatgtttc ttgtgatgag gaacataagc catctccaat 95700
gcctggggcc acacat'agca gatgccctat aactatcatc attgtcatcg tcattcttat 95760
cttcctcttc ctcctcatca taatctacta catataaggc aaatttgtgg gtcaggcaca 95820
cttcacataa attagattta attctcacaa caatcttacg aaatttgtgt tgtccccagt 95880
ttatagttga aaagaccttg catttaggaa gtggtaaaat gggaatttgc gaccctgcca 95940
tttggttcca gaatccttcc tcctaaccac tctataccat atgcttaatt aagaaaaaaa 96000
gaaacaaata ggtgagaaaa aacaatgatg tgaagaattt tgctgccccc agtattagga 96060
ttttttttct tcttcttgct agactctaga gggcccagat cctgtggagc tgtctctctg 96120
aagggaaggg tcaggctgtt caccctgatt ttcctggagt cacagataaa cttctgccct 96180
ccaccggatg cctctatctt acacaattat tttcctttac aaatttggtt gatgacatat 96240
tcacttggga taattgggtt gtccctccta ctttgaaact gtgagagagt tcactcaatt 96300
tccaactgcg tatgaagctc ttgagtcaga tttttttgcc tgtaacacct cagctcacac 96360
cagtgcagaa atggaagttt taattggctg taggattgaa gggttggttt ggtgcatggt 96420
ggtattttaa gaaaggcaaa gttttattta aatgaggaat attctccctg ggttttttga 96480
gttagctact gggccatgca acaggcctgg ctgcttgtga gaaaatgaga agggtgatca 96540
agtacaagaa gatgcagcca aagaagtgga cacaatccac gtcaagttcc atcttctttg 96600
tggcagccat gattctgaag gtcactgaag ggtatttttc cctgagctgt ttttggagcc 96660
tgtgccactg gcttcaaatg ctgggtcttg gccacctcag ttgctataaa atatggttat 96720
gagtgcttcc gCttCCCagC atCttgCtga CaaagCCCCa CttgtgCCtt gCtCagCCCC 96780
acttcattgc tcctgccctc tctggggaga gggactcacc acctgggtga caaggttagg 96840
gcttcttgct gcactttttg gcatcttgct gctccctgta taagggcaaa gctaaccttt 96900
27
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tttttttctt ttcattgaga cagtctcgct ctgtcaccca ggctggagtg cagtggtgcg 96960
atctaggctc actgcagcct ctgcctcctg ggttcaagtg attctcctgc ctcagcctcc 97020
cgagtagctg ggattacagg cttaaaccac catgccaggc taatttttgt attttagtag 97080
agatggggtt tcatcatgtt ggccaggcta gtctggaact cctgacctca aggaatctgc 97140
ctgcctcggc cttccaaagt gctggcatta ctggcatgaa acaccaccac aactccgacc 97200
ttcaaaagat ttaaaaaaac gtgaaaactg aaatgaagac tagatactaa tgaaacattg 97260
gactcattat gactttgtta agtcgttttg attttattaa aatcaaacat taataaagca 97320
gactgtgaat aaataaatta tattctttgg ccatttcttc attagacaag gatgctatct 97380
ttcatggctg tgttattgtg gggatggctg atagctcata gaaccaatct aacatccaca 97440
gatttttttc atagttctgg actaggtttc ttagcataat gcgttgttgt ggtcctcatg 97500
gtctgtgatt ctctcttgcc aaccttgttt catcagtccc ctgttgtcct gcagattttt 97560
gaagcattgg aatcctagca acagatttct catttaagta ggatggtcct gatcactagt 97620
ctcccacaga gagttggtaa aaagttttgt tcttcttatc acccacagaa cttccctgaa 97680
acattttttg ttgtgcttgc tcagaaacca taagcttagt agaaaaatgc accttgcttg 97740
tgaatacaca atcaggtgtc caaatgagat ggtcccctcc tagaagataa tatttcggaa 97800
gtcttgcctc agtgggaggt acttggttgt ttgtttttgt tttttttttc atttcaatag 97860
ctttaggggt acaagtggct tttggttaca tgcatgaatt gtatagtgcc gaagtctggg 97920
attttagttt acccatcact cgagtagtgt actctgtacc cagggtcctt ggattttatg 97980
agcttgtttt tgtttgcttt tatgttaaga tatgaataat atgatatgct ttggctctgt 98040
gtccccactc aagtcttatc tcgaattgta atccccataa tctccacacg tcaagggagg 98100
gacctggtgg gaggtgattg gatcatgggg ggcaattccc ccatgctgtt gtcataatag 98160
tgagtgagtt atcatgacgt ctgatgtttt tataagtgtt tgaccattcc accttcacac 98220
gctgtcactc tcacctgccg ccatgtaaga catgcctctt ccccttctgc cataattgta 98280
agtttcctga ggccacccca gccatgtgga actgttgagt caattaaacc tctttccttt 98340
ataaattacc cagtctcggg tatttcttta tagcagtgtg aaaacagact agcatataat 98400
agaaggctct ttaccttttt aaacttggaa ggccaaatta atactgtcct ttccattata 98460
agaatcttca gattaaatat tttctcattc attgtccctc agatcatata catttgcttt 98520
ttaactctaa gttacatgta ataaactaaa caatgaaatt gtattgtgga tcataaactt 98580
gagttttaaa aagatttttc tcctaatttt aaaagtaata aaaacaataa atacttactg 98640
tattccaggt agtgttcctt tttttttttt tttttttttt tgagatggag tttcactctg 98700
tagcccaagc tgtagtgtgg tggcgtgatc ttggctcact gcaacctcca cttcccggcc 98760
tcaagcaatt ctcctgcctc agcctccttg gtagctggga ctacaggcac acgccaccaa 98820
gcctggctaa ttgttttgta ctttagtctc tactaaacag ggtttcccca tgttgcccag 98880
ggtggtctcg aactcctgag ctcaggtgat ccacccacct tggcctccta aagtgctggt 98940
attacaggcg tgagccaccg cgcctggccc aggtagtgtt ctaaggggca tgcttccatt 99000
aattcatgga attcacaata accctttgtt gcagtaacta ttattatccc cactttacag 99060
ataggaaaga ggtacagtga ctggggcaga gagaggctct gtgactttgt gcaagcagca 99120
atgtaggcat ttgaatttcg gcacgctggc tcctgagtcc attctcctaa aaattgtgct 99180
gtatttaatg cagagaattt caaaaacatg agataaaaaa taagagaaga atagcatcaa 99240
ttttcccatc attcaaaggt atctgttaaa aggaaacatt taaaacttag ctatatatac 99300
tttctgaatt tgtatgtaca tataaactta taaaaaatga aaatgctaat tgttttcaca 99360
cgtactgttt ggtagcctcc ctttggtatg ttcccagacc aaaaattatt attcttcccc 99420
atgatttttt tcagctacat aatgttctat tttatggaag tacatcattt ccataattga 99480
atttcttatt aagacatatt atttgcaaat ctgcaacaaa tgtgcatgtt atttttagac 99540
gtatgtttgg ttatttcttt acgatagagt cctagaatca ccggctgagg caagggagat 99600
gcacatttga agcctcttta ttcatcttgc caattgtcct caagaaacat tgtttcaagt 99660
cccattaatg caagcaatga acaaaagttt ttatttttct ggatactgga tgcctctggc 99720
ttatttttct ttctattctg tttctttaat agacaaaaca aaagaaaaag tttctcatat 99780
caatgtgcat ttttttgcga tttgcaaaaa gttcaaaaat taacaaaatt tatctattcc 99840
ttgagtaaat gtatgtggtt caagatgtca aagaaacaaa gtattgtgca gtggaaaatg 99900
agtgcacctt cagcacctgc ctcccagaca tccatcagta accctctcag gaggcgacca 99960
ctgttaccat ttccttgact agccttccta gaataattaa gcatatacaa gcaaagaagg 100020
gtataagggt acacacacaa ataagcatac tacatatatt gtttttgccc ttgtgttttt 100080
cacctaacaa tatattttgg aaattattcc atattaataa tcaaataatg atattattat 100140
ttttgatgcc tacctactat tgcattataa gggaattata agggaagggt tgcaaatatt 100200
aacatctgtt aattagcttt ggatatttct tcttttgcaa atacttgcca gtgttctttg 100260
agcag~tctta gaattgtggt tttaatgttt tgttattgat gatgatttgt aagtctttgc 100320
tgtgaaataa gatgaccgac cattggtatt aaatgatgta aattttattt cacatttcat 100380
tgttgtcttt tcaattttgt tttctggtgg taggcttatt ttgttgttgt ttgttttgtt 100440
ttggtgtggc tatggaagtc tttttgggca atcaaatcta tcaatcattt tgatttgatt 100500
tgtgaatgat tttcctggat tttcctggat gatcagaggc tagtgttgtc tctttgttta 100560
28
CA 02426405 2003-04-17
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cttagattct tttgacaagg gctttggcta ttgtgaatag tgctagtatg aacatggatg 100620
tgcaaatatc tcttcgagac cctgctttca attattttgg gtatatgtcc agaagtggaa 100680
ttgttggatc atatggtagt tctattttta aatttctcag aaactgccat actctttctc 100740
ataacagctg caccatttca caatcccacc aacagtgcac aaggattcca atttctccac 100800
accctcacca atgctcgcta ttttttgggt gttatttttg acagtagccc atcctaatag 100860
gcatgaggat caattgttct gaacataaca tttctgtcag ggtttttaaa aagtttccaa 100920
aatgacatcc ctccagctcc acatattcta taagagcaat atcataaatt agaagctgtc 100980
tatgaaaact tgtagttgga agatgtttgt tttctgtggg ttagttacat ttcacatatg 101040
cctcatttgt gaaataattt ctaatgtgca tgagctggaa ttcaatgcct gtagtcaaag 101100
taggcttaat tttgaattgg agttgattaa aatgaaatga ctaattagct ttatattgac 101160
ttgggagttg tcccctaagg aaggcattgg gacaatgttg atactctgat tacctctatt 101220
cctacctctg ttagcttaaa atattagtac tgcattcagc acccagcaag aatttctagt 101280
atctgaaggc agcaggatac ttgcagccat tttcaaacca tggaatatgg atgattggta 101340
gagacttctc tatcttgagt cccttctaat atttcatgct ttatcttatt cataagaagg 101400
ggcttcacta agtaggactg tcttgtcttg accactaggg gatcaaggtt aagtttctta 101460
gtcttggtaa ttgtcagatt tctagtcttt aaaataggga taatgtcatg gagtacctat 101520
gtcagagttg caaggaccaa acgagctaag gcatgaaaag catttagcaa ggtccctggc 101580
aagtaagggc taaataaaca tggtgtttct tgatgttatg tcttgtaacc attgtaataa 101640
tctcagtcaa tcagatttat atcagggtac aggttctttt ctggggaatt tttctagcac 101700
caggtatttt ctgtttatct tctatgtgga tggcttttcc ttatttcttc tcattgacac 101760
caagggattc caagtcccat tctgattgtg tattgtcaaa gtgaaaaaca gctgtggcca 101820
gcagagccat gactataacc attttcaaag tcctgtgtgt aacaaacctc aaggattgat 101880
ttttcactaa gcctttctcc ttgactgtca aatgacaagc aagggtatgc agatgataac 101940
cccgaacccc tttgatccca tttccaaaat atggccatgc catagatgaa ggcaaattgt 102000
tttatttcat cttgttggcc ccattgtgta tgctctaagt tcattttgga cttctgtctt 102060
tactgatagc aatttctatt tctttcagac agaagcccct tctttcatac cttttagttg 102120
catttcttag cattctggcc gcagtcttct actacatggt ccttatttgt catctcttcc 102180
ctttcttcct ctctccatcc cttttttcca ttattcatcc agcaatattt attgagaacc 102240
aaccatgtga ggggcagcac actggacatt gtcttggctt cctctgtcac tgcagattta 102300
atggatcact ttagacttat gcctgtatta ttgccagggt tcccctatgt atattgaaac 102360
aaatattctc tggggatctt tccattttct gccactgatt ttttctttct tttctttttt 102420
tttgagatag agtcttacta gctctgtcac ccagcctgga gtgcagtggt gcgacctctg 102480
ctcactgcaa cctatgcttc ctgggttcaa gtgattcttt tgcctcagcc tcctgagtag 102540
ctgggattac aggagcgcac caccatgcct ggctaatttt tttttttttt tttttttttt 102600
gtatttttag tatatacagg tttttctcat gttggccagg ctggtctcaa actcctgacc 102660
tcaagtgatc tacctgcctc ggcctcccaa agtgctggga ttacaggcgt gagccaccac 102720
acctggccat tttctgcctc ttctgattgg gctgtgtatc tgagctgtgt cctgggccac 102780
tgtgccatcc cacagctgac aaaatggctc tcacctccag gaaactctta cctcagcatt 102840
ttttcctctg tcttgagctt ttcttttgtt ctctgggaat agtcctctta ctttcttgga 102900
gcttctttag ttattttttg atcaattttt tttacacagt tttttgtaac ggagcaaaat 102960
attttcagaa cttgtttctg gcatgtgtgt gtctgtctca tctatctgcc tgtgtctatg 103020
ttaaccgttc tttgaatctg atgcccaata ttctatttga ttctgttgat tctgaaaatt 103080
tctttttagt cattggttta gcatttctac ctcttctcct taaaccctag gattttcttt 103140
aaaaagtgtt gggactgatg ttctgttctt cagattggcg aacatggctc aaagaccact 103200
agtgtttaag cagcagcagc ttttctatat tctgcttgct gtgggcactt gtgatgtccc 103260
actgtggctg ccatcagcag agatgtggat cctggtggtg gctgtgtctg cctcctggcc 103320
agccagcttc ctttataggg aagaaatgct tccgcttctt actggggtgt gagaggcggg 103380
cccgtcagtc actgctgctc cctagcactc atagcaatgt ccattttcta tcctttgtgc 103440
cctgatgata atctttctgg tatcataact gtcttctcct ccccttccct gtctcctctt 103500
cctgcttttt ttcttcttcc tccttctcct cctcactcca gtatcaaggc ttagcttaaa 103560
tgtgttgcac tataaaggcc tcatatttta aaaatataat tcattcagtc ctcctctatg 103620
cctaagctta tttctttgtt atggcacttt tcatttcata gtatagctct ctaccgagga 103680
gcgcatacgg gataagggca gagtatgagt attttttgag cccaaaaaat aatagtcatt 103740
tttattggta tagcttcaag catagttcat ttacatgatt tatgttttag gaaatttcaa 103800
gtgcagaaaa attgcccagc agttagagat gattgggtta tcaatatgct ccctgttttt 103860
tggtgtattt tttccagctt tattgaggta taacttacaa ataacattgt atatgtttaa 103920
gatgtacaac ttgatttttt caaaattaat tatttttttg aagtaaattt tattgtgtat 103980
acttaaggtg tacaacatga cgtgatgaga tatatataga taataaaatg attactacag 104040
tgaggcaaac taacgtatcc atcatctcac gttgttatcc aacactaaaa tctacgcatg 104100
gagcaaaaat gcggaataca gtacaatatg attaactata gttctcatgt tgtagattaa 104160
atctctagac ttgttcatcc tatatctgct actttatagc ctttgatcta catcttc.tca 104220
29
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ttttcttccc ttcccccaac cctccccata accactgtgt tatgttctat ttccgtatat 104280
ttgacttaat aaaagattcc atatataaat gagatgatgc aatttttttc tgagtctttg 104340
tttatttcac ttagcacaat aacctccacc aggctcatcc atgttgtggc aaatggcaag 104400
atctcattcg tttttaaggc tgaataatat tccatttgtc catttgtcca tgaattgtca 104460
cttaggttgt ttccatatct tggctgctgt gaatagtgct gcaatgaaca cgggggtgca 104520
gatatcttta cgaggtggtg atttcattcc tttggatata tattcagaag agggttttct 104580
ggatcacaga gtaattctat tcttaatttt ttgagaaaat ttcatactgt tttccgtaat 104640
ggctgcagca atctacactg ccaccaacag ggtacagggt tcccttttct ccacacgctc 104700
accaacactt gctatttctt gtctttttgg taatagaagg gcagggcatc attaatattg 104760
tttcccttac atgtgctgaa caaacacagc agagcagtta ccagcgctaa ctctggaact 104820
ggcttgctca tgctcatctc ttgtccctgc cagttcctaa ctgcggaaac ttgggcaagt 104880
tgcttaacct ctctgtgcct tcctttgtta cttggagctg ataaaaataa tgcttagaac 104940
agttactgcc atataaaaag tgctattaag tgtttgctat tatgtgttga attcagctta 105000
atagaatcat catcaggatc accagcaatt tattgagtga cagtgtgtgt tttattcatt 105060
gatcgtcatt acacttagaa tagggtcggg gatatagcag gcattcaatc aatatttttg 105120
agggaatgaa ttaatgaatg ggctagatgt tatatgtaca aagaaatatg tctaatttct 105180
ttccttcagg tctcacagat ggttgagaat acaagatgga gataagacga aaattgaatg 105240
gtgcttaata tgaagccctt caaggctgcc tctttcagaa tcatttagga ggcttattaa 105300
aattgcagat ttgctagcca aactctcctc gatctcagtt ccatagatct ggacgtgggt 105360
ccaaaactct acagtgccaa gaaagctccc caggggcttc cggtgaattc ccaagaacag 105420
ccaggactgg gatcgcaggc caggcagtaa atgatacagg agatgagagg agggagagct 105480
ctgggggctg acactgttgg gaaggcctgg tgagagggga ggtacctgca agggcatgta 105540
gggcttgggc atggggtgga cttgatcgtg ggggcttaga ctgcagtaga gacattctgg 105600
tcacatttgc ccgcccatga gttccttccg tctcctgatg tgccccagca atttcatgtg 105660
caaagtacac aagagccatt tgttggaaag tacctaaatc actctattta ctgagtgctt 105720
tacttgcact tataaatcta aaacaaattt tcaagcaaat aaacaagtgt gtggatatgg 105780
agcagaaata ccactcatgg catcctgaac ttggccctct gactcagtaa ttagtatcct 105840
aaaactgagt tcaagcatca cattttattt tcaggtttta catacttcat agaacttggt 105900
ctctgatgtt acagagatca cagtaacagt ttaccttatc tccagaattt ctaacttctc 105960
aatggtggca tctctcatta gaacaggtag tcaccaaata gttccacaca aagactctcc 106020
caatgtgtca tttattaaaa caaacaaaca gatttgatat acaattaata taccacaaaa 106080
tcacccatct aaaatgtaca gtctggtagt ttttaacata ttcagaattc tgcagctttc 106140
accacgaatt aatcgtagag tattttcatc accccagagc cacccctccc tacctttagt 106200
cacttcccat ttccccggcc cctgataatc actcatctgc tttctgtctc tgtggagtac 106260
tattctggaa atttcatata aatggaatga tacaacatgt ggccttttgt gactgacttc 106320
ttttacttag catactgttt tcgaggttca tctatattgc agcatgtgtc agcacctcat 106380
ttctttttgt gctgaacact attctactat ataaatatac ttcattttct ttatccactc 106440
attagcttgt acacaactgg atttccactt tttggctatg tgcaaagttt ctgtatgcat 106500
gcatgttctc atttctcttg ggtacccact taggactgga attcctggga catgtgctaa 106560
ctgtatttat ctaacttttt gagaaatctt caaaatggtt cccaaagcag ctgcactatt 106620
ttatatgcct accagcaatg catgagggtt caatttctcc acatcctcac cgacatttgt 106680
tattgtcttt gattatagcc atcccagtgt gtgtgaagta gtatcttgtt atagttttga 106740
tttgcatttc cctaatgata aatgacataa agcatctttt caggcatatt ggccatttgc 106800
atatcttcct tgagaaaatg tatgttcaat ttttttccat ttaaaaattt gatgatttta 106860
aattttattg ttgagttgta aggattcgtt atatattctg gatagtagac ccttatcaaa 106920
tatatgattt gtaaatattt tctcccattt tgtgaatctt ttcactttct tgatagtgtc 106980
cttggatgca caaaagtttt tagttgtgtt gaaaaacagt ttgtatatct tttcctttgg 107040
ttatttgtgc tttatgtgca tatctaagaa actgtttcta atcctgggtc aggagactta 107100
caactctgtt ttcctctaag agttttatag tttcagctct tatatttagg tctgattcat 107160
ttagaattaa tgacttgtat atggtgtgag gtagaggttc aaatctattc ttctgcatgt 107220
ggctatccag ttgtccgagc actaaatgtt tagtccattt tcatccttcc attttgtctt 107280
gtccaggctg ttgaagtagc ctcctcacag ctctccctgc tcttagctct tctccaccag 107340
agtccatctc ccaccatact accagttatt catcttatac acagatatga ttatgtcctt 107400
tccttaataa aaaaacttta ttctttcctt agtttctata aaatagttca aatattcaac 107460
ataaaattcc aggtcctatc tagcatgacc tcaacccacc tcctaatttt actgtgttcc 107520
ttctccccac ttgctacccc atcccagcca tccttgactt cttagctggt ctctttctgg 107580
cctgagtgag acatttggcc tggatatata tgcatggtat ggctttggtt gcttactgtg 107640
gcattggtgc ttatgggata gccattgact ttaattaatg gggtgttatc agcacattta 107700
tcctattgaa atgactagag gaacccataa gaaaccacat tttcaggact agtaatctat 107760
tttagcatca tttggaagac aacaaacttt cattttatgg gtagactaac attcacaaat 107820
tatgacatat atcatataat cataatcatt aagttatatt ttaaataatc aaccatccac 107880
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
catcccaaac tctaagactt tgttggtaag ttttgtatgt cacaggttca tatttttcac 107940
attctgacac ctacattcaa ggcctcaaac tttaccagag actttttatc attgaggtaa 108000
aactagaagt cattaattta aaaaattata ttatttttaa ttatggtaaa aacataaaat 108060
atacatttta ccatcttgat tttttaaagc agtttactag tgttaagtat attcaacaga 108120
tctccagagc ttttcatctt gtaaaactga aactgtaacc catttaccaa caactccttc 108180
cccatttcct tctcctccca aggcctggca accaccatta ttctttctgt ttctgtgaat 108240
tttactactt tagatacctc atataaatgg agtcatatgg tatttagcac aaggtcctca 108300
aggttcatcc atgttgcagc acatgacagg gttttcttcc ttttcagggc tgaataatac 108360
tccattttgt ctctatatca catttttttg tttatccatt gctctgttgg tagacatttg 108420
tgttgcttcc acttcttggc tgttgtaaat aatgctgctg tgaacacagg tgtgcaaatc 108480
tctttgagga ctctgctttc agttctttgg gatatataca cagaagtgta tataggatta 108540
ggattgcagg atcagatgat aattattgtt ttaatttttc aacttatctt ctcgaatgag 108600
aacactaaat taaatttgtg gggtttgtgt cattttagac atagctcacg aagaagatgg 108660
taactttaaa ttgtccctgc aacaatgatg atgggcttca gtgattgtct taaatgagtc 108720
atcattattt ttgtgtttta taaccaaccc tatgcatctg aacacaaaag tcaaaccttt 108780
ttaatacctc aggtgtattt tacaccaaaa tacagggaaa aggcatcaat caaagctgct 108840
taacagctga tatgatagtg attacatgtg atatggtagt tgagactgaa atgctatttg 108900
taatacaaag attatcttaa ctgagtctga tttgaggtga aaaaaggtac taattagggt 108960
gacaatatga atttgattta actttaaagt attatgagag aaaacatact atgtcacaac 109020
tcttttgtat aacgaactgg gatttaggta tggagtgggt agaatagtgg tcaagagcag 109080
ggattctgga gtcaagtgtt tggcaccaat cctggctctg gccattgcca gctgcatgag 109140
tgccactggg caagcttctc acagcaccag atttttcatc tgtaaaatac ggttaataat 109200
ggattgtggt ggcattacat gaattaatat acgcaacatg ccggaatgac atctggcagg 109260
gaggaaaagc catataagat tttgtaattg attttctagc acaagctatc-cattcttagg 109320
ttgttgtatc ttccttgtgt catcccacat atcaatattg tcatctgcaa aaaatataca 109380
cgtatgtctc ttttaactaa tgattttaaa atgtggacta atcaatgatc taaaatcccc 109440
cttcctttta gtcaattagt agttcataaa ttgaagatgt gatggataga acatttcgta 109500
cccagaaagc tcttagattg taaatgctga gggaacactg ggagattcag tgagtgcagc 109560
acaaatacaa tctaggtgac tggaatagtt tctaatgaat gaatcactga ataagcagat 109620
gggttgtgga aggcaaacca tgagtaaatt ttttctttta ctacagaaat atttctgaaa 109680
ggtaaatacc caggtttatg atgatagacc ttctttaaac tcatgctatt tttctttctg 109740
ggttttgttg tcaacacaat ctcatctgct ctttgcaacc attacctctc agaatgggta 109800
tgaagatcag gtgcaaccat gtatgtgata atgcttctaa aagctatttt ttttccagtt 109860
ttattgaaat atattttgca taaaaatata aaatccaccc atttaaagta caaagctcag 109920
tggttttcag tacattcaca gagttgtgcg atcattgcca caattaattc ctttctgtct 109980
ccatggaatc taattttgaa cattttatat aaatagaaca atacaatatg cagtcttttg 110040
tgtctggctt atttcattta gtatagtgtt ttcaagggtc atttatattg cagcatgtat 110100
cagtacttca ttctttttat tgccaaataa gacttcattg tatggatatg tactacattt 110160
tattttctca ttcatgagtt gatgaacatt tgggtttcca cttttggcta ttacaaataa 110220
aattgctatg aacgtttgtg tgtgagtttt tgtgtggaca cacatcttta attctcttga 110280
gtatatgcct aatagagaaa tttctgagtc atatggtaac cctatattta gcacttccag 110340
gaactgccaa atggctgtac gattttacat tccaaccagc aatgtgtgag ggctccaatt 110400
tccctacact gtcatgtaca cttgctatta tctgttttgt cataatgggt atgaagtggt 110460
aaaactactg aaaaaagtga catattcatg gagtaaaagt aaaattgaaa catgcagaaa 110520
gtattcttca ggcccagaca gccccccaga attacagttt tttttctaga gtccttgaaa 110580
gttgtctatg cacatatgac gtatccctag atatgtattt gcaagaacac atgtaggagt 110640
atactatttt gtatcattct ttatcactta ataatatacc taagagcaat tgctatagaa 110700
caggttgacc tgcctcattc tttttactct tagcagagta ttttttgtga cgatgtacct 110760
tcgttcgttt taacagcttt tctaatgaag ggcattttgg ttggttttgc tcttataagt 110820
aatgccatgc gcatccacaa gacatacaat tgttcttgag tacatttgtg aagatattca 110880
caggaaaaaa caagttatac tgctatatac caccatcaac aggggatgag agtgcctatt 110940
agcccacagt ctttccagct taacactgtg tgttatcagc ctttcccatc ttggccaatg 111000
tggtaggtaa aaaatagttc agtaaaagtt gatttgacct ataaggggca aatcaagttt 111060
atgttataaa gcttgaagtt caacattgaa gttgaactcc agataatatg gttaaagctt 111120
tcaaatttct gagaaatatg caggcataga gattgtgtct aaatttgcct taatacatag 111180
tatatccatt tgctaattga agaaggtgat tggttcattt atttattcaa ctggcattta 111240
ttcagcattt atcgtatgct aggtgaactt taagtgctag agagaaggat gaataagaaa 111300
cacacattgc ttacaagtaa tatatagtct aataaggggg acatatatat ataaatcaat 111360
aagcataatg gacatgaaat agaggcaagt attatacaat aagctgtgta tattaggcca 111420
taggctaagc tactgtgaaa aaaaaggacc ctcaaatact tgggaaattg cttttgggaa 111480
aagacaaaaa aaaaaaaaag cttgtggaaa agggtgaaaa gtggacatga gagtaaggag 111540
31
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
agtaagccat ttttaaaata aaattttatt ttaacttcga ttgtcatatg gtaagtgtac 111600
atattcatgg gataaaaatg aaaggttttg acacatgtgt gcattgtgta atgatgaaat 111660
cagagtaatt agcaaatcca tcatctcaaa catttatcat ttctttgtgg taaagcattc 111720
aaaatcctct cttctagtta gtttgaaata tacgatgcat tattgttagc cacagtcacc 111780
ctgctgtgca atggaacacc agaactgatt cctctcacct aactgcaact ttgtaccagt 111840
tgatcaacct ctccccatag ccatttcctc ttaagcaaga aacatggaaa ttgtacacat 111900
tacttctgaa aatacactgg caagccactt ctagttgcag ggtagacttg gaaaatgaag 111960
tctaactggg tgaccctgtg cctccacatt attctggagg aaggggatca cggagctagg 112020
gtccccagtc tgggaggctg gtagagaggc agctcgctgt gctactctga tatttttagc 112080
tccgtggggg aaaaagaact gctagacaga gctctgtcaa cacagatctg acaatctcat 112140
tcagaaacaa gttacagaga cctcaagtga ttaataaaca agattattct atagaacatc 112200
ttatggtgac ataatcaata tgatttcaac actcagctaa taaatgctat gaaatacaat 112260
ttatgtaagg tgttaattga catgtcaggt tttaaataca aaaggaatga gggagggaga 112320
catgaatata gatgggtgtt atcagagaat gacacttaga tacatttcat attgtgtcat 112380
gtaaactaat acctactttt tgggatattt cttcatggtt tagtttttaa tgtagattca 112440
agagttttat atattcaaac tcttcatgaa aaaaattcag ctctggttat gtacatccac 112500
atttacagga attgaatttt tctttttgta cacttgtgag tatatttttt cctatggcaa 112560
acgttttcca gaaagcaaaa gttatttgtg ttactgtccc tgataatcga tgctgtgtaa 112620
taaatcgttc tcagcaatgg cagtttggac actgatggac agttggtgac tggtaatttg 112680
tacagtatgt ttagtgggac ggcgggcaag ggggaaaagt ggcatttggt tcctcagtcc 112740
cagatttggg tcaatgttct cataatactg gtgagcaagg agcctaattc tttaggaatt 112800
ttaaaaggtt tcttttagtg aagaacattt cccaggtgtc taatgaaaaa ttataaatga 112860
ccaggtataa ttttgccaag ctttccaaca tagttttcct ttagggtgag aaacaatcct 112920
ttgattttct tgaagtagaa gtctcttctc gaatgctaac agtaaaacaa gaccttttca 112980
gacagatttt gtattttgcc atcaaatgtg caatttttga agatacggga cttgagaatc 113040
aggtaaactt cgttctgaaa accaggctta attttatgac tgtgattaga aagttgaaaa 113100
aaaaatcacg ttctcacaaa tgaaaacaaa agtcagagtt caaactgttt atcctgtttc 113160
tgtaagcttt tgtttcagaa ggccaaggat tatttgagga gaacctggaa aattaactca 113220
aatggaggaa aaaaatggcg tttatgcaaa atgcagcaaa agcagacagc cttggagaac 113280
tgaagcttaa atagcgtaag agtctgagta ctagtcttca gatacttaaa acagcatttg 113340
atagacaagt tagatattta aggaaacatt taatcagctt ggcatcagca ttagtggctt 113400
caatttttgg ctgagcctga ctttgccata tgatcctaga caaatttgcc taaaatgggt 113460
gatattaact tctttaggga aaggctctgt actgggattt ttttgaggcc tatgatttat 113520
ggggtcaagc tataaaacag gaggaaacac atgctcattt gtataatttt tacatatatt 113580
tggtccataa ttgtacagct aggcaattca tttattatct gtttgagagt aaaagtttga 113640
ttattttaat gttactactt ctggtttttt ctcttctcac atgttcccag tgactccttt 113700
ctgataaccc aacttatcat catagaacgc atgtaatgct gagaataaga cacagggtct 113760
tggaaaatga atgacagcaa tggtgctccg atggcagttt tgtcagactt tgaatggttt 113820
atgaaatcac tgttgataaa agtgaacacc ttctactgaa gggagaaatt taggggggaa 113880
aaatcccaaa tagaaggagt taatatccaa acctggagac ttacctggta aggttcactt 113940
aactggtaaa atgtgatcca atttaaacaa agtattttta gttttctcag aacaaacatc 114000
ctacataaac acaaaaaatg atatgagaca tagatataac ttggttcaca atattttcca 114060
aaactataat gtaccagcca gttggtacag cacaccagga gagaagatca ttattaatgt 114120
gctaatagca gcattttatt ttgaaaccca ctctgcatgg ttacagggct caaaacaaca 114180
tattctaaca ggaagataca ttaccgaaat attttaatga gaatatttaa tatgcattga 114240
gaggtccgca ttttcttgca gagaccttgt aggtagctct ttgagatttc tgtctctatg 114300
catttaagtg aaggagttgg ttgggtattt tagttggcaa attttgcaga catgtagctt 114360
tggtagtgga gaggtaatag taccatgccc tgcgtgctgg cgaggaagcc ccacagcaac 114420
agtggctttt agcagctacc agatttgcta aaagcagcca tgtccaatta gcagtaagtg 114480
ccatgcacct gcagttacta ggaattgaac ctcttttgag gctgaatctt aatgtagcct 114540
tttaaaaaaa tagcaaaaat cttactcata ctctgagata ataaagaaaa attagcaatg 114600
gcaaaatgga cgcactctga aatgtattct taataatgat ttagaatatg gggtaaatgt 114660
agaggcaatg acacatttaa actgcattat ttttaaatac tgttttatca gtttacttcc 114720
taattttgaa ttcaattttc atatctatac tgcaactgct tttttttttt ttttttagaa 114780
atctataata ttgctgcagg ctccctatgt atgtttccat aattttctgc aaagtgtttt 114840
caccagaata aaaaaaaatt acagttcaaa attgcaaaac tgtagaaaaa atatgctctt 114900
tgacttcttt tctatgtgtc aaattcacca caatggaaag gactacacta tagaattaaa 114960
acgttatttt caacagatag tacttatttt aacatgtgtt cagcatttaa aaatatttaa 115020
tattcttttc taaaaatgct tacattcaga aactatttat gagggttctg agcagtatga 115080
tgtttctttc tctgatttac tgctttttct cttttagagg atattgtagg agaaaaacat 115140
ttgttaagca atttccagaa ctactaggtt ctaataagac caataggcta ataattcatt 115200
32
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tcattgcaac tggagtgtgt acttttcctt tattctcagt cataattttt taaaagagcc 115260
aagaacacca aatcatcaaa tctaatgttg aacatgtagt aacttttatt tgctgatcat 115320
actctgagat tcaccataac gaataaatca taagtattaa aatttcagct ttttaacata 115380
cccactacac tgctagcctg gtaacacagt caccaactac acagcttctt caactgttga 115440
cgtgctttaa agctaggatt atggtatcct gccaaaaaga tcctacaaac tgtcactatt 115500
ttggtttgtc ctgccagcca ttgagaagta gacaatttct atatacacaa accagtttgg 115560
aaaatttatg caaataggaa gttattctca aaatgggtta tttgattgca tttttttttt 115620
tttttttgag acaaggtctg actctcgccc aggctggagt gcagtggcgt gatcttggct 115680
cactgcaacc tccacctccg tggttcaagc gattctcctg cctcaatctc ctgagtagct 115740
gggaatacag gtgcatgcca ccactcctgg ctaatttttg tatttttagt agaggcaagg 115800
tttcaccgtg ttgactaggg tggtctcaaa ctcctggcct caagtgatcc acccacgttg 115860
gcctcccaaa gtgctgggat tacaggcata agccaccgtg cccagcctga ttgtgtttta 115920
atgtattggc tcccaaccag tagcaacagt ttgggtgcac agatattgcc gtagtgtttc 115980
tattcaatgt gtcaaattat ttaggtaaaa gtttggctta actttgttga catggaattt 116040
ctatatcctc cagtttctgg tttaactggt ttatgtggaa atgaatggaa acacatggtt 116100
aagttcccca gcctccagct tctctcttcc tcttacctat atttgtactt gcccactttt 116160
cctcttgtgg gcctgttcct agaatccatt atgttctgtg ggtgacatca gcctgctact 116220
gcgggaagaa atagaatttt atggtgccca agataaaatc gactatgatg atgcagaatg 116280
aagacctgga gaggagtcag agattgcagg ggataaaaag agagaaatca gagatgctcc 116340
cacaaacaga gaaaaccttc agaagcagca ggaaggacag agtaaatgga gaacaaaaac 116400
tcaagtcaaa atagtcaatg gaaataaaca gttttgaatt ccagttataa tttggaaaag 116460
aagcaaacgt ttattttaaa ttaagaaaaa agtcgcttat aatttcctga agtttagaaa 116520
agtgaaaaat agttaaacct cctgttgtta gctaagaagt gtctattatt ataagtttgt 116580
cgctggagag aacataaaaa tctctatcta ttgctatttt tttttttttt tgcataaggg 116640
atagataaaa gagtgtttat tttatttagc ctttggcctg taaagtaaga tttatgaaac 116700
aaaggacaat cggaaatgat aagaattttt tcctaatttc taattattta gctaaacctt 116760
gattgatttc tctcaggcta gtgcccatat tacagcagca gtcagccttc atttatctta 116820
cctgggacca ctgctaaatc cgatgtcact tttcagtttt tatattatgt gaccatttag 116880
ccacatttca cctacttgat cattccctcc atcttgagac ctccctcgac ccggcttcca 116940
acatactttg ccctcctggt ttttctttct ctgttggctc actttctcag tctcctctgc 117000
tggttgctcc atttttccac aatctctcaa aactggtgct cctcagatta agtccttgga 117060
cttctctcct tagattgaca tctggagtca tggcttcaaa caccacctat cactcccttt 117120
ctccttgaac tctagacgtg tccatccaac tgctacgtga catctccact gggatttcta 117180
agaactttgc caaacttaac atgtctaaaa ccaaattctg ggctgggggt ggtggctcac 117240
gcctgtaatc ccagcacttt aggaggctga ggtgggcaga ctacttgagc ccaggagttc 117300
gagaccagtc tggccaatag agaaaagctg tctctacaaa aaatacaaca cttagctgga 117360
cgtgatggtg catgcctgta gtcccagtta ctggggaggc tgaggcggga ggattgcttg 117420
agcctgagaa gttgattctg cagtaagcta tgattacacc actacattcc agcctgggtg 117480
acagagtgag accctgcctc aaaaaaaaaa aacaaaaacc aaaaccaaaa ccaaaaaaaa 117540
aaagcaaaga gcaaaacaca aaaaacatat tccaaatctc ccctttaaac ctcctcttct 117600
tacaatgagt cctatcttga tttatggcag atccttcctt ccagttctca agccaaacac 117660
catggggtca ttcttgactc ctctcttcca tgggctcatc taaacatcag agtatcctgt 117720
tggctatctg gaatttaacc acttcctatc actgccattg ctacccacct gctcttagtt 117780
atcaccagag ttccctggag tgttggagcc gccgcagagc tggtttccct gctcctgcct 117840
ttcctgccca tgctctgtcc tgccagtcag ctctgtcctt taaaaatgga aatcaggtta 117900
cctcatgact cttttctttc tttttctttt cttttttttt ttacagaatc ttgctctgtc 117960
atccagcctg gagagcagtg gcatgatctc tactcactgc aacttccgcc tcccagattc 118020
aagtgattct cctgtctcag cctcttaagt agctgggatt ataggtgcca gccaccatgc 118080
ccagctactt tttgtatttt tagtagcgaa ggggtttcgc catgttggcc aggctggtct 118140
tgaactcctg acctcaggtg atctgcccgc ttcagcctcc cgaagtgctg ggattacagg 118200
tgtgagccac cgcgcccagc catgactctt ttcaaaaact ccccatcttc tccacttcca 118260
ttcagtaaca gtcagatctg catggccccc tcctgacctt ctgatgtcat gttctttgct 118320
accccttgag tgcattgaac atgcctctga cccagaactt ttctgtttgc tatttcctca 118380
agtgcatatc ttgttccttc attttcttca ggtgattatt aaaatttcac ttccatgagt 118440
ccttccctgg cccccatatt taacactgca tcttcctcca tcttctttcc ctcctcccca 118500
tgtacatttt actcccttac taaatttttt ttcctatctc actttctttt ctttttgaga 118560
cagagtatta ctctgtcact taggctggag cgcagtggcg caatcttggc tcactgcaac 118620
ctccacctcc tgggttcaag caattctcct gcctcggcct cccgagtagc tgggattaca 118680
ggcgcgtgcc accatgcctg gctaattttt gtatttttag tagagacagg gtttcatcac 118740
gttggtcggg ctggtctcca actcctgacc ttggcttccc aaagtgctgg tattactttc 118800
taacctcctg tgtatgctac ctatttattt gtctgtctct ctacactaga atataagctg 118860
33
CA 02426405 2003-04-17
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ctatgagggt agacttcttt gttttgtcca atgctctatt tccaatattt ataaccgtac 118920
tggccggtag gtactgtcaa ttatagtttt tgaataaatt gagagtaaca aattctaact 118980
ggtgaaaata aattaaatgg gccgggcgtg atggctcacg cctgtaatcc cagcactttg 119040
ggaggccgag gcgggcagat cacttgaggt caggagttca agaccagcct gggcaacatg 119100
gtgaaacccc gtctctatta aaaatacaaa aattagctgg gtgtggtggt gcatgcctgt 119160
aatcccagct actcgggagg ctgaggcaca agaatcgctt gaaccctgga ggcgaaggtt 119220
gcagtgagcc ggcattgagc cactgcactc cagcctgggc gacagagcga gactctgtct 119280
caaaataaat aaataaaata aaaattaaaa agaaaataaa tgatctcaca ggatatcatt 119340
tcttgattgg aggaggagag aaaaatgtgt atgtgtgagg gtacagagag agttcctttg 119400
cattagtgag ggttcacatc agaactgtct aacctcccta ctcagtgggt cctgttacct 119460
ctctcctgaa tccaataata ctctggtgca caccttttac tggtactgag gctattttaa 119520
cgttccatta aaaaaaaaag aaaacattta aaatacaaaa acaaggctgt actactttaa 119580
ctctgacctt agaagactct cagttttata actgtttaga gaaaatgtgg aaatgtttgc 119640
tggccccaat ctttttatta ctcatctcta taaagaggct tttaaggaca tattaaaaag 119700
tttecatctc tcttgtctct tgcctttctt ctcatcttcc tttcttgtac cccaaatggc 119760
tgaaagcaag accctgagag tctggaagaa atatattctg gtcagagcag actgagctgg 119820
agctggccta gaaccttgga tcctgacctc agaattgctg ctcaaattac tgctctctga 119880
aagagtgagc tcatgcatgt ttattattac tgtgaacaaa tttagctgtt gtttcaccca 119940
aacattgaag ttctcgcttg gacccctttg cttgtttgtg cttttgcaaa tgtgttttct 120000
catgtgctac tagaaccaag atgaaagctt cagttctcag aacaggtgcc acgaccgagg 120060
agacaaaaca agagctatag aggggtgtgg tgtgtgaaac tgagaaagca ggtagttttt 120120
cagaaaaact gagagccagg aatgacttca tccatttcct gtaataaggc aatggtctga 120180
ccttgaggaa cctattagag tgtgcttcta aacagaggcc atttcgaggc tgaatgtacg 120240
ggagtattta cctttgactg ttttctgaag caaggtattt tataaactgt aaagtggctt 120300
atacaatttt aggaatggaa agttttgcaa agtctccaaa atccctggga gttttgaatg 120360
tgcaggccat atgaattctt tgtagtttca tggtcttgct gttcagcatt ctttagagtc 120420
acctgcatgg tagaagttta gtaggaattt gggtagttat gggctggttt ctttgttttc 120480
ccaaatagag gtagcaaaat ggatgctaag aagcaaatta cttttactat tttagatgcc 120540
tctggggaca tcctgtcata atgcaactta aaatatactc gtctcctcag ttccttttta 120600
tgtatttatt taatagtctt caaccaattt gttcttcatt agctgttcta caatacttca 120660
agagaagtca tgataatgat gcatttagga tcagaaaaat atagcatgtg tgagttcctg 120720
gggactttag agaatatcta gcccagtctt tcattttata gaagaggaag gccagggatg 120780
gtggctcatg cctgtaatcc cagcactttg ggaggccaaa gtgggcggat cacctgaggt 120840
caggagttcg agaccagcct ggccaacatg gtgaaaccgc atctctacta aaactacaaa 120900
aattaggcag gcctggtggt gggtgcctgt aatcccagct actcaggagg ctgaggcagg 120960
agaattgctt gaaccaggca gaggttgcag tgagccaata tcatgccact gcactccagc 121020
ctgggcaaca gagtgagact ctgtctcaaa ttaaaaaaaa aaaaaaaaga agaaggagag 121080
gaagctgggg gtgaggacag gcagtgactc acccagggtc tcacactgat ttgctggcag 121140
agttaagcat gaaaaggtgc ctctcctagt ctctttccag tgttcttgtc atcacaatga 121200
gttaaaataa aaattactag caacttggga gtaataacaa taaacttctc aaaatctact 121260
acatggtcta gaaaaccaaa cataaggccg gacgcagtgg ctcacgcctg taatcccagc 121320
actttgggag gccaaggcag gcggatcagg aggtcaagag atcaagacaa tcctggccaa 121380
catggtgaca ctctgtctct actaaaacca cagaaattag ctgggtgtgg tggtgcgtgc 121440
ctgtagtccc agctactcaa gaggctgagg caggagaatt gcttgaacac gggaggcaga 121500
ggttgcagtg agccgagatc atgccactgc actccagcat ggcgactgga ctctgtctcc 121560
aaaaaaaaaa aaaaaagaaa gacacccaaa cataaaacca gaatattcct gtgagttcca 121620
ttacatagga caatatggtc ctgctgatct attaaaatta tgtttataaa ttagaggctc 121680
ttcattggga gatatactta atgctagatg acgagttagt gggtgcagcg caccagcatg 121740
gcacatgtat acatatgtaa ctaacctgca cattgtgcac atgtacccta aaacttaaag 121800
tataataata ataataataa aaaaagaata acaggaaaaa taattagagg ctctttactg 121860
tatttaaggt gttcaaataa ttgaagctag gttagtatct ccttagcctt tccccagcat 121920
gccctgcagc tttgacgctg cagaacacca gttggtggct gatatttaga tgatggaaat 121980
acttggacac attttgcatt tttgataaaa tgacatggca ctgatggtta cattttacaa 122040
atatttttgc ggatgtatat acaggtggca tacccaagaa ggaacagacc ttcctcaggg 122100
gtccttctta ggaaagtaca gctttgcttc tctgatcatc agaattggat ccttcaggta 122160
ttaggttggt gcaaaagtaa ctgcggtttt tgccattcaa agtaatggca cctgaaaggg 122220
ttggtaaaat tcagaatatt ataaaatcag taaaagctta atcaaatttg cctaaatcta 122280
tcctacagat tagtctatgc atggtttatt aaacaaccta actgaaacac acatgcatat 122340
gtgtgagtaa gctgacatca gggatcacct tatcatggaa aatctaggga aggttggctc 122400
aatcttcaat ttgtgaagac caattcccct accacgtcca tatatacata ttcccaggag 122460
acttgtttct tcagggctct ctttggttct cagctcttcc tttctgaatt agtgggtcac 122520
34
CA 02426405 2003-04-17
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tttaacctcc cttgggtcac agtcgtgttc cacactgggt gggtccagag gtagaactca 122580
ttgcctttct ttgaatccca cacaagacca cccaacaagg cattgtagtt ggtggaaaac 122640
tccattgaag aaagggtcta tattgcaaca aacaagcatc tagaaataga atattaaata 122700
tccctcctct taaaaatcca ttgtccaatt cagacttcag cataatgtaa tcttctgtct 122760
tcttttctct gtgtttccat cttgagagcc atcctattat ctgtgtcctt tctttgttgt 122820
cttaggaaga atattttggc ttatcctttg ttttgttctc tccttcccgg acctattatg 122880
gtaaatgtgg aatttgcaga taggcttatt tgcgctcccc agcctgctcc cttaatgctc 122940
tctggtaaga cacttctttg agtcctccga ggcgagttgc tgccccccag cacctgctct 123000
tccccatcgc aacccatgac agtaaacgca ctgcacatac ttatcccaca gactgctgtg 123060
agaactagat ggaggctatg tgtgaagctg caagctcttg gtaaagtgct acagaaattg 123120
gtagacactg ttactatgat aagatgttca gaaaataatg gatcgattaa agtttcactt 123180
atctattaaa agataaaaaa ctctatgatt gagacctttt tggaatattg gaaaatattt 123240
ttgtgtgctt attagcatac tgatatgttt cagtacacat ttcatggatt tatggctaag 123300
gatgttactt tcaagaaggt aactatacat cgctctctac tagcatgctg ttctgttcct 123360
gagaaatagt ggctgggcga agggtatgca aacatttctt aatatctcat ccaataccat 123420
tttcccacta ctaattattc aacacatgga aatgtaggtc aaagcattaa aaaaaaaaac 123480
tagaacagca ataccttggt ggttggcagg tgtttattta aaatatttac gttttagcct 123540
tattttttaa tacttctttt tcatatatat tagatattta actaaagaaa ataataatca 123600
ttctcatgga atactttaaa atagtagaaa caatcatgaa tagaaatgaa gatttaggcc 123660
tatactaccc taggctctgt cattcttatt cctaaccatt tgcataggaa atttagattc 123720
acccacttct ctttcttaga ataagattca caggtttttg ggcatattcc cattgcatgc 123780
ctgactgggg aggtgttcaa atccctgctt ttctactcct cagccctgtg accctgagca 123840
atttctgtgg cttggtttcc tcatctgtaa aataggatat taatagaaca tatcccttta 123900
acgttgcagt gatcacatta attagttgat gcaaaacagt ccatctagaa cagtaagccc 123960
tcaataaatg ctagctatca ttatcatttc atagccagcc ccaccatgga tgggtcatgt 124020
gacctgaagc aaatttaaat tctctggatt tcagttatct ctcattgaag gaattaggct 124080
ccatcagtgg ttctcaaact caagtgagta tcagaatcac agggagggtg tgttatgaca 124140
ctgaaggccg ggccccaccc tcagaatttc ttattcagta gatccaggag ggagtgcaat 124200
aatttgtatt tctaaaaagc tcccaagtga agttgatggc tgatctggag acacaccttg 124260
aaattcttct gcttactcta aacaaaacgt gcttttttat cttgagtgca catcagaacc 124320
ctctggggag gttaaaagtc ccagtgaaat cacaacctct gcagatggta accagatctt 124380
agtggctttt aaagttctcc aggtgcttcc attgagcagc taaggttgac aacacttcta 124440
acaccgcttt caggtgaaaa agaactatca ttctaactta aatgaaggag aaaatgaatt 124500
catcattctg acaccgttat ctattctttc atgcatgggc ttatcctatg agaaataaac 124560
atttactaag gtgtatgcat gtttttagaa catccattgg gaagcatgtt gtacagcttg 124620
tagtaaaaca gcatggtgca tgctgaaact gttataggct ttgcaagtta ttttttataa 124680
attagttttg ctggtgtgct gtttgattat tggagagtgg tgtgaacatg tttctatgca 124740
tcccaggggg ttgctgtcac ctttaagggg cctctttaaa tcccagctct ttcatttaca 124800
aattctatga ccttggatga gtttcttcac ttttctgtgc cacaagttct cagtaaaatg 124860
gagataatta tagaacttac ttcatagagc tttgagaatc atacaggtaa agttatttta 124920
cgtaattagc actcaaaagt gaccattaat aatctaacgt tttaaaatat attaataggc 124980
cagatgcagt ggctcacacc tgtaatttca gcactttggg aggctgaagt gggtggatca 125040
cttgaggtca ggggttcaaa gccagcctgg ccaacatggc gaaactccgt ccctactaaa 125100
actgtaaaaa ttagctgggc atagtggcgt gtgtctgtag tcccagctat tcaggaggct 125160
gaggcaggaa aatcgcagtg agccgagatc acgccactgc actctagcct gggtgacaga 125220
gtgggactcc atctcaaaaa caaacaaaca aacaaaaatt aatagtttaa atatttttaa 125280
tatatttcaa tatataaaga tgtaattttt attttaaata tattaaaata gataagttta 125340
aaatacataa agtaaatata taaaattaat atgttaaaat gtttactgaa agtttacatt 125400
tttctctgta ttgctaagag caatttattg ccttatatgt tgtgtaatat ctagaaaaca 125460
cacctatgta atttccaaat tataaccacc ttggctcctg gacaagtagg actgtgtctg 125520
attttttttt ttgcatcctt gtcactacct gccactctga gatcacttgt tgtctttcca 125580
tatataatca cctctaggta cacttctttc attatttcta cgcatcctct ccactttgct 125640
gcattcttgt gtgcattctt ttctcccacg ttggaaagaa atatgcatat tgagcgattc 125700
caacccccaa aggcaaaaat tactagccag tgttgaaaat gaaagcaagg aattttttgg 125760
ttattgttgc tgtaactttt tgatgtgcgt acatatgtgc gtcttttttt tccccctagg 125820
ggtggaatgg ggtggtgtta gtcagggatt actgacagga cggtgttgcc tactgtgttg 125880
gagagactaa gactggggaa agattctcca aggctgggaa atgcagacgt ccagtcttgg 125940
aaaacagttt gtcgttggtc gttatgtcag aagaggagtg tattcctgga agaaggccca 126000
caaaatatac ccagagccca ggtgcctttc taagacgaat caacattcac tcacaagttc 126060
agctaatata tgacagaaat acaagaatga acaagactcc tgacttaagc ttacagctga 126120
tgggaaactt gggaactgga cagagaatta aaatacaacg tggttaggta caacttacct 126180
CA 02426405 2003-04-17
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gcgccagagg agtgacggaa ggccttggac ggggagtgat gcctggagga tgacagggcg 126240
acaggtaagt tagggggctg ggaaggggaa gggcggccct gtgggtaaag ggaaggaggt 126300
taaagtcagc agggaaacag gcagttccct gttgctggag caaagcgcgg gggtgtggct 126360
ctcctgtctc tggctttgct gtcaacaggc gagattggca agtagggcga ccaaccggcc 126420
tggtttgctc gggaccgggg tttcctggaa ggtgggactt tcaatgctaa aactgggaca 126480
gtcctgggca aacaaatcag tacggttggc caccctatct ttgtgtgggc atctgctaac 126540
tgagtcatgg gcctgtctgg tttatttatt tatttttttt ctgcctgagt aacagaagaa 126600
tgtgttaaac atatggagta tggaagaaga aggagagggg agataggatt tttatgttat 126660
agattggaag aagacatcct tgatgaagga gatgttttta ctttggagaa ggactgcctc 126720
agccgcgaaa gaccaagggg tggcaccaca gggagaagtc tgcactgcgc ttgtcaggac 126780
ggccagtggg gggctgctga gcgcagggag tcagtcctcg caatgaagat atagtctcgg 126840
ggagataatg ctggaaatcg atggaagaag tggaacagga cacaaattta gtggaatttc 126900
tttacaatgt gtgcttcttg tcaccagttc gttaaccatg ataaaaacgg ttatgttgtt 126960
acattcatca agatccaaat tttctaccat tttaagatgt ctatcagtca caatgatgat 127020
cactgaagac cgaacgagat catttcctct aaaaattatg ttacatttat ccataatggc 127080
atcagtgtct gttacacgtt tgctttaatt ttgaggtcaa atacgacatt tgtaaatcta 127140
gcacttcatg tgattctgta agcactaaac agctaaacat atttacttct tttttttgaa 127200
tcaattagaa cagtgctgta caatagaaaa atagaacagt gctgtacaat ggaaacagtg 127260
ctgtacaaca gaaatctgtc agccacacgt gtcgtttaaa cttttctagt aatcacatta 127320
aaattgtaaa aagaagccaa taaaagtaat tttaataata tattttgttt gacataatat 127380
agctaaatat caattttgac atgttctaaa tataacaatt attaatgaaa aatattacat 127440
tcttttggct ttgtactaaa catttgaaat gtggtgtacg tttttcactt atagcacacg 127500
caattcagat gctacatttt tattaggaat atttaatctg tagatagata tcgtaaaatt 127560
tacatttgaa aaaaatagat tcagacacct aagttgttac aagcatactt aaaagttttc 127620
aatgactgaa ttgagtatca gttttaaaat ttaaatcaat gaaattaatt aaaatgaaat 127680
gaaaatttag aaactattcc tcagtcacgc tggctacatt tcaagtgctt catagccaca 127740
tgaaagctgt attggacagc aaagaagtag aatatatttg gaataaaaat tttaaagtgg 127800
acacattgtg ttactctcgt tagccatgct attgctattt tttttcctat agctaattaa 127860
aaccttaaga tccagtaggt tctccacctt tttttaaagc attagttcca tgtcgaccct 127920
gtagatggca gcactttctt cctaaaacta catggaggag ttgcctgggc ttgtcactca 127980
gattctggca cttttcatag aaagagtctg aattatctgg aaaattcttt ggtaacatag 128040
gtcagaatct tttcagctct attgttattc tgcacagatg gctgttgctt atgaaaacaa 128100
tctctcagcc tctagtccag gatattactc attcctcagt tcaagaaact ctagggtgag 128160
aggagaaagg ggttcaatta cagaactgtt atcaaaatgc gttggtttat gcacatccgt 128220
gttttggaca tggtgattcc aagagactct taataaaact tttcaaagta gatgagagac 128280
agtttttccc tcacatgctg tggcaatatt aatctatgtt ttcatgttcc actggacttt 128340
gtaattgaat tttaaggaat gcatacaggg cttcatattt atatataaaa tatccatatc 128400
cagtgttgaa agaaattaac aataaaatat gtacctgtat aaaatttgtg atttttgaag 128460
cacccctctc ttcctcttcg cattgcattt gtggtaggag aacatgagac aaggaacgag 128520
gtactaagga caaagaagga gcgattcaga ggtggatttc ctgaagacca acaacatttt 128580
tgcatagctc gtgaggactc tctgatacta aactccaata aatgatggtt tggtgttttg 128640
attgcttttg attgacattt aaaaattaca ggagactgag ataggaggat tgcttgagcc 128700
tgggaagcgg aggttgcagt gagccaagat tgcaccactg cactccaacc tgggtgatcg 128760
agtgagaccc catttcaaaa caaacaaaaa aataaaaaat aaaaaaaaac aaataaaaat 128820
cacacgcctc tttttttcac tcaatctgtt ttccaaataa aatatcaaga ttctatttga 128880
attttaataa tgattttgct gagttttata gcttgaatac tatggcaagt ataatgtcta 128940
aaatgctgtg attttgactt aagaaaaaat ttacagtttt cttaatatac tctttagttc 129000
ttttaaactc taatacatga aatggattgc taatgagggt aggaaggggg aaagactggg 129060
gagaaaaata gctaactttt ctagcgatag atacatgtca gaagctgtag taggttcttt 129120
tgcatgtgtt tacttacatt accttctgta atctgcattg caattttttc atagacaagg 129180
aaacctagac ttagagaagt acaatacctg tcatctcgta aatgacagat atagttgagc 129240
aaatctactg aaatggttta gcttcttatc tttccagaca acagataagg acttattcta 129300
tatgaagaca tctgagaaat gaaaatatgg tttcaggttc atagaatctt ttacaccacg 129360
tatttctggt tctctttctt ctattcagat cattctttca tctgtttctt ttgtcttctt 129420
ttccaaaatg tagcaattgc cccaaattca gtacttgtct ctcttcttaa caatcacatc 129480
caatcccatg gcctcaacca tcttcccttg catataattt ccacatttac aactttattc 129540
tcttgattac tcaggataag ataattgctg aacaaataac agcatatatc tcagcttaag 129600
agagtaaaag tttatttttc tctcatgcaa attctattgc agatattccc cacctccttc 129660
cctaggttgt cctcaaaatg cagtgactca gggaactcct ctttctgtct taacctattt 129720
taggtcttag acccctttgg cagtctggtg aagccaataa atctcctctc aggacagttt 129780
ctaaatgtga taaaagaaaa aaaagatata gtgacagatc taataattaa aattcaaagt 129840
36
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
taatttcaaa ttagtgatag gtaaatatat ttcaagatgt ctgcactgaa tacagcgtga 129900
taggtaatat atatgattta tcttggtgac aaagacattg gtattgctaa cactattata 129960
gctgccatct gtattcacaa agggagatgt caaattccag ttaaaagaaa gattttctta 130020
acccaagttc ataggacttc ctgaatggta cagatgctaa ggtctagtgg ctccacaact 130080
accaaagcct tcttagtgtt ctctgctgga tcttatgcat ccaattgact gacaagcaaa 130140
gaacctgcag aataatagga gacatttgtt gggtggggag agcaaaccta gaaggggcat 130200
atacccctta caattatagc tctatgcgct agaattagtt atatcattcc tcctagatat 130260
gaggggacta ggcactgtac ttcagctgtg tgtccaggaa aaaggtaagg tatggggaat 130320
gtggagcaat aattatttga agcaagaatc accagtggat gctaaaattc gtgagggaaa 130380
acaggaccag aaacaggata tttttaaagt ctccaagtac ctccacatag gatacttatt 130440
aattgcaaag ggaaaatagt aactttacag agaagaagaa atctggcaga cactaccata 130500
tccaagtgat caaaggtgac atcagtagtg ggacacatta acatcatgtg cttctgatat 130560
gatacacaaa ggagaaacaa cctcattctt gtgatgttcc tgccaaaaat ccataacctg 130620
aaagaagcat cacaaaatcc ccaattgagg ggcattccac aaaatagctg gctagaactc 130680
ttcaaaattg tcaaggtcat gaacagttcc agaccaaagg aggctaaaag agacaggatg 130740
cctcaatgca agtataatcc tgaattgggt cttgggtcag aaaatgggca ttagtaagac 130800
aattggcaaa atttgaataa ggtcaataga tttgaaaata atactgtacc tatgtgaatt 130860
tcctgacttt gatcaaagca ctggggttaa gttaaaacat aagatgttgt ttttggaaat 130920
acatgctgct atatgcaact tactctcaaa catctcagaa aaaaaaatag ataagttcat 130980
agatagatag atgacaggat aataaagcaa gtgtgataaa atgttagcat ttggggaatg 131040
taggtaaaag tatatgggaa tattttgtac cattttctca acctttcctt taactcgtaa 131100
attacttaaa agaaaagcaa taaccctggc tcttataaaa ctaaggaaaa tggtccatcc 131160
tttcctgtgc cttgtgtttt cctgctggtc aaagaacctt tggtaatgac aatctgagtt 131220
ggtcactgat attctagtaa attcagaata taacttcctg ggctatgtag aaaaatatag 131280
ctcttcatat tttaattcat tttcctgaca gcacgtttct gtgcttttat gtatggatac 131340
tgcctagtaa tgtgcacacc agtcctgcag atcctggaac attttattat cttgatattg 131400
acttacgtat ttaggtagat ctgaatagca gaattgtcag tcgtttcacc aagacattat 131460
cgggaaatct ggacttggaa gtctacttct gccaggcatc tctccacgct ggcttctggg 131520
ccacagaaga aaagatctaa tcaaactcat ttattaacaa aggcttataa tattgaatag 131580
cagcttccag gaatctaaga aaatgttcac ttttatttct gactaaggag gaactattat 131640
agtcttttta taccagttag aagtgatgac ttggtattaa acttattcta attctcaata 131700
gccctgatct cgactctgac cacatgcgcg cacaccctcc cccaaccctg taagtgtgat 131760
tatggcaagg ggaaagttaa agtggagtga atggtgagtc gtggaatgac agagagcatt 131820
tagcatttgt aattgacaga gttggtgatt gactgaatgg acactgaata tctaggctaa 131880
aagtaattga atgtggatgg tgtagtgaga tggagaacac tagcaggaag atagactggg 131940
ctacgcaggg gctagatcat gtgttcagtc tgggatatac taagtttgag gtttctgtaa 132000
aatgtccatg tgaagatgtc caattgggag ttggatattt atttatgttt ccattcccat 132060
caatcgataa gcttcagagg aaataagagt gtaagatttt tttgaacaac aggaaaggaa 132120
gattgtagta agatatgatg gcataatggt atatggaaga gttttaaata aaagttagcc 132180
aggcatggtg gcacgcgtct gcagtcccgg ctactcggga aactgaggca ggagaatcgc 132240
ttgaatccgg gaggtgaagg ttgcagtgag ccaagatcgc accactgcat tccggcctgg 132300
gcgacagagt gagactccat ctcaaaaaaa aaaaaaaagg gatgaagagg gatgaggaga 132360
actcaagtta tattagcctg aatggaatag atgagtggag agatgggcat gataggtgag 132420
ttaagaagga aattctttgc ctcagcaacc aactcagatg ctttgtgaat ctaaattatg 132480
tgttgacatt ctagtagacc tagacctggg ataattcact tcagcattat gtaatcttaa 132540
tttttcattt ataaataaga aaatattatg caatacttgc catagttttc taaaagctga 132600
actcagaatg ttaatgaaat taaaatggga aagctatttt gcttagaaga tattttgtta 132660
taaacatttc ttaaatgaag aggctctaga aatatttatt ttatagaatt taaaatatag 132720
ccatcactaa taaaggcagg cataattcca acgatttcat aacacatcag ttattaaatc 132780
taattaatat ataaatgtaa ctaatatgta atttaatata accctaattc aatgtttaac 132840
caactgaagc tggttaaact atgaagaaga atcttcaaat tgaccatttc tttccaagcg 132900
gtaaaggtga tacgggattt tgtctataca tatagagcaa aggagaatta agccaagatt 132960
tagaatttta ggcaaaaagt gtttatagta tcattaagtg gttacatatg taattttact 133020
gttataaata tgactgagtc aatttttttt tcaaagattt tgtcacaatg ggaggcacaa 133080
ggagtttaga cagatgaaga ctctttctag aaatctacct aatctatcac attagacctg 133140
gagataattg gtttgacaat ttcagttgtt tctcagcaaa aaaaataaga aactaaaagt 133200
gttcagatgg cagagaaaaa agtttgaaga ggagagaaag aagaacaaaa agaaaaagga 133260
aacagtagac atataaagaa agcacctaaa ccagtgagat gccccagcta tgcaccagca 133320
gcatggtgga ttacagtaga gtttttctac agaactattg taaatcactg gaaaatagtg 133380
tccaacttat ttgcttaaaa ttttcagtta atgtgctcca gcagcattct gtagacaacg 133440
actctcactc tccccttatt atggaggcag agctgtttct ctttgtcccg ttctctagcc 133500
37
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tgtgatatac tttttattgc tcaagagcta tagaattgta tccatgccta ttgttgtcct 133560
cctgatggga attcatgtaa ttgaaagcgt ttatcctctc ttagtagaaa aattgggcac 133620
ttggaggcaa tgaaaatccc ccacctttgt ccacggcact ggaaatactc ttcagtctgc 133680
tttgttctaa agtttctact tttcccagta taacctgttg aaaatttagt ccttcatgag 133740
aaatacggct ggaatttctt gtggcaggct ggccgccggt gttcatgtag ttacaccttt 133800
tgttgctatt tcaccactga tcaaaaaata aaattgtatt ttttcaaaag aaacatggaa 133860
tgacatgaag aaagtcctta atatatcatg gagtgaaaaa cagcaagttg ccatgcaaat 133920
gtcaaataga tcctatattt ttaaataagc aactgcatat gtatcattta aatatatatg 133980
tttagatatt tgctaaatta tgaaccgcag ttacccctgg ggagtgaggt taggaaaagt 134040
aaagtgagat tttcactttt tacattatac tttttacttt acccacttct gtattgtttg 134100
aatctttaaa atgaacaagt gttattttgt aattaaaaaa aacaacaact gacaaataac 134160
tatggggagt aagaaattac ttggaatgga atatgtttaa ataattaatt tgttgataca 134220
ctgcttgact attattttct tttgctaaat caaaactccc ctgcttttct caggaggttg 134280
ttttgaaaag aagggtaaat gtttctaatg aaatgaacag ctcaaccttc ccacctcctg 134340
cctaaatgcc tcattttggt tttgttacta acaaatgcaa cacgcaaggc tttatggtaa 134400
agcaagcaat gtgggtttct aacagggcag tacacacccg tagttgctgg gaaaccactt 134460
tagtaatggt ggatttattg aattggaaca ggaatggaga tttggaacaa caggaagtga 134520
ggtacctgta ggggtctcag ttgtcctggg cactgtgaca tggcacccaa atgtcatgca 134580
agagtggccc ttccaacata tgcaccaatc tgaatctctc caaagtttct tgattacacc 134640
ataaaacaat gaagagaaca gcattgccaa taacttcagt aataactttt gcatcatatt 134700
acaaagggtg gtgggtggca ctttgtgtgg tcatgggtat gtccaaaaga agggagtggt 134760
ggctagactc agttctcctt tagattttaa ggcaaaattt agcaaactct atggcagatt 134820
cttcaactat ttgtcagaca gacattgtct acttttctgg ggatttatga ttgaggcccc 134880
ttttgagggg agctttgagt gcagtgaggc cagatagaag ggccaagaag gatgggagca 134940
gctgcatgct agtgagcaat tcaaagttgg attgtgctga ctggaaaatc ccggttagca 135000
aatcaactat cacagacttc atattctttt cagatgtgca gcctttataa catatttgta 135060
aatgctaaag gactgctcca cagggaggtt acaaagagaa aagctctggg tggttgtaaa 135120
atggacaaat tgtaaagcct tactagtagt cttaccattc ctctcagctc ataaaaaagt 135180
cctcctcttc atttgactat gcctcaaatc tactgcttct tggattatta aacactcttt 135240
tcctccagga tcttaaaatc tctctgttat aagttgaatt gtgtccccct caaaaatgat 135300
atgttgaggt cttaaacccc agtatcctag aatgtggcct tatttggagg tggggtcttt 135360
acagggttaa tggaattaaa acaaggccac tagggttggc cagtcctttt tataaggaat 135420
ccagtatgac tggtgtcctt attaaaaggg aaaatttgg.a cagagacaca cacataggga 135480
gaaagacgtg atgatgaagg cagagtgggg ggtgatgctt ctataagcca acgaacccca 135540
aagattgcca gcaaaccccc agaagctaca gagaagcatg caacagattt tctatcacag 135600
ccctcaaaca gaaccaaccc tgccaatgct ttgattttgg acttttagcc cctggaactg 135660
tgagacaata catttttgat gtttaagcca cccactttgc ggtgctttgt tccagcaacc 135720
ttgggaaatg attacacttt ctcatctgtg atcacagtga ggccttgtca caatcttcac 135780
tcattccttc tatagaaagc tgaaagccta tggacaagga taattgcctt ggctgacgca 135840
tatgtttgaa ggcagctgct ggcaggcaac cggagacttt accctggtcc tagtggagag 135900
gaagtctata ggaggaggca gggagccttc ctggctggca acccagtgac tcaggttgtt 135960
ttcttactcc aaggatctct gtgcaagtag gaatcctgac atcttctctt tttcacttgt 136020
ttatgagacc ctgcttgttg tagagtaaag agcagaactt aagaatggaa tctaatcacc 136080
ttgaaagaat aatctctcat ctcctctggt ggcaaaggat tgggatgtgg aggttatagt 136140
tggaaaattg attcctaggt caatgtctgt gggtgaattt ctctttgaat tgttatcagc 136200
aatgttatgg tgttcggtgg ctttcaacga aataaacaca cctgacatcc ttagtaaaga 136260
gaaagctttc tgaaataaga gtgagggaca gactgggaca tgatgctttg catgaaatag 136320
gtgttcagta agtatttgta gagttggaag aagttagatt aaacagggct attgtatggc 136380
acattgtcat tagggagtta gagagggctt ctggaaaggt ttggtcagtt ttgacttacc 136440
ttgcaataaa tttggactat aataaccatt tcactagttt gtaaaaggta ctggcaacca 136500
aagatgggga atgccactca atctcacttg ttctactttc aaaagcttgc tttggtcaca 136560
ttgaaaggtt ccatttggtg aagtatagca tatcacagaa aacaatggag tttgggagtt 136620
cgggaacaaa tggttgtttt gtgataatga ataactttga catttcgttt gaagttaagt 136680
tatgttgttt gaacttttct gtccctgaac aaggcatcgt atgccaagaa caggtaacag 136740
tttctggatc actggggact cattagtcat ggatggttag tggtactaca ttgtggtctt 136800
ccttcaatat tgaaagctgt aagaagcttg tgacaaattc ttaccttggc cctcacacag 136860
tactggtagg gctgggatgt tattgctttt gtccaccaac ttccaactgt agaagtctag 136920
gatgatcaca gcagttagag atgatccatt tagatagtct atattaaggg aaagtatcct 136980
tcatccatgg tgttgaacat tcgtaggatt aaaatgaaag aagccaaaac ctttctagat 137040
ctttattggt atatcaacag aattagctga ttaggtatgc agaaaaaact tgggacttga 137100
agacaccatt aaataaataa ctgtacataa ccatacatta aataactgta acaccattat 137160
38
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ataaataact aactataaat aaagagctct acattcaaac tgcttttcac tgcatttgtc 137220
agatttcact tttaatataa ttttagttga cttatccctc atcttacctt aagaagataa 137280
tgagttgagg tggatcttga gccagtgttt agtccaatat agccctttga cttggggaaa 137340
gatcaaactt cgaaatttat atgcatgact cctctctggg caaggactga agtggcagga 137400
gaggtgaaag aaggaatcag gacaaaaagt agatgctaaa aggaaaacag tctgtcccgt 137460
ggagaggaag tacccaaaga aacagaagaa ctccatgatg gagagtaata caagttgaat 137520
atcccttatc caaaatgctt gcgaccagat tgttttggct ttgggattat ttcagatttt 137580
ggaatatttt catacccgct cagtatccct aatctgaaaa tccaaaatct gaaatgcttc 137640
agtgagcatt tcctttcagt gtcatcttgg ccctcaaaaa gttttggatt ttggagcatt 137700
ttgaattttg gatttttgga ttagggatac tcaacctgta ctagcgtgtt aaaacagtcc 137760
tggccaggcg cggtggctga cacctgtaat cccagcactt tgggaagccg aagcgggcgg 137820
atcacaagat cagaagatcg agaccatcct ggctaacacg gtgaaaccct gtctctacta 137880
aaaatacaaa aaaattagct gtgccgtggc gggcgcctgt agtcccagct actcgggagg 137940
ctgaggcagg agaatggcgt gaacccggga ggcggagctt gcagtgagcc gagatcgcgc 138000
cactgcactc cagcctgggt gacaaatcga gactccgtct caaaaaaaaa aaaaaaaatc 138060
caaaaaaccc aaaacagtcc tagaggctac agcctagagc agtgggcaaa gagaagcaga 138120
atctacagaa gatattgttc aaggcctgct atgctaggtc tcagatagca ccagaactgg 138180
gcagggcaag aaacgtcagg cccaggggtc tggtttaacc agaagaggtg ctgaatttta 138240
ggatctgaat agcaagggtt gtggtcagga agtcagtttc atgtaagaat gaaggtgagc 138300
ggatcttaaa tccctgaaag gaggcagaga gaagaatata ggaaatgggt ggataatttt 138360
tgttgcgagt aaaaatgttc aggactttgg aggcaggaag agcaggtaaa gcaagttcga 138420
ggaaagaggc tgggtcagag gggatctgaa agcaggagtc agaaacatcc attggaggcc 138480
tggagaacat aaatgggagg tgaatagact ggggacatag tgcctgggtg gaaagaagct 138540
ggctcgagtc cgaaaccaca ggctgaaata ttaggaaaaa gagacccagg aattcagttc 138600
agaataggag ggatttgtgg ggcaagacca gtggttcttc cagacatttt atcagagata 138660
acaaagcaga ggctgtctgt tctctgccct tggtgtgaga agaaaaggac tgacaggagt 138720
gcttggcagc tcaagccagt tatggagctg tgggtgctag tggctattaa ctaccaggga 138780
attagctctg ctgaatgagt cctcacgcag aggcagggat agaacgttgc attcagaaga 138840
ctggccacgg aggccggctg gggtggctca cgcctgtaat cccagcactt tgggagacca 138900
aggcaggagg atcatctgag gtcaggagtt cgagatcagc ctggtcaaca tggtgaaacc 138960
atgcctctac taaaaataca aaaattagcc aggcttggtg gcgggtgcct gtaatcccaa 139020
ctactttaga ggatgagaga ggagaatcgc ttgaacccgg gaggcagagg ttgcagagag 139080
ccgagatcac gccactgcac tccagcctgg gcaacaaaga gtgaaactcc gtcttaaaaa 139140
aaaaaaaaag gaaaagaaaa gaaaagaaga gtggccacag attggcttgg ctggagaagg 139200
cattttttta tagggagata tacgtgagtt tgacgggatg ggctagcagg cggacattca 139260
ggttttatgg gataggcaaa aaggtacaaa tggtatttgg ggggatgtga atggcatctg 139320
agaaaggttg atccaggctt gtgtggaagc tggctctgag cataaaatgc cagagaaagg 139380
cttgtacaac tctgaggtct tttcttttct tttcttttct tttttttttt gagacagagt 139440
cttgctcttg tcgcccagcc tagagtgtag tagtgtgatc tcggctcact gcaacctctg 139500
cctccctggt tcaagcgatt ctcctgcctc accctcctga ttacctggga ttacaggcac 139560
ctgccaccaa gcctggctaa ttttttgtat ttttagtaga gacacggttt taccatgttg 139620
cccagggtgg tcttgaattc ctgacctcaa gtgatctgcc cacctcagcc tcccaaagtg 139680
ctgagattac aggtgtgagc caccgcacct ggcctatttt ctatttttta accagtccca 139740
agtaagggta ttggttaggg ttgaggcaat ggaaatctga aagaaagggt gagttaggta 139800
tttcactgga cacatgtgga gaatgttggt gatttaatgc agagggaatt gtggttaaaa 139860
aggttaatgt aagaagggtc atgtggggac tggaaatcac aatagagaaa cagaggccag 139920
aatgctgaac tcataggaag tgggtgacca tgggtgatta aaatgtacaa tagggctggg 139980
tatagtggct catgcctgta atcctagcac tttgggggac tgaggcagtt ggatcacctg 140040
aggtcaggag ttcgagacca gcgtggccaa catggggaaa tcccaaccct actaaaaata 140100
caaaaattag ccgggcacgg tggtgcatgc ctgtaacccc agctacgtgg gaggctgagg 140160
caggagaatc gcttgaaccc aggaggcaga gggtgcagtg agccgagact gcgccactgc 140220
acttcagcct ggggaacaag agcgaaactc tgtctcaaaa ataaataaat aaataaataa 140280
aaataaaaaa ttaaaatgta caatagagtg tgtaaaacca ggaaatctac atcttgacac 140340
ttaactaccc aagacgcaat tggttcctcg tctgattttt aaaagaagtt tccactttct 140400
tcggaaaatc acgacagtcc ttgttctcaa tttctttgtt tttaagaaga gaaatgttgt 140460
atgatttcac ttatataaac tacctagaat aggcaaattc acagggatag aaaggtggaa 140520
tggaggtgac caaaggtgga aaggaaggag gattgttcaa tgggtacaac atttctgttt 140580
gggatgatga agaatttctg gagatggaca atggtgatgg ctgcacaaca ctgggaatgt 140640
gcttaatgcc attacttaaa aatggctaaa aatcatgcat tttatgttat gtatatttac 140700
aacttttttt tttttttttg agacagtgtc ttgctctgtc atccaggctg gatggcggtg 140760
gcatgatctc ggctcattgc aacctccacc tcccaggttc tagcaatgct cctgcctcag 140820
39
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
cctccccagt agctgggatt acaggtgtgt gccaccatgc ctggctaatt tttgtatttt 140880
gagtagagat ggggttttgc catgttggcc aggctggtct cgaactccta acctcaagtg 140940
atctgcccac ctcagcctcc caaagtgctg ggattacagg tgtgagccac catacctgcc 141000
atatttacaa cttttaaatc ataggaaaga aaccactaat gctttgacaa ctgtgagatt 141060
ttgaatctca actgtgagat tatggtttgt ggaaatttct ttatgtgatt aaaaaagata 141120
ctttttttgc caaaaaattt gttttcgctg tcatgcaagt tctcctgggt aagcaccttt 141180
ggtcttgttt tgtgcatagc atacagagca gcaattgtat attgctaaag aaagcctgtt 141240
ttttttttct tgttaattta tttaagttcc ttgtagattc tggatattac cctttgtcag 141300
atggatggat tacaaaattt ttctcccatt ctgtaggttg cctgttcact ctgatgatag 141360
tttcttttgc tgtgcagaag ctctttagtt taattagatc ccatttgtca attttggctt 141420
ttgttgccat tgcttttgtg ttttagtcat gaagtctttg cctatgctta tgtcctgaat 141480
ggtattgcct aggttttctt ctagggtttt tatggtttta ggtcttatgt ttaaatcttt 141540
aatctgtctt gagttaattt ttgtataagg tataaggaag gggtccagtt tcagttttct 141600
gcatatggct agccagtttt cccaatacca tttattaaac ggggaatcct ttccccataa 141660
ggatatgaac agacactttt caaaagaaga catttatgca gccaacaaac atatgaaaaa 141720
aacctcatta tcactggtca ttagagaaat gaaaatcaaa accacaatga gatactatct 141780
cacactagtc agaatggttg ttattaaaaa gtaaaaatat aacaggtact ggtgaagttg 141840
cagagaaata ggaacacata tactgttggt gggagtgtaa attatttcaa ccattgtgga 141900
agacagtgtg gcgattcctc aaggatctag aactagaaat gctatttgac ccagcaatcc 141960
cattactggg tatataccca aaggattata aatcattcta ctataaagac acatgcacac 142020
gtatgtttat tgcagcacta ttcacaatag caaagacttg gaaccaaccc aaatgtccat 142080
caatgtttga ccgaataaag aaaatgtggc gcgtgaaccc gggaggcgga gcttgcagtg 142140
agccgagatc ccgccactgc actccaccct gggcgacaga gcgagactcc gtctcaaaaa 142200
aaaaaaaaaa aaaaaaggaa atgtggcaca tatacaccat ggaatactat gcagccataa 142260
aaaagaatga gtttatgtcc tttgcaggga catggatgaa gctggaaacc atcattctca 142320
gcaaactaac acagaaacag aaaaccaaac actgcatgtt ctcactcaca agtgggtgag 142380
ttccataatg agtgggtgag ttccacaagt tccacaagtt tcacaagtgg gtgagttcca 142440
caagttctat aatgagaaca tatttgcaca gggaggggaa catcacacac cagggcctgt 142500
cggggggttg ggggtcaagg ggaagaatag cattaggaga aatatctaat gtagatgacg 142560
agttgatggg tgcagcaaac caccatgaca catgtatacc tatgtaacga acctgcacat 142620
tctgcacatg tatcccagaa cttaaggtat aataaaaaag aaaaagaaaa agaaaaaaaa 142680
ccctgccttt tgctttggca gtcatcattc cttccatctt ctcatgtttt cttatttaac 142740
tcagtagttc tcaattgaca gcacaaaaga attactcagg agagttcaaa aaacacctat 142800
ggctgactcc cccaagattc tgatttcctt ggtgtggggt agcctgggca tgaatattat 142860
ttaaaaactc ctctcatgat tctaaggtgg tagccaggat tgaaaaatgc tggactttca 142920
agtttttgtt ttctttcttt tcttccaaaa aggtgaagcc ctgacttggg aagaattcaa 142980
atgcgagtta ggcttatgtt tgatgtcact gattcctaaa gatcagtcca ttgattctcc 143040
tcattctcag gagagcattt ggtgtcaaaa tcacagccca aaactcttac cctagttcag 143100
catctaact,c tcttcagtcc tgaaactgtt tttgtcactc tgtccatata atcacagtgt 143160
tgtagaaatt tccagctaaa cattgtctca aactttttgt acctagtttt aaatcaaaat 143220
gtagtacaaa attattaaat acaacgggct ttaaaatatt gagattttgg tgatcttttt 143280
tgtagaatgc aaatactaat gaaactaatt ttttcttttg ctttcaaact atacatttct 143340
tctaaaactt ctttcaaagt agaatttcat aagtggaaga acccttgaag attattttaa 143400
tagaattcct taattttaga gatgaggaaa ctgagactca aatatattaa ttaatttatc 143460
taagtgtctt agtccatttt gtgctgctat aagagagcat acttgagact gggtaattta 143520
tattgaacag aaatttattg gctcacgatt ctggaggttg gaaagtctga tatcaaggtg 143580
ctggcatctg gcaagggcct tctggatgtg tctacatggt ggaaggcgga agggccaaga 143640
ggtaaaatgt ggctgaattt gtgcttctat tatggcatga atcccatcca tgaaggtgga 143700
ggcctcatgg cctaatcatt tctcacaggc accacctttt aatactgtta caatggcaat 143760
tacatttcaa catgagcttt ggaggagaca aaaattcaaa ccatagcact gaagttatac 143820
aactagttaa gaagagagaa cctgagactg aaaccctgat gttttgactc ccaatccaga 143880
atgtttgatc ccctacatcc caccgcttcg ctgtttccat tcctttctcc tgttttcatc 143940
tattttcact aagagggcaa gatatttgct aactgctaca cacccaaatt gtataccagg 144000
caggtcagaa tgactctaac attttattta atgaggcaga ataaaatatc ttcctactaa 144060
acagtgacaa gtgtttgttt taaaaaaaag tattgtgcac aaaaaaaaaa actactttca 144120
gcataggcta tattttacaa aataaattta cagtgggaac cacagagcta tttagagtgt 144180
ctggtataaa tgattttatt gttactctgc ttttttgaaa aagaagtgtg tgaagcagag 144240
gtaagtagta ctgaggaaat aataactaaa atactaagga cgagatgcac atgggaaaag 144300
ttcttcatta actgtaacgt ggtggagaaa tgtatgttct agacaggtca atcatggaat 144360
tagaaaaagt tgggatcttg gattgttgag ttcaaatcct tagttttaaa actgaagact 144420
tcaaattttg attgactaca gatcaatcaa caacctgttg gagttggaaa cttgaatctg 144480
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
attctccatc cttgtttggg atatgaaaaa aaggaagaca tttaagagta tttttttatt 144540
tatgaaacta atgtatcatc atgtaaaaat atgaaataga aagtgttaaa aattataaag 144600
aaacaagaat gtgtttttat aatctcattt tcttacttta cgtaagatgg taagtctatt 144660
ttggaattaa ttgtttttaa gaatagtatt ataattcaat gttagataaa gatttattta 144720
accctttccc ctttaacaag tgtttgggtt ttttaagttt gcttccaagt tttcggtaaa 144780
tgatgcttca atggatatct ctgtttgtta tcttagtatg tatcttagat taattcctca 144840
agataaatat ttaaaggtat ggtatatgta atattcttga tacatacttc catatttccc 144900
tccagaaatg tgtgcaccta tttaaatgtg tgtggaggtg cacattttaa cattcctcat 144960
tattctggct gccttctata aatcaagcta ccctggtatt atggctctcc tccagaaatc 145020
taatcattta aacacatgaa gtgaatgtgt gaatggacaa ttaagtgctg gccaaatgtg 145080
gaaaaatgtt aagtgtaaat caaaggcaac tgaaacgtta aatacacctt ccattcctcc 145140
gccacatcca tgctctttcc catactccac atctgctcac taaaattgga aataaactgt 145200
aatgaaccag aaatgtctga cttactggtg tgtttaggtg agttttattg aaacactgac 145260
tgaccccacc actctaatac catcacctta atgtttgtat cttagattaa ttcctcaaga 145320
taaatattta aacgtatggt atatgtaata ttattgatac atacttccat agttccagca 145380
accacttgtc atcctgtgtc ccccaaggac actgcaatga ctgtcacagt gacttgtgct 145440
cggttgagga gcaagtggtg gctgaaatcc agccccagtc agctccccaa accaaaccac 145500
ttttacacag tgtctatgtg taaagttggt ttgctttggg gagattgatc cccataaggg 145560
atcagcacca gccctgtgtc tatctcttct tctcctgggg agatgttggc tattttgcta 145620
gctggagaag ggcacgcaat ttgttgtcag gagacaggtt cttaagttcc attggtacat 145680
gcagggcaag acaggcagag ggaatctgtc actgctacag gcacttcata agcccaggta 145740
tagacgataa ttgaaatgga ttgatttcat agtagtctaa tacagagtgg tgctacaatc 145800
tctgtatgtg cctatttaga aaataacttc atatttaatt cttcacttta cataaaagat 145860
atgtgtatta aatacacctt ttattttaga acagttttag attttagatt taaattggga 145920
agacagtaga gatttcctat ctaacccaca cccagctccc gtattagtaa ctaacatctt 145980
gcattagtat ggtatattac aattaatgaa ccaatactgt tattttatta ttaacttaat 146040
tcatgcttta ttccagttcc cttagtttct acccaatgtc cgttttctat tccagtatcc 146100
catccagaat accacattac attctgttgc catgagtttc tcagattttc catgtttttg 146160
atgaccttga cagttttgag gaatactggt caagcgtttt gtagaatgta cctcaactga 146220
gatttgtctc atgtttttct catgattaac ttggtattac aggtgttttg agaggaagac 146280
cacagaaatg aaatgccatt cttattacat catatcaagc atatattcta acaatatgat 146340
ttatgacaac taatgttgac cttggccaac tggctggggt agtatttgtc tagtttctcc 146400
tctgtaaagt ccttccttac cccctttcca cactgtactc tttgaaggaa gtcactctgc 146460
acagctcaca atgaaggagt ggggagctat gcttcccctc tttgagagtt gtgtatgtac 146520
acaaatt'att tggaattctt ctgcatggga gatttgtcta ttctccccta tttatttatt 146580
tattgaatta tttatatcag tatagcttca tggatattta ttttagactt tgggctaaaa 146640
aacaatacta ctttatttta ttgttcaaat tgttccagct tctagaagtt atatttttat 146700
agagaagata tgtttttaaa tataaaaaca ctttaaaaaa atgaagtcaa cagaataaaa 146760
tatttttaaa ttttccttaa tgggtgttct ttgtaccatg tttccatcaa ataacattct 146820
gattgaaatc taaaaattag tgtttgtatt ttaagtgcta agatcagaga aaaagtcaca 146880
agtttcccag actgagttag gcaacatgtg actcagagtt ataaggaata cctttcccat 146940
tcctgcattg caaccagtgt tacagttaca gaagtgacta gtgtaacttc ccctcctggg 147000
ttccagctgc caggacttac tttagttctt ttaacatatc cttcccacca aagataagtt 147060
ttttgaacag tttccccatg agtgctcccc ccaccccaac ttgtgccttt tattcatgtc 147120
tttataatat ttattggttg gctggtgcaa ttgcagaggt tggcaagtct gaaatttgta 147180
gagcaggcca gcaggctgga aactcaggca ggagttaatg ctacattcta gggacatttt 147240
tttcttctct ggaaacttca gtttttgctg acaagctttt caactgattg ggcaaggccc 147300
acccatgtta tgagggggaa ctgtacaatc agttgtcatt taagccaatc agtcaactga 147360
tggttggtgt caaccatatc ttcagaatac cttcactaca acatctagac tcatgtttga 147420
ttaaataact gggtgccata accttggcaa gttgacacct gaaattggcc atcacagtga 147480
ccaagacaga aagtgtaatg agcaggaaag caccccagtg acaggacagt gaaagatgag 147540
cctggagacg gggagtggga ggagtgcttt gacagaatgg tcaagagaga tggcatctgg 147600
gtggagatat gaaaagatgt aaaagaaggg aaggaaccag ttctgccaag aatttatact 147660
tctacaattt cccagatgat attgatgctg ttgccctgga gcccatactt tgagaaccac 147720
agagtaaggg tatacctctg ttattatcca atgaatcctg agaaagccca ttaatatctc 147780
agtgtgacca ttttttctca aaattcctac ctcacatgct ctgaggggct ggcagctttt 147840
ctgggaaggt aaaatctcaa gagggaggct ttgaatgatt ccaggacaaa gtgaagataa 147900
catactaccg caggtaaagt ctaggtttac ttggaggtgg ctcaaaacac aaatcctgtc 147960
aattttaatg acacatgagg ccatgactct gggtcgtcac tctgggcaag ccattgaacc 148020
cattagaacc tcagttttcc catctgtaca aaaagaggtg ataatgggta agcaatcctg 148080
gactgcattg tggtagtgcc atcaagcaat gagatttgtc aggaaggaag tgtgattcaa 148140
41
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gtacaggcac tttgttatct gatgcctgtg tgttgagtgt gaaggagggg ttaattattc 148200
ctctattcat gtcctttcta ttctcaaaat ttcttatgtg ggaggaaaat cttggtgcgg 148260
taaagatcac agccaccctg gggtcagaca gaggactgtg tcaagcttgg taagcgtcac 148320
cattcaggtg agtgggaaag agactgaacc ccattaaacc agatgacctc caaggccctg 148380
cccgccccaa catctgaggg ctgcctggct tgtctgcaca gggtgctcac agtactcctg 148440
actttgacat aattttaaca ttaaagtcac aaggatgccc tggatcacaa ctgctggaga 148500
agagatggta gtgggatttg tttcccagga gactttctga ttctagtggg gccaggacca 148560
acctccaaaa taagaggtct ttgcaactgc tgcgagcctc ctggcacctc taccctctag 148620
cgagaggctg cctctcctgc cccaccccgg tttcaagcac gctgcagggc aggaactcac 148680
tgtgctggca aaggtgagct ggagacctgg cacggcataa agctttttta actgaccctt 148740
tttaatttca tcttccctgg acttaatcta gagagtcatt gatgaaacaa acatgccatt 148800
ttctcccgat ttcacgcttt taaatgtcaa caacaaacaa acgtttatat acacaaatgt 148860
tgctgaagga gacttttggc tttagacaag ggtaaaaact gaacctctta gtgtgacttt 148920
ggttgatttt ttaaaaaatc tgtaatttga catataaaga attattaaga cttttttttt 148980
tttttctggt aggcattgaa tgtgtccttg aaaagaaaaa aaatatgctc agtttcaatc 149040
ttctgtctat gggtagctag ttatcccagc cttagttatt gaataaggag tcttttcacc 149100
attgcttatt ttattttact ttttgagatg gggtcttgct ctgtcaccca ggctggagtg 149160
cagtggcacg attttggctc actgcaacct ccgcctccca ggttcaagcg attcccctgc 149220
ctcagtctcc caagtagttt ggattacaca tgtgcaccac cacacctggc taatttttgt 149280
attttgatag agacagggtt tcaccaagtt ggccaggctg gtcgtgaact cctgacctca 149340
gttgatccac cccacttggc ctcccaaagt actgggatta caggcatgag ccaccgtgcc 149400
tggctgcatt gcttattttt gtcagctttg tcaaagatca gatagttgta ggtgtgtggt 149460
cttatttctg ggctctctat tctgttccat cagtctatgt gtctgtttgt gtatcagtgc 149520
catgttgttt tggttattgt agccctgtag tatggtttga agttggataa catgatgctt 149580
ccagctttgt tctttttgct tagattgtct tggctatttg ggatcttttt ttggttccat 149640
atgaatttta aaatagtttt tttctagttc tgtgaagtat gtcactggta gtttgatagg 149700
aatagcattg aatctataag ttgctttgag cagtatggcc cttttattga tattgattct 149760
tcctattcat gagcatggaa tgttttttcc atttgtttgt gtcatctctg atttatttga 149820
gcagggtttt gtagttcttc ttgtagagaa tttcacctgc cgggttagct gtattcctag 149880
gtgttttatt tcttttgtgg caattgtgaa tgggattgtg ttcctgattt ggctctttgc 149940
ttgactattt ttggtgtata ggaaggctaa gtgatttctg tatgttgatt ttgtgtcctg 150000
agagtttgct gaagttgttt atcagctgaa ggagcttttg ggccaacact atggggtttt 150060
ctaaatatag ggacatgtca tctgcaaata gggatagttt gactacctct ctttctattt 150120
ggatgtgcta tatttctttc tcttgcctga ttgctctggc caggacttct aatactatgt 150180
tgaataggag tggtgagaga cggcatcatt ttcttgtaac tggacccctt ccttacacca 150240
tatataaaaa ctaactcaag atggattaaa gacttaaatg aaaagcccaa aactctaaga 150300
accctggaag actactgagg caataccatc ttagacatag gaatgggcaa aaatttcatg 150360
atgaagatga caaaagcaat tgcaacaaaa gcagaaattg agaaatgaga tctaattata 150420
ctaaagagct tctatataac aaataaaact atcaacagag taaacagaca acctacagaa 150480
tgggagaaaa tttttgcaaa ctatgcgtct aaccaaggtc tactatccag catctataag 150540
gaacttaaat ttacaagaaa aaaacaacct cattaaaaag caggcaaagg gcatgaacag 150600
acacttttca acagaagaca tacatgtggc caacaagcat atgaaaaaag ctcagcatca 150660
ctgatcatta gagaaatgca aatcaaaacc acaatgagat accatctcac accaatcaga 150720
gtggttgtta ttaaaaagtc aaaatataat agatgctggt gaagttgcag agaaatggga 150780
acacttatat aatgttggtg ggagtgtaaa ttagttcaat cattgtgaaa aacagtatga 150840
tgattcctca aagacctaaa aatacaacta ccattcaacc tagcaattcc atgactgggt 150900
atatacccaa atggatataa attgttctat cataacgaca catacatgca tatgttcatt 150960
gcagcactat tcacaatagc aaagacatgg aatcaatcta aatgcccatt gatggtagac 151020
tggataaaga aaatgtggta catatacatg atagaatact atgcagccac caaaaagaat 151080
gagatcatgt ccttttcagg aacatggaag gagctggagg ccattatcct tagcaaacta 151140
atgcaggaac agaaaaccta atactgcatg ttctcacttg taagtgggag ctacatgatt 151200
agaattcatg gacacataga gaggaataac agacactggg gcctatcaga gggtggaggg 151260
tggaaggagg gagaggatca ggaaaaataa ctaatgggta ctaggcttaa tacctgggtg 151320
atgaaataat ctgtacaaca aacccccatg acacaagttt acctatgaaa caaacctgca 151380
cgtgtacccc tgaacttaaa ataaaagtta aaaaaaaacc ccaaaaggtg aagtgttggt 151440
gaggatgtgg agaaaaggga acccttatta cacaattagt gggaatgtaa attagtgcag 151500
ccattttgga aaatagccaa ggaaaatttt tttattgagt cagatgatgt taccttacag 151560
caatagcttc caaaggggat gtcctgaata gtagaacttc tctttacatt ttcaaacctc 151620
tttttacttt ctgattttga gtttcataat gaacatgtat caatacaata gcacactatg 151680
tattttataa atgaacaaat atgggaaaaa taagatatgt tcactttcct ggctgaccct 151740
agttagtcta aactatcagt tataggatcc atttgttcta aatattgaag gcattgttgg 151800
42
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gggcagtggg gagggtgaat gatagacgca aattccttga aggaatagaa atgtgactac 151860
tatgctgaaa agcaggaccc atggagtata aatagagtat tcactgtgct tttacatttg 151920
tttccctgga ggaaacgtaa aacaaatctc aagactttct ggtcatttct aagtcataaa 151980
cggccactag tcactaattt atataaccag cccaatgtaa atatcaaacg tgtgagtttc 152040
atttcatctc acaactcctc ccctttccca gttctggccc catacaagcc cgctgcctgc 152100
agtgggatgg aggaagatgg tttctttttc cttccctccc atttatttgt ctttgtgcat 152160
cttaaagcca gcctgaattt ctactcccta caaggttgaa gtgggtgggt caggaggtgg 152220
ggagagagct aaggaacgtt ggcgtgagtt gttgttgtgt ttgagtctgg aaggtgttgg 152280
gagctgcccc ccctcactca gggcctcatt tatgggctct tcggataacc cccatgctct 152340
agcactggga tcttgccctg tggatccctc catgcaggtg gcaccacacc ctctggctgg 152400
ttgtgatggg ccttctcagc tttgagaatt agcaacacac ttcctattga agtcatctgt 152460
ccctgtgggt agcccacttg ggctggatgc aaactgaacc tgcactgatt ctctcttgca 152520
tgtggcccac atgagctcca ttttcctccg caaactttgg gtgcacagcc ccacgacgac 152580
acagacagct tttcttgcgt gccaccaaag tggtgggcca gagttctctt atccttaaga 152640
ttttcaggtg tcaccacgtc caccaattct tggcagacat gaatcaatac ttccaagggt 152700
tttggtgaag cccttttccc tgggctgcag atgagggcag ccatgtcctg tctcttccac 152760
ctgttgtgga aggggttcat ggcaaacatc ttcgaacatc ctctaatttc ccaattcttg 152820
atcctttcgt atgcttgatg tgtgagagag aagagagaag agagaaacgc ttcttgctgc 152880
tttttttttt tttaatccca catggtgacc ttagacttta ctttggaatg tgccatttaa 152940
tatctgggga cctcagccca acacagggac taaatagctc tgttttaaca ttttgtttat 153000
atacacacat tcatttgacc aaatgaacat gttccagctt ttttaaccct tgcccagcaa 153060
atcacttaat tcagttaata aaaagactaa aataatgagg ccaaccttat tggccacgaa 153120
catctgttgg gtattcctaa attgatccct gagttaatct ccacctttaa ggagtttata 153180
attttatttg gcaaattgat gttataatga aattcctggg catgaaaaaa acctaactat 153240
gtaatgttgg atagtgtgag ttttcccaaa agtaccagta taagcaataa atgctataac 153300
tgatcatgaa ttgtttacag tgattgagta gaatcattgc~atctggtcat gaatagaaag 153360
agcacctccc agacggctgg tctgctgcca ggtgtgcagt tttaggggtc tccacactca 153420
ttctattcac atcttttgac tttatcagct gtgtggtgga tctgtggtta caggctgatg 153480
tggtttggct gtgacctcgc tcaaatctca tcttgaattg tagctcccat aattcccacg 153540
tgtcatggga gggatccagt cggaggtaat tgaatcacgg gggcgggtct ctcccgtgct 153600
gttctcgtgg taatgaataa gtctcacgag atctgatggt tttataaatg ggagttctct 153660
ttcacgagct ctcttgcctg ccgccatgta agaagcgcct ttgctcttcc tttgtcttct 153720
gccatgattg tgaggccttc ccagccatgt ggaactgtga gtccattaaa cctctttcct 153780
ttataaatta cccagtcttg gatatgtctt tattagcagt gtgaaaatgg actaatacat 153840
gagccacatt gttacagagt ttctgaaggt cattaagaga agtccatgct gtgggctgag 153900
ctgggactca agaatctcaa aggagagcca gtgcaatcaa cacgaagggc ccatcttgaa 153960
ctcctaaggc agggcagagc tgggtcttat ggagacatgt ggctttcagg taatccagtg 154020
agcacctgtg ttttcctcct ataattcttg aggaatggat att.gttctat atttcagata 154080
gtataataat aaatacctgg aaaatactgt atgaccccaa acaacaggta aaatgtcaaa 154140
aaaaaccttt tatctacaca aagttagaca acaaattcaa ataatcttat ccgtttattc 154200
attctcttcc aatacaatca tgtatcattt aatgatgggg atgagtttgg aggaaggtgt 154260
tgttaggaga ttttgtcatg gtgcaaacat catcaagtat acttatgcca,acctcagtgg 154320
tatagcctac tacacatcta ggcttggata gtacagcctg ttgctcctag gctataaacc 154380
tgtacagcat gttactgtcc tgaatactgc ggcaactata aaataatggt aagtatttgt 154440
atatctaaac acacttcaac atagaaaagg cacagtgaaa atatggtata agagataaaa 154500
aatggtccac ctgtacaagg cacttgccag aatggagctt gcaggactgg aagttgctct 154560
gggagagtca gcgaatggct gatgagtgaa tgtgaaggcc tagggcatta ttgtatgcta 154620
ctgtaaactt tataaacact gtgcacttag gatacactaa atttattaaa aatttttctt 154680
tcttcaatca ataataagtg aacattagct tactgtattt ttttttttac tttataaact 154740
ttaatttttt tttagagata gggtcttgct ctgttggcca ggctggagtg cagtggcaca 154800
atcatagttc actacaacat tgaactccta ggcttaagca atcctcacac ctcagcctcc 154860
tgggtagctg gtactgcaga catacactac tgcacccagc taatttttaa attttttgta 154920
gcgactgggt tctgctatgt tgaccaggct ggtcttgaac tcctgactca agcaatcctc 154980
ctgcctcagc ctcccagcat gctgggatta taggtgtgag ctactgcact tggcctaaac 155040
tctaattttt aaaatcttct tgactgtttt ataataacac ttagtttgaa acacaaacac 155100
attgtacagc tgtacaaaaa tgttttcttt ctttacatcc ttattctata agcttttttc 155160
tgtttaagtt tttaaaaatg ttttagtctg agtgcggggg ctcacgcctg taatcctagc 155220
actttgggag gccgaggcgg gcagatcatg aggtcaggag atcgagacca tcctggctaa 155280
cacggtgaaa ccctgtctct actaaaaata caaaaaaatt agccgggcat ggtggtgtgc 155340
acctgcagtc ccagctactc gggcggctga ggcaggagaa tggcatgaac ccaggaggcg 155400
gagcttgcag tgagctgagt ttgcaccact gcactccagc ctgggcgaca gaacgagact 155460
43
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ctatctcaaa aaaaaaaaaa aaagttttaa acctttttaa aaaatcaaag tcacagacac 155520
atgcattagc ctaggcctac ccagggtcag gatcatcaat gtcactgtct tccccttcca 155580
catcttgtcc cactggaaag tcctcaggga cagtaacacc cctggagctg tcatctcctc 155640
tgataataat atgggcttct ggaagacctc cagaaggacc tgcctcctgc ctaatgctgt 155700
tttacaggta atattttttt ctagtagaag gagtacacta aaataatgat aaaaactgta 155760
gtaaagtaaa tatataaatt agtcatatag tcatttatta tcataatcat tatgtactgt 155820
acataattgt attgccagac ttttatacaa ctggtggcac aataggtttg cttacaccag 155880
catcaccaca cacgtgagta atgtgttgtg ctgtgacatt aggacagcta caatgtcagg 155940
aggcaatagg aatttttcag ctccattata accttacaag accactgtca tatctgcagt 156000
acaaaacatc attatgtggt gcatgactat atttactgag caccaaatat gtgcccaggc 156060
agtgtgctag gggctggaag tgacctcgaa gtctagtaaa aaaaccacaa cagtaaaaca 156120
atatgtgtaa ttcaaagtga catatcctgt aatagctggt tgcctacctg ctccccagag 156180
agaaattaaa cctgcttgct taacttatta attttaaatt catgtacttg caatataaaa 156240
acatatttta aaacatatta ggagaatagg atgtcttctg tagtgatagg ctatttaatg 156300
ttctcttcac tgtgttctaa aaaaatcgtg atcgagtgta acaaaatggg gaagggaggg 156360
ttagcataaa ctctcctttg atgtctatgc tgtggatcag aaaactcatg aatatgttaa 156420
caactggatt ttctcctaat atgaaaacaa ctctttggct tcttttgcaa atgtgaaaag 156480
ttaaccataa atataagacc ttttctttcc actaaaacta gggcacaatc attgttttcc 156540
tcttattgga gtccaaatgg gtttcca'taa tcttcagatc tagtagttgt atttatcgat 156600
gacataaatg gaaagactaa aagataaagt taagaaaaat tcagtggttt atggcttcaa 156660
ctctactgat aattttgtat ataaagggat cctaaattag actgtacaca catttgccat 156720
ttgagttcca agcattttag caatagatca aaagatctta atgcctgata gttgaaagat 156780
tacttccaaa ttttttttat ttttgtgaaa gccaaagtcc ttttctcaac atgacagtca 156840
caattttgtc aacaatctac ccgttattta caaaggttta aaatctgata atagatattt 156900
acttggacta tacaatgtct cagtgggagc aatagatggt ttacaatggg tctgaaaatg 156960
ttgcaaatag tcaaaactgg cattgcaaca attcatttcc aaaaacacac tagactcgtg 157020
agtttttggt ttttaagttt atatagcttg cttctggtgt taacgttctc cacacctaag 157080
gtgccaacat gcatggctac tctttgtccc cagagaaaca ttgctaattt gtaccaaatt 157140
tcaatgatgt gtcaagcaaa ctgtcatttt ggaatgatag taagcacgcc ttcaacaaca 157200
gctctttatt tcgtccaaaa cctttgggcc acacaattct gacctttatc acactctcag 157260
tacctttcat tcattattag cttgtgcttc tggggccccg ggaattgtca actatggtca 157320
aaataatgga gcaaaatagc aagaagaact tgcgtttcct atatcattgc atttaatctt 157380
tgcaacaact ctttgaggtg gaaattgccc caattttata gattcagctt aaagaccttg 157440
atttgtccaa~gatcacacaa ccactaggag gtataatgtt caaataaaaa tgtctgaaaa 157500
gagctgggtg tggtgggtca tgcctgtaat cccagcacgt tgggaggctg aggtgggggg 157560
atcacctgag gtcaggagtt tgaaaccagc ctgggcaaca tggcgaaacc ccgcctctac 157620
taaaaataca aaaattagct gggtgtggtg gtgcatacat gtaatcccag ctacttggga 157680
gactgaggca cgagaattga atgaaccctg tgaggcagag gttgcagtga gctgaaatcg 157740
caccactgca ctccagccca ggcggcagag tgagactcca tctcaaaaaa aaaaaaaaaa 157800
aaaaatctgg aaagatagat tacttggcct caatcatagt aaaaaagtgt cagttaaaac 157860
tgcatggaga gatactattt tgaaaagcat caaaaagttc gaagatccat catatttgta 157920
aggctatggg agtttaaatt gtacaggcgt tatgaaggca tttggttaca tctaccaaaa 157980
ttaacaccgc acatatttac tcatgtgcaa attgacttat gtacaaattt actaattgta 158040
gcattgttga taattgtaaa atattaggaa cacacctaat tgccattaat ggggaactgg 158100
taaaataaac tagaattcct ctgtgcatgg aatactatgc agtcatcaaa aatgacgaag 158160
atgtggccgg gtgcggtggc tcacgcctgt aatccagcac tttgggaggc cgaggtgggc 158220
ggatcatgag gtcaggagat caaaatcatc ctggctaaca cagtgaaacc ccatctcttc 158280
taaaaatacc aaaaaaaaaa accaaaacac aattagccgg gcatggtggc gggtgcctgt 158340
agtcccagct actcgggagg ctgaggcagg agaatggcgt gaacccagga ggcggagctt 158400
gcagtgagcc gagattgggc cactgcacgc cagcctgggt gacagagtga gactccgtct 158460
caaaaaaaaa aaaaagaaaa cagaacaaaa caaaaaatga ggaagatgtt tatttagtga 158520
aatagaaaga tatccaagat atgttgctaa taaaaacaaa aaaaaacaca tggcacaaat 158580
aaggtgcatg ttactatctg ggtcttttaa aaaggggtgt ggaagaatgt gtgtgtgtgt 158640
tttcttcaat atgtgtagaa tatctctgga aggaaattta aaaactggcg acctcagctg 158700
tctccagaga gggaaaattg gtgggttgca ggcagaggtg aaagattttc ccactatgac 158760
tttgaaaata tcttttcaag tttaaagcac caactgcatt atatatcaag agtaaataaa 158820
atacaatttt aaaatgaaat ggcatttgta aaacacttga tagatgttca gttaacagcc 158880
atcaggattt attagtaatt gtggtttttg ccattaaaag taattttaaa agtaatggtt 158940
ttgccattag ttttaatgac aaaaaccaca attagttttg caccaaccaa ataccttacg 159000
cttctggtga gggctcagaa gagagatcat aagtaaagaa cactagaaag gatgtttaat 159060
attatttccc tttttaaaac tggtggttgt caaagcagtc tgaaggaaaa gtctccagaa 159120
44
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ctggtgatca tgttcacata gcagtagttt ggagtcaaca gaaatcatct tcaccatcaa 159180
cctagctccg aaagaggccg agccaatcta gttcccttgg ccaaccacct tcctcccaac 159240
ctatacgttg.gggtgatcca ctacaaagct ctcaagagta tacacaatgc tactacagtc 159300
attgtgagtg agatctgaag ggagcatagg ctaggactca tgagattata gttcagagtt 159360
tctactgtaa ttcctttcag caaagtgaag agcatgtcac tggggttaca agtgttactg 159420
gctacttagc tagtgctaga ttacccaaaa aagtaaccgg gtctcatggg cagaggtggg 159480
aaagtctgtt aagcacatag tgaaggatga atctgggctg attggaaaac atttgtttga 159540
atgaatgtag catttatttc caagaataag catgtccaga ctgattgagc aagagttata 159600
tttagttcag tcgttctgat gtccattttg agaaagctaa accagcatgc cagaaggggt 159660
caaagatcac attttgcatg aaagaaaagc caatggaaat gggactgtta gacttaaact 159720
tttgggtatt ttacactagg acttagaaag gactttattc ctttttatat tttctgtctc 159780
tagcattgca agtagcaaca gagtgaattt ttggtatttg gaatactctc tcctcatttt 159840
tcctttggga aaatcattag cctatttgat ttgactgctg ttgaatatgt tccatgacat 159900
ccataagtct accttcaggc attgcttgtg cttgtttatt acatatgatt aattgcttac 159960
ataagaacaa tgatgatccc tgcaggggga ggagggatgt gaagaacaac ttacttaggc 160020
attccagggg ctaacaaggg atggtttgat acagctcatt cttgttttga atcttcatgc 160080
ctcttgagaa agaaaggagc agaatatgct ttgcatggcg ctatgtcctc ccaggtccta 160140
tgttttcttt tttgtatttt atcagttctc tacgtaagga ttttctcagt ttaatataat 160200
ttccattttt aaaattcaaa tacctacata tgaggtggga aaggaaatta atcagatgca 160260
ttcctataaa ctgcagactt aaattaagac cttgagcaaa ctggcatttt gatgacttga 160320
ggattcagtg ggtgggacag ttgtacatct tgaactctgg gtacactgcc gaaagcgagg 160380
cctgagaagg ctgtgttgag gaaggagtgt cagtgactga gcctgttgga aagggaggct 160440
gagagagatg aggacacata cgtaagggag aacacattgg ctggccaggt gttttttttt 160500
ctgctgtggg ttttgattag aattctgggt ctcattaagt gacccatgtt gaatagagat 160560
tggatagggc tggcttggaa agccctcagt gaagagatga actcgacagc atgataagga 160620
agtagatgca aattcaggac aggaaatgga gaagggcagg gtgagaaaag ggaacaaatt 160680
tacaatttgt gccattagcc atttattaga atttggtata agaatttgtg gaattattgt 160740
ttccttctgg atttatggta caaaaaccta ctgacaagtg tcactaaaag tgatgtcttt 160800
attcaattat caaccaaaag ttttacacta aattcttttg agtctttgaa tgtttatgtt 160860
atttccaata atctttccag ttcttttaaa aggctgattt ttaggaaggc tagcactttt 160920
tgatcacaga atagtttccc caatgagtat gatagcttca atatctttca aattagattc 160980
ttttggaaat tgaactgtgt caaatcaaat aaaacaagta gggttttttg ctgttattgt 161040
tgaaggtatt atatttgcaa gtttgtacaa tttagcagat ataggaaagg tctaattttt 161100
ttctttagct agaatgttca gttcaaatta tacagatata agcatgagac ctaaatgaac 161160
tctcttctga tgagtaatga atggaaggta gattactcat ttcttcatgt tcaaaaaaca 161220
aattatgtct ctgaacacag ttgtttcaat gtttttaact tatgttctca agctcttccc 161280
atttctttat cagtgatttg ggaatgtgaa ggcagtcttg ttgtagtttc caaagattta 161340
ggcatttttg agactctaag aatagttcat taagccacca attagtccct taattttatt 161400
taagctgagc aagcaaggcc cacactaaaa gtcagaagaa tgcggcatct acccagagag 161460
gctgagggtg ggatagaaag aaggaggcac tccaagtttg gagacacaga ttctattcca 161520
gttcctcaag ctgcatgacc ttcagcaagt ctcctgtgtt gttcaggacc ccagtttctt 161580
tataagtgca atgaagagtt tggactcaac aacttataaa gaaacattca ttctaattgt 161640
ctattgtgtg aaaagaatgt gagttgttct agaaaatatg aatctgctcc ccaattgtcc 161700
tccaagctct ggttctaaat ttcagttatt atagttactt ctttcgaggt aaatcattga 161760
ggaagtcagt taatgcagag atgatgtctg gaaggagttt acaagttcat tgttcaaata 161820
gtatttgttg ggggccaact acaactacac atcagggatt gtgctcacat tggactagtg 161880
tctttggaaa acagagtcct tgtgtgccct ttttgaattt acaggccaac ttggggaagc 161940
agagagacaa ataggaaatc caacagcatg ataagtagta taatgagaat gtttagggag 162000
atacgagcat ttataggagt agcactcaat aggaaatcaa ggaaggcttc ctggtggcta 162060
tgatgtctca agggagactt gaagcatgag taggagtatg tcagatgaaa agggatggga 162120
ggaagatttc aggtagggta atttgcatac gtgaatattt agacccagag aaagtccaga 162180
gggactgagg aacttaaaag aaatccagta tgggaggagc atagtacctg ttggggaggg 162240
tggggactct tgataaatga ggatagtaat tcaagttctt tggctcttga gttacttttg 162300
gacaagttga gcttcaagta gctagtacat aggaggagct taataaatat ttattgaatg 162360
aatgaacatg taagtaaaaa tgtctaatag gtacctggca aagtggactt cctagtcagg 162420
aaagagaggt tggttggaga tttctatttt gaaattttca atgtatatat gaaagtaaaa 162480
acacaaggag tggttgtgat catccaggag aaggtatgca gaggagggaa gagggtctag 162540
gggctgaatc ctggggtacc cacacctgag aggagggaga ggaagagggg ctctcagaag 162600
agcctgagca ggaagggcca ttgtaatagg actaaacact aagcccctga agtcagctct 162660
ctgggggcag aggtttttgt tctgtttatt ttgggatgcc tgctgttgac cagattatgc 162720
tcccctaccc acccaaattc acatattgaa gccctaacac tcaatgtgac tgtatctgga 162780
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gatagggtct ttgggaggta attatggtta aatgatgttt.taaggctggg accctactct 162840
gataggactg tggccttata aaaagagctc tctctttttc tgtcctcctc cttctacctc 162900
ctccaggacc caccccaacc ccacactgag aaaataaatc gctgttgttt aaatcaccca 162960
gtctatggta ttttgttaca gtagcctgag ctgaccaaaa cagttctccg cacttagaaa 163020
tggtcctggt aaatacagct aatcaatatt tttttgagtg aattgaatga atgagtcatt 163080
cactggcatg cttataaatg cattactccc tccacagtgt gattgtcatt gagcaggttg 163140
ggagaaggga ggagctctcg caaacatgga agtcctgggt gcttagggag aatgggaagg 163200
tgccgtggtc acaaaatcgg aagaaagagc tgaaaggctg aaaggctgaa aatgctaaac 163260
tgctcaaatc tcctctgtct ttttttaaaa aaaatcattt ggctaggctg gctctgaaat 163320
tggggatggt tcttggttga ttatgtggtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg 163380
taaaggccct tcttaacatt agataggact atctgaatct aagtgaattt aggcacaatc 163440
tagatattgc tcttcataga gaaataatac tctaagctgg caatgaaatt cctcaagtaa 163500
acaacagata aagggaagga gagggacaca gtgtaacaat aattggaata attggaattc 163560
ttgtatcact catggcactt acagtgaaag tactttctac attgtcttct attacatgca 163620
acataggtac attatataaa aagatcctaa aatattgtta aaagaaattt tcccagaaaa 163680
tgtaagataa aagttactaa attctattaa gcttgcaagt taaatccaaa tcattcattg 163740
actcataatc aagaacagtc atgctgcctg acaaccaaaa aattcaaact gtcttcatca 163800
agtcctgggt gggaagccag gaaatgggat ctgagatcac aggctttgtg agagtcaggg 163860
tctttggcgt gattcttggt cacaaatcat gcattttttt ccttggagag atagtgggaa 163920
agaaaaggct gtttaaaaac atgttaaaga atactgattc catttgactt cttgttaatg 163980
tgtacccttg cagacttggg taaaacttga tcatgttaaa agccattgta cttaaagatt 164040
catgactaga gtgttaggac aattctgtgg ccttgggggt cccattgcag caagaagagt 164100
Ctgactgaga agaggatagc tccgtccttt gatgcctagt aacctgcatg cccagcactt 164160
tgctggctgg gccattggta ggaaatgcgg tacatgcact tcaatctgta agagatcatg 164220
gtccatagag atcatagatt tattttgcca cctggcccag atggtgatag aagtcaggac 164280
aatggttgcc tagaggggtt gggagtttat tagaatggga cacaaaggga aatttctggg 164340
gtgatggaaa tactctatac tttcattggg atgattgtta catggacata tccatctgtc 164400
aaattcatca aatggtatgc tttagataca tgtatttcat tgtatataaa ttttgcctca 164460
agaaacaaaa actcaaggtc aggtgaaaaa agtccaggag ctaatcaaaa acccttaaaa 164520
taagtgacca aactatttgt gaaaatgagc agaaacttaa agggaaattc tttgttattt 164580
ttccacatta gaggaaaatt gatggtatca gataaatgct caaaaataag cttccaaaca 164640
gagcatttat aatcagtaca ataataagtt tgaacacaga caaaccttca tgtctcagag 164700
tgaaggaacc atttctagta gtataagcta ttacggagat agttccacat ttattttctt 164760
tcatgtttct tttggaggaa taatgttttt gtaaatgtaa aatgctttta atggagctag 164820
agaagaagct atgtttggtc atagtattat ctgcttgcga actaaaaatt cagagctctc 164880
ttgtgaatca tgctgccaag aattgcagac ttaagcctca agattgtacg aatttaaatt 164940
ttgactttat ggcctcagtt ggcatgaaga tacaaagata atcttctagc aaaaacagtt 165000
ttgaaagacc gggcgtgatg gctcatgcct ataatcccag cactttggga ggttgaggca 165060
ggtggatcac ctgtggtcag gagttcagga ccagcctggc caacatggtg aaatcctgtc 165120
tcaactaaac atacaaaaaa attagctggg tgtggtggcg gacacctgta atcccagcta 165180
cttagggagg ctgaggcagg agaatcgctt gaacccagga ggcagaggtt gcagtgagcc 165240
gagatcacac cagtgtactc cagcctgggt gacaaaagtg aaactctgtc tcaaaaaaaa 165300
aaaaaaatgg tagaatgtca catggaaagt taacttttag agatagtaat ccagacacct 165360
ataatattac attgtccttt taagtatcta tatcaataaa ttaaccaaca tttgttgact 165420
taacatggcc agggacagtg ctgggttctc ataattccca agtaattcta gccagacctt 165480
gtcctcaagg agcttatgag cagcatgagg agataaaaaa cagataaata actctaattc 165540
aggaagaatt tgataaatgc atgataacta ctactagaat tcagaggaga ggaaattttc 165600
tttgaataga gactaaagga aggaataatg aatgtggtag catttgggct ggacctatta 165660
caagaggcat gctttcccct gacaagccaa gaaagtgggg atttaaggta gaagaaaaga 165720
aaagccttga gttcttggag tattaaaatt ttgcttggct gaagcatagg ttacagtcgg~165780
aggagatgga ctaggaagga tcgttatggg cagagaggaa gccctgaact catgggggaa 165840
gctatgattt gggttaaaga cagagctggg tcatgtcaag atggatcctg aagcagtaaa 165900
aaaaaatcca agaaagtaaa caggttgcag ggtttaggat gaagtccggg aggaaagggc 165960
agagtggtcc ttaggaggcc gttaggacag gtaaggtaat gggtctcaaa gggagtggcc 166020
gaaatgcaat ggaaaaagag agattgtaaa gctagaaggc ttaggaattg cctcttgatt 166080
aggtgtggaa ggcaagggaa aatcagccct cgaagaagac agtgagattt taatctgggt 166140
ggctggagag acagtgatgc tggcacagac acgggaagtt gagaggaaca ccatgtttga 166200
gaatggtgac tcatatttga acaagcctgc aatgcccagc agaccgctgg aaaagtgggg 166260
ctggagacac attcaacgga ggagccagat caatctttac ccttcttcac ctgagagagc 166320
cagtaagtca cggctggaac gtgtgtgtcc agcaggagag ggtagggagg gaagccaaga 166380
gagctgggag cccaagagtg aagtttttgc caaaggcaga agaggaaagt cggcgtagca 166440
46
CA 02426405 2003-04-17
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cagtatactt tcccacccat gctcaccaag cccagggaca aggctcacca agatgagttt 166500
ggaagagaat gctggagaga aagtggttaa gaaaactgcc tttactgaac ttcttgggct 166560
aactttgatt gtaagtctct gaacaatcaa agcctgtgag gagacagcca accttcttat 166620
tcttcctatg tcaatagtga acaattgcag atcccctttc ctttccttct cctttcccct 166680
gttcctctct cctccctccc tgaatactct tgcttttttc tgggactggt ctagagcatg 166740
ggtggccatt gttgacctac aggaggcacc actgtcacca acaaagggta acagtctttc 166800
ttttcaatat ttatttatat ccagtattta ttttcaatac tgactatgga gagagctctc 166860
ctgtgctcaa acactgcaat actgggggtc tttcaaagca caaaaacata tatttgcatg 166920
atggcatcat taacattttt atggctttct atttcttttt tgtactggtc tcaagagcca 166980
ctcataaatc tctcagtaac tgcatagtgt cccagggcca gagaccggcc actcctggca 167040
ttgtgattag agtcatttaa tatccaaggt ggtgactaat gtctggcaac aaagcctcca.167100
ttgggtgtca tgtgtcctgg gaccctgagc gtgggcactc taggagcacc tcagtattgc 167160
gtgttagtac tatggccgag agaatagttg agaaagtggt caagaggtgg atccatgtga 167220
acgccactgg gaaatgagag acctcgttcc caatcacggt cagtgcaact cgaaagccta 167280
aaatcagttt aaaacaaagg tatctacctt tatcttatgt tcatatccta ggcttttaat 167340
aatacgtatt tttcacatgt ttacagaaag cagtcaactg agctattcat ggaaaggttt 167400
gtgggtttgg ttaacgaagt ggaggagtat tacatttcag ctggaaacac atccctagaa 167460
tgccaaaaca tttattccaa agtctggttt cctggtgcaa tcggaggcat ggcaatgcct 167520
ctgttcagag actgggggct agggccagta aggcatttga tccacatgta tcccagaagg 167580
cttttattgt taaattatat tctttcggaa aaaccaccca tgtcctattt tgtaaacttg 167640
atatccatac acttttgact ggcattctat tttagccgta agactatgat tcacagcaag 167700
cctgtttttc ctcttgcttg gggtggcagc agaaagcata gggtactttc cagcctccaa 167760
gggtaggggc aaaggggctg gggtttctcc tccccagtac agctttctct ggctgtgcca 167820
cactgctccc tgtgagcaga cagcaagtct cccctcactc cccactgcca ttcatccagc 167880
gctgtgcagt agcccagctg cgtgtctgcc gggaggggct gccaagtgcc ctgcctactg 167940
gctgcttccc gaatccctgc cattccacgc acaaacacat ccacacactc tctctgccta 168000
gttcacacac tgagccactc gcacatgcga gcacattcct tccttccttc tcactctctc 168060
ggcccttgac ttctacaagc ccatggaaca tttctggaaa gacgttcttg atccagcagg 168120
gtaggcttgt tttgatttct ctctctgtag ctttagcatt ttgagaaagc aacttacctt 168180
tctggctagt gtctgtatcc tagcagggag atgaggattg ctgttctcca tgggggtatg 168240
tgtgtgtctc ctttttcttt caggacttgt aggattcttt gtgccatttg catataattt 168300
ggcaggttca cattttttaa gagccctatg aagtgctttt tgcatgtgtt ttaaaaaggc 168360
atttgaaaat tgaaagtgtg atttatggaa attaaatcat ctgtaaaaaa ttgctttgga 168420
aagtaatgat tgctggccat aaagggaaat atctgcgatg cacctaatgt gtttttaacc 168480
ctttatttgc tgacaatcta tagtcattaa tgctaaactc gattttggct tcagctacat 168540
ttgcatattg tccaacaatg gtctattttt gtaagaatta gataaaatgt atacttgata 168600
taaaatagtc aaaaatgtaa ctcttagtaa cagtaagctt ggcatttaga tagaccatga 168660
acacttcgtc agatactctg ttgggtgttt gggatagcaa ttaaaacaaa gtattgatag 168720
ttgtatcaga gtctattagg ctgcagcaaa ggaagtttat tcaaaagtat aaactatcca 168780
agattataga cgcatgatat acttcaccta ttttttgtct ccttaatatg tatatatata 168840
tatatatata tatatatata tatatatata tatacacata tatgtgtgtg tgtatgtgcg 168900
tgtgcatgtt taacttttaa ttcagttaaa aacttttttc tatttgtttt .tcatctggat 168960
atttgattct gcatatccta gcccaagtga accgagaaga tcgagttgta ggactaaagg 169020
atagacatgc agaaatgcat tttaaaaatc tgttagctgg accagaccga caatgtaaca 169080
taattgccaa agctttggtt cgtgacctga ggttatgttt ggtatgaaaa ggtcacattt 169140
tatattcagt tttctgaagt tttggttgca taaccaacct gtggaaggca tgaacaccca 169200
tgtgcgccct aaccaaaggt ttttctgaat catccttcac atgagaattc ctaatgggac 169260
caagtacagt actgtggtcc aacataaaca cacaagtcag gctgagagaa tctcagaagg 169320
ttgtggaagg gtctatctac tttgggagca ttttgcagag gaagaaactg aggtcctggc 169380
aggttgcatt ctcctgatgg caaaatgcag ctcttcctat atgtataccc tgaatctccg 169440
cccccttccc ctcagatgcc ccctgtcagt tcccccagct gctaaatata gctgtctgtg 169500
gctggctgcg tatgcaaccg cacaccccat tctatctgcc ctatctcggt tacagtgtag 169560
tcctccccag ggtcatccta tgtacacact acgtatttct agccaacgag gagggggaat 169620
caaacagaaa gagagacaaa cagagatata tcggagtctg gcacggggca cataaggcag 169680
cacattagag aaagccggcc cctggatccg tctttcgcgt ttattttaag cccagtcttc 169740
cctgggccac ctttagcaga tcctcgtgcg cccccgcccc ctggccgtga aactcagcct 169800
ctatccagca gcgacgacaa gtaaagtaaa gttcagggaa gctgctcttt gggatcgctc 169860
caaatcgagt tgtgcctgga gtgatgttta agccaatgtc agggcaaggc aacagtccct 169920
ggccgtcctc cagcaccttt gtaatgcata tgagctcggg agaccagtac ttaaagttgg 169980
aggcccggga gcccaggagc tggcggaggg cgttcgtcct gggagctgca cttgctccgt 170040
cgggtcgccg gcttcaccgg accgcaggct cccggggcag ggccggggcc agagctcgcg 170100
47
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tgtcggcggg acatgcgctg cgtcgcctct aacctcgggc tgtgctcttt ttccaggtgg 170160
cccgccggtt tctgagcctt ctgccctgcg gggacacggt ctgcaccctg cccgcggcca 170220
cggaccatga ccatgaccct ccacaccaaa gcatccggga tggccctact gcatcagatc 170280
caagggaacg agctggagcc cctgaaccgt ccgcagctca agatccccct ggagcggccc 170340
ctgggcgagg tgtacctgga cagcagcaag cccgccgtgt acaactaccc cgagggcgcc 170400
gcctacgagt tcaacgccgc ggccgccgcc aacgcgcagg tctacggtca gaccggcctc 170460
ccctacggcc ccgggtctga ggctgcggcg ttcggctcca acggcctggg gggtttcccc 170520
ccactcaaca gcgtgtctcc gagcccgctg atgctactgc acccgccgcc gcagctgtcg 170580
cctttcctgc agccccacgg ccagcaggtg ccctactacc tggagaacga gcccagcggc 170640
tacacggtgc gcgaggccgg cccgccggca ttctacaggt acccgcgccc gcgccgcccg 170700
tcggggtggc cgccgcgccc ggcaggaggg agggagggag ggagggagaa gggagagcct 170760
agggagctgc gggagccgcg ggacgcgcga cccgagggtg cgcgcaggga gcccggggcg 170820
cgcggcccag cccgggggtt ctgcgtgcag cccgcgctgc gttcagagtc aagttctctc 170880
gccgggcagc tgaaaaaaac gtactctcca cccacttacc gtccgtgcga gaggcagacc 170940
cgaaagcccg ggcttcctaa caaaacacac gttggaaaac cagacaaagc 'agcagttatt 171000
tgtgggggaa aacacctcca ggcaaataaa cacggggcgc tttgagtcac ttgggaaggt 171060
ctcgctcttg gcatttaaag ttgggggtgt ttggagttag cagagctcag cagagtttta 171120
tttatccttt taatgttttt gtttaatgtg ctccccaaat ttcctttcat ctagactatt 171180
tgattggaaa tatgtcagct atgatgatga ctttctggga agcgattcct gtcacccgct 171240
ttcccctcct ccccacccca cgtcctgggg ctttagagag cgattgggag ttgaatgggt 171300
ctgatttcgg agttagctgg ctgagtccgc gctggagcgg attgctggca tgtgacttct 171360
gacagccgga aatttgtagg tgtcccgcga gtttaaaaca agccatatgg aagcacaagt 171420
gcttaaaaat aatctcctgc cagcccagtg acaagcctgt cccacccggg gagaatgccc 171480
cggagtggcg tgcgggtcag ccagggtctg cgcctcgcag ccactgtgga aggagcgcgg 171540
ccggtccagg acacaggaga ccactttgtg acttcaatgg cgaaggttgt gtgtcctcat 171600
tttaattttt ttccctacaa gaattgttct ttctccctct cctctccctc ccattttctc 171660
ttgcccagtt~tctccttttg ttttttgttt tttgttttcc tgatgggcct gcagagggat 171720
taggtgggcg cttctggtga acaccttcct aggtggccac aggacaggtg taccccggac 171780
tgggtttgga agcttcaggg cgccacatgg ctgggtcctg aattaggcat ttcccaactg 171840
tacactggta tccggactgg tgtccctata tctttctgcc ttgtaagccg tggaccagtt 171900
tttgttcagt attct,gtttc cagggatatt tatagcagaa ggaaggggac taaagtgcag 171960
tttggcccca gaggatactg aagggcagat tctgggggta ttcagtgtgc atcttcagcc 172020
gccttggaga aatttagagc atcccacagc cacgcagatc caagctgtct ttactcaaaa 172080
gacaaacaat gaacaagact tttaaaggtt ggcatatttc aaattaattt tacttgtttt 172140
aatttagggt taaaacagag aaaaaggatt tcttctgccc accttttttt ttttaaatgg 172200
aagaacaaag tacagcgatt aagtctaatt ccacacaaca tttaaaactg cttgatgtga 172260
aggaaggcac tggtatgatg tgaattccat aaccttatga tggactccag aaaccatttt 172320
cttccctatt taattttcag ttcttttatt gcaaattaat gctgctgaat ttcaatgggc 172380
actaatgaga ctgctccttg gtagattatt tactgccttg ctaataatta caaagtgaac 172440
ctggtcaaat acagagggga tcgcatctta ttcaaaattg ttcatcatcc cagtgataag 172500
tggtatcagt gtaatatgcc ctatcttaca ctttctgcat tacatgatat tcaaacactc 172560
ttagaataat aaaaaaagag acaaggaact taaaaattaa aaaaaaaact tgcacaaatg 172620
ggactctgtg tggaaattca gttttagaat gatttttcct gtgttttatt tcccggatta 172680
tctttcctct tttgttagaa ttctgcctgt tattatccag caaggaaaag aagcatctat 172740
gcaagttctt catatggaca gatattattt agtatttttc ccctctcagt ttttctgctt 172800
aaatgactct gggtataaag gaaaggattg attgggctct tttaggaaac tttaagtttc 172860
ttaagtagtt ctcaaaagtt ttggggctga aagcagtgtt ttcaaactgc ttgtcatgac 172920
ccagagggtc atgaactcag tttagtgagt ctagaatatt ttttaaaagg actaaaatgg 172980
aaaggaatat aatagaaaat atcagagtgc atggtatttc gtaaggataa gttttgtttc 173040
ctgaaaatct gttttaatta tatgtgcttc tgtgtgctga ttgtgatgta aaatgtattt 173100
cttactgtgg attgaattca aagaaaaaat tagaaagcta atggcctaaa atattatatg 173160
ttcagtagaa aacaaaaaat tcaggcaagt ggctggttgt ttttacctat acaaatcaaa 173220
aggctatttt gattgtcttc attttcccct tataaattag gttggtgtct ttagtcattt 173280
aggctaagtt ttactatctg attcttaact tttctattgt agaatggtgc tgtcatgtgg 173340
actgtcctcc cgaatgtccc actggatgtt cagagaattt atgtgaaggt cacgtcattt 173400
agcattgaga tgctgtggtt accttcttcc atttcttcca taatatgcag ccacatctat 173460
gtgtgaagaa atgtaataga taaaatttct ctggacgcat aataatgtga gaaagattgt 173520
cacatgtccc agcaaattgt tattaatata aatttgttac ttggcaagct gagattttgc 173580
aagatgttac tcaaaatttc acaatgaagg aaacagggag tcatcttatc ctgggttcct 173640
tttttagatt tcaaacaact taggaacttt gaataaaact aaagatgaag cttaactata 173700
tcaactatcc ttttaaaagt tctaattagg aatttaatgc tgcatgctta tttcagtttt 173760
48
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
attactcagt attcttaaaa gttagacgtc tctcacttct ccaaaaaact tggcaaatgt 173820
ataaatcttt tgcatcaaaa tcaatgccct gctaatttgt atcctggcca tctgcatatt 173880
ttggacaact aatttttcca ctggtgatca tttgaaactc tttctcaact ttgaatagag 173940
actgatttcc aaagtgagat ttaagtgact aagtttcaag tttccgatac atttttcctt 174000
ttacttagat aacatttcag cccccttcct ttctgatctt acttttttat taatttaaat 174060
tgttactgat tacgtgacac tttgtgctgg tctaagaata gtccagagtc acatattccc 174120
tggtgaatga gcatattttc ggatgaaaac ggaatcacat cttcaatccc catttcattt 174180
tcacctcctc catgtggctt gtacctgttt ggaagaaagc tcctgaagga taattgccac 174240
ttattctaat ctttctcaca ctcatttaat ttggatccct ggctaaagtt gttatttact 174300
tttgtgatta tacttagtct atgacattca taatttggga aaattctcag gtttgagaat 174360
tttggcggct tgggatttct tttagtttct tatagtttta aggatatgta agacaggtgt 174420
aagaaactgc caaggggagg aaccatagat atcaggaaaa actagaaaag atgccagact 174480
taccattaat gaatgatgag acaatagtaa ctttgttaag tgagattgta tatgtgaaag 174540
tggtatagaa actaaacaaa cattaggtgt ttttattatt ttactcacat gttaatattt 174600
gttttggtgc tttcataggc taaaaagctg ggaaataaca gatttaagtg gtcaggaatt 174660
ttgttataaa tatagaatga tgattatatg aaatcttttc ctgtgaaagt caaatttaag 174720
taaaatcttt atcaccatct gcaacatttg tctgcagcct ggcttaccag gttatcataa 174780
agaacattta ttttacagat acattaaaga aagtcaaaac cctgattatg tgtaaacaat 174840
tttacataag gaaatatatg aattttaatt atatttttct aaaatccgta ctcagcatga 174900
aattaataca tcttaacccc tccctgtgac ttcattatta tttttaatgt aactttagaa 174960
gaacccagta gagagagcag cgtgctaagt gtgtttcttt cttttccaga caactttgaa 175020
tggagaggag caaattagtc ttttggttta attctgtctc agtttgctta tctaaagaaa 175080
ggaaaacaga gtggctacac ttgtttagaa ccatatgcat actccagaga aagatgctct 175140
attaatccaa aaaatacagc cacttgaaac cagccaaagc gaaagtgtaa gggacttcat 175200
ggaaaggagg cagttcacca aagttattga ggggttttat attttaaact ccgccagtga 175260
attgacgtgt aatgtcactt acaaaaaaaa aaaaaagtat gtctgagctg ttcgctactt 175320
cgtctctaaa atatactcat actgatctct gaaatcccag aatttaagtg ggctggaggt 175380
tacgggaagc acctttataa tatccttaat ctcatgaggg aagaaaccat aattgctgaa 175440
ttctctgcct tggataatat caggagggac tctgaagaaa gttttgcagt aatcaacaat 175500
gttttaaatt atgtgtatat ttttagatca cctcaaaaaa tataggaagc acagaatgac 175560
aactattctg gtctcaactg acacaatttt atgtagttta ataaagtaat aatttcaaga 175620
aacgtgggca aataagaaag agtatgactt tcttacaacc cgcttgtaag tgatgtggtg 175680
gtggtaatga tccatgattt tgatgatgac gatgatgatg aaaatgaagt ttttgtctca 175740
gtttgggtag gtggtatttc tggatgcctc ctatggaccc tggagatgtt catcctatac 175800
agaaatccaa tcctttaaat ctacttggct cattgtttta gaattctaat tccatagtct 175860
gaaaatttta ataatgatat taccaataat attagaaact tattaagtac ctataattgc 175920
tatacaaaaa atttaaaaga acccaaaatt ccaagcaaga ctgaaaattt tttgtctctc 175980
ctctgaacta tttagaggga caaattagtt tgttcttata atatctactt taaataaatg 176040
tgccatcttt aataagatag tagacttctt tgtttggtaa tgttctattt tttggagatc 176100
ctatgagtta cacttgggaa aattataaaa gttcacttaa agttaataaa atccattaag 176160
taatgttcag aactagacat ttccaaatga gcccttgaaa agctcaggtg ggttcttttt 176220
gagagttccc caaatgttgt caaccccagg aggaatggaa gacctctgca gttttgttat 176280
tcagattctc atctccttct cagaagccgt agaactggcc gggccctaag gtccacgctc 176340
cttggttcca gttCtgtCtt CCatCCttCg gtcccgggct Cattctgcct gttcctaaac 176400
ggtggcaagt taggggcccc agcagccaac ttgtgcttac ctggcactac ttcctgggca 176460
gttttcttgg ctccttgact tgttgggcgg cttgggattt cttttatggc cctgaaagca 176520
aaagacaatg ttctctttta gtttcctgca attaaatgat gttagaaata gtcatcttca 176580
cattggcgta cttcctcttt cttctgtagg tcttttagaa ttttgagtcc attctcatat 176640
tttcttgttt catttgcttt attttctaat acatagaagt ttaaactccc tttaaagagt 176700
ttttggcctc ttttacccta ttaagctttc ttttttcttt tctgttttag ttgttccatc 176760
tgtgtattct cagatatttt tctttcacct tttctggttt atttctttat tgacctgtct 176820
catctgttat tttaatgaaa tttggaacag ggctaaacag agttcctacc tcagccagta 176880
taagaatata ccgtaataac tcagagtggt attaactaga ttaaaagttt caaaaagtga 176940
tgtttttctt gtctctgagg atagaaactt caacaaaata aagaagaaat tttcaattag 177000
tagaatttct ttgaaagttt gttcattcat tcatttggct accttattcc aaattgagtc 177060
attcattgag ggcttagact atataaagtg tggttttgtt ttcccagcag ttcatgcaac 177120
agcattgcac ctagcagctg ggaagtctta tagcatgaat aggtgagatt ctaataccag 177180
aatctcctgc atgtgtaaac taacagtgta gtcttgactg ttgtctccca gtaaacttgg 177240
tttcaggagt tttagatcca tgtgaacgtg tacaaggcat ttttgctaac tgtaacttcc 177300
cacttaatca acaaaaacaa aaacactcat ttctgaacat tcagtgcatt catgattaat 177360
cttaattaca ccacaaaggt atttttcaat ggtgattttg cgggagtggg gtaacagttt 177420
49
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
cgaaagcaac attgtcagaa acatagttga ttttaaaggt tctttctggt gactttgact 177480
tctgcttttt tagaagacct tacacagagt tgtatttatt tctcctggaa tatttcaagc 177540
aattcagagt gaaagggtat acattccaat ttgcgtatga gataaaattt agttacattg 177600
agaagctatt ttctttagtt acagggaaaa aattgtaggg cttttggaag cctctttgat 177660
ttctaatagg aggaatccct gagcactggt ccaaacagaa atcatctctt cttcattgct 177720
gtatttccct caagctctta gcaaagtgca tggcacgtga aagcccggag aagctgttgg 177780
ttgaaagaat ggatggtggt gggcaggaag catcagggac atggtttgct tcagtctatt 177840
ggctgggaga aaggccattt aggaagggat ccttagatgc cactggaaga atgtgggaag 177900
tttgtgaatc tctctttctc aggaacaaaa gtagaaaaag gactccacac agcattccaa 177960
gtacagtcgg ccctcattat tcatggattc tgtatttgca aattcgctga cttactgacg 178020
tttatttgta accttcgagt caacactcac ggtgctttct cagtcctttg cagacgtgtg 178080
gaatggcaaa aaaatttgag ttatatgacg tatatgttcc cagctgaggc tgagcaaggc 178140
tcacttctcc ttgcagccct cagactataa acaagtgtcc ctcttgctat ctacttcgtg 178200
ttatgatttt tgcattttca taatccctgt tgatgatttt gctgtttaaa atggccccta 178260
agcatggtcc tgaagtactg tctagggatt ctaagacaag gctctgacgt gtcttaagag 178320
aaaatacgtg tttgataagc tttattcagg catgagttac aatgctgttg gccatgagtt 178380
caatgatggt gaatcaacag gatatattaa atacagtgtt tttgaacaga aaaacatata 178440
aaacaaggtt atgtattaat gagttggcaa aaatgctgtg accaaaggct cccaggaacc 178500
taccctattt tcccctcaat gcaatggttc agtatttgct aattcagtgt ttgaggtgac 178560
tttatagaac atgagtacca tgaataatga gaatcgattc tgtataatag agtgatgaaa 178620
gcacaggtct gggagccagc agctatattt ctattctggc gtgactcctg tgtagttgtc 178680
atcactggca aattgcttaa ctgtgtgcct cagtttccta atctgtaaaa gctacatcgt 178740
ttggatgatg tgaggattaa acaaattcat agatgtctag ggcttataac attcctggca 178800
cataacaagt cattattttt tattactact tcggaaggga attgagtact ataccctgaa 178860
gaaggtgagt atgggaattc tctacgggtc tggaatgtcc ctatatttgt ttattttgcc 178920
ttcaagtgac taactttaat accctattgt gattagaagt taaacttctg caaccaaaag 178980
gaagcaggaa gctagtattt cttgaagtgc ttattacatg ccaggtactg tgctacaaaa 179040
acaaaacaaa acaactgtaa aaaaaacttc aaatttggct gcgtgcagct gctcatgcct 179100
gtcatcccag cactttgagg aactgaaggg aggattgctt gagtccagga gttccagacc 179160
agcctgggca acacagtgag accctgtctc tacaaaaaaa caaaaacaaa aacaaaggca 179220
ctccaaatca gtaaaaatta atcaatcaat aaaaagagtg aggggcatta agtattgtgg 179280
actgaagcaa tcccagagag ggaattaatt gaagctgagg taagcagctt atggagaagc 179340
tatgatgtac agagggcaag gaaggaattt ttctgtaatt tggaaaaatg ggaactgtga 179400
gaaagaagga gttggaagct catacttagg gagcatctac aaggacgtct ttttcacgtt 179460
ggttggaata tccaaatcaa ggattatttc agaatcaccc agatgattaa aaaactactg 179520
agatccaggt tgtatttcag cagttctgac aattgctctg ggtcgaagct tgaatcagta 179580
gttaagaaaa acaacaaaca aaacaaattt tggggctttt ctcactgatt tacagttaaa 179640
gctcatttac tcttcctatg actttagatg gaggatattt ccaagtcttc aggatggaga 179700
catggaggga agtgagacta gtgatgtgcc tcaaggtttt gctgttgttc taaccatgag 179760
gagcactatt caaacccagg tctgctagat ttccaagtct tcatttcctt gggcctcttg 179820
gatttcagaa gcagagggta aaaggagtgc tggggagaaa gatcacagta gctttcaatt 179880
ctactcctca gctttccaaa ataagtttca agactggccg ttgcatttga tatggaataa 179940
atacaaagaa ggtagattga agggtatgaa gatgcagatt tttgatacca gatatgaaga 180000
taacattagg aagcaatcta aaacatggac acaaacacac acctgtgcca gttagcctgt 180060
ataattcgat ttttgttaag tgtttagata actgaaggta atttaagccc tcatatcttc 180120
ccttcatagg gttctttttc cctctggttc atcagagagt tgccaccaat tcaggctgtt 180180
agtggtacac ataacctcta gcattgttga tacagctata aaatcccaaa tatcagtaca 180240
attgttgatt gcataaaatt tccagttgca tggttggaaa gtcctgtaag tttgaatcct 180300
taaaccagtc ttaaatgtgg aggaggactc aattaaagct ctcctcgtgt cctccctctg 180360
acgtatttgc aaaatccttt ccacaaatag aatactgttt ttaatgcttc cccagtccaa 180420
ttttgcgttg tagaagacga atttatggat gagggaagtg gcattcaggc actccagctt 180480
ggtatagaag cccatggtgt ctggtcctca gtcctcaagc ccgctcattt cctcatgtga 180540
actcagaata agcagctgaa agcaagtctt caaaatctca gagatatgta taaatgcaag 180600
tgtttgggtg agaagtgaac atgggtctcc tctagtgccc acactacttg actaacaggt 180660
tttgggctcc acacaatgag ggattatcaa cccctgtccc agggctctct gggtcttggt 180720
tctttgtttt tgatgctcag caattgtgat cagtgaaacc aatgttgctt ttctatcaag 180780
agtccaaccc ttttctaaga agggttgtgt ttgatattag ggaatagcta gcaaagttat 180840
caagtaactt gtagaaacat tcttttgcaa gagttcttat actgaatgac tgtagttgac 180900
agcagtgcag tactggtcat tttctaggac atcttaaaaa cactgatgag aagtttcctc 180960
tcagatgtct gtcatgtcat tcttgccttt ctctacacag ggtcagtttt ctcttattgc 181020
tgttaggagt tcctcattgg tttttcagct tttgggcttt caaactctaa ttaatcataa 181080
SO
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gctactagag tgtactacct aaagtgtgta tatacacata tatacacaca cacacacaca 181140
tatatatacc tggtatacat atatatatat aatatacata tatcatatat actccccaac 181200
ctgatctggt tcttcctctg cataaaagac ctcaggccag tcagagaaaa catgtatgtt 181260
ccatggtgtg gcaatcaagc ccttgtattt ggttccaatc agtctcctaa ctattactcc 181320
aagaagctct tgttgaaaga gccatgttta aatggcatgt tcctactttc ttcttcatag 181380
tgatcttcat ctgtaccatg tacccttctt tcttcttgtt ccatctctgt taggctgatt 181440
ctacccagaa gtcaaggttc agctcaaatg ctatccctat caggtgaatt ttccacctgg 181500
catttgttcg gtgtgcattg tgtgcataca gcaccttttc ccggtacctt tactgtaatc 181560
accagataat tcctttcatt ttagttgtaa atagagttgt cttccccctc tatggaatag 181620
attttattaa tgtatagagc agcagtcccc agcctctgga ccatggactc gtactggttt 181680
ggggcctgtt aggaactggg ccgcacagca ggaggtgagc agtgggcatg caagtgatgc 181740
ttcatctgta tttacagctg ctccccatcg cttgcattat gcctgagctc cgcctcctgt 181800
cagatcagcg gtagcattag attttcatag gaatgcaaac cctactgtga actgtgtatg 181860
tgagggatct gggttcttct tatgagaatc taattcctga tgatctgtca ttgtgtccca 181920
tcacccccag atgggactgt ctagttgcag gaaaacaagt tcagggctct cactgaatct 181980
acattatggt gagttgcata attatttcat tatatgttac agtataatac taatagaaat 182040
aaagtgcgca ataaatgtga tgcactggaa tcatcccaaa accatcccca gttccatctg 182100
tggaaaaatt gtcttccatg aaaccggtca tggaactggt gccaaaaatg ttggggacca 182160
ctcttataag gcatattaga gtaatttcat agatttccta attcatttat catattcatt 182220
cactcagcaa gcattactgg atgttgatca tgtactggct ttggtggtag gtgcagagat 182280
tgggaacatt gtcatcaagg agtttatggt tgagtgaggg agatgacaag tggatagaca 182340
atgaaaaaac agtagaataa gaactgtgat'agaaaagaga cagccaggag cattgaggag 182400
aggcacttaa ccagatggag gatcttggtc cattgatatg gaggtcaaaa tggtttaata 182460'-
gagcaagtga ccctttcaac tgaatttttt aagaatgagg atttagccag acaaagaagg 182520
gcaggtgagg ttgtgaagag gaactgagtg gtactcttca gagctccagc ccagttcctt 182580
ggacagaata aatgcttact aacttataga gctgaatatt gaattaataa aataagggta 182640
aactgttaag aatcagagaa ataacttaaa gaacactgat agctagtgtt ttttgaacac 182700
catgtaccca ggtgccttgc cgaaaacctt aatgatcatc ttgtttaaac cttacatttc 182760
tcataagagg ctggtactat tgttattctc attttatggg acgtagaaac taagacttgg 182820
agaggggaag tgacttgccc aaggtcatac aaccagtact ggagaattag ggattctaga 182880
tctagaattt ggactctgga gcttaaggtt ttaacccacg acattatgca gagaaattga 182940
caggattttt ctgttgctga tcaatttact tggcagttag tttgttactt ccttgtcttt 183000
attttagttg tgacaatgct ttcatcttag actgtgtccc gaggctgctg cttttatttt 183060
tatgggaaat ggctattttt atgatccttg ctaaaagcat gtttaaacaa ttttccatta 183120
agtaggggga tgtttttcct tctaatatca gaagccaata aatgaaattc tacaaagact 183180
tgctggtagc aaccttagga atttctttgc atgtgaaacc catctgagaa cttaaaatct 183240
gggtaaaatt gtagtgtaat ttggtgcaat cgtctctttg cacaaataac atcataaaat 183300
catagtattg tcatctagga ggggccttag acatgatgga atcctacctt ttatattttc 183360
caggtgaaga aatca~agtc tagaaaggtg aaggaacttc ccccaaagtt tcccagctgg 183420
tagagacaga accagggcta ggtcctctat tctgactcct gaccactacc tcacacctaa 183480
tagatggagg catgcccagt tcctgttcac cgagggcatc agaccatgcc atactcattg 183540
ctactgttcc agcatttata gtagaagctc aagcaagcag gatgacagaa tacctaattc 183600
tggtcactac aacattataa tgatggctaa agtgaatgcc ccagccatgc ttgtctagac 183660
aggccatctg tttaattggt atatggttca cgtgagaatt tttaacctct gtttgtcgag 183720
tcggtgttag ttctctagtg atgaattatt tcctatactt ccatttagat tatttactct 183780
taatttaata accatacatt gtttactttg gtattgaaga ttcccttgtt tttcttcttt 183840
ttttctgttt ccagggctta aaggttagga gtgaccttgc cagacttccc tggagactta 183900
cactgtctcc tttcagattt ctgaagcagt tgggtgctat ttttagtcca ctatcaccaa 183960
tgtgaaaatg gaacttgcat tatttcatta tagatatttc actttagtat tgacagaatt 184020
aaaaaaataa tttgatctgt gcttgatcta gcagccaggt tacaatagac atttttagtt 184080
acctggtcca catgttgaaa aacatgtgtc ttctctgaga ctaatgacta agcccgatgt 184140
tggttatata ctgtttacta ttaaattttc cccttgtagt ttaatattgt tccaggaaat 184200
gaaatgaaag tttaataaga atggcaattg atggacccat atgtcggaag tataactaat 184260
gtccccgtta catgtgttaa agaaaggcat ggctggtggg ttgtaactgt actacaccaa 184320
gatgatttga cacaacttat tctacagaga tatatattta tcaggataga atttataact 184380
aaacaaaact atagcatttt ttcactttga ttttttttaa atgagtcaaa gaactgctag 184440
aattgtcagt taaaaaattt taaaaggaga tatgaaaaaa tcttacaatt cacaatgctg 184500
taaagagata atgtagggat taatatgttc ttgatatcaa tattttatga cttttataca 184560
tgtagaagca aaacaatttg aggtaggtga agttagtatg gacttcttga gattgtcctt 184620
cacatttctt ttcctttcgg tgaaaaattg aaggccaaaa tgtattttct tctggttttg 184680
aaaatactgt caagatcctt gcaacaaaat gagttcctct aaggagctga aaacaaagct 184740
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cactcccctc gtgatactct gagaggcttt gctcagcatc ctgcattctg gtgattcctt 184800
ggagacagat gatgctaaac acaggaagat taggtcaatg gtaacttttt ctaagtcaat 184860
atttcttctc cttgggagat gatcatttta aatcttcccg aagtccaggc taaacctttc 184920
taattgaatc tccatgaagg agagctccag caggtggaga ggaagtgaga aagagaaatg 184980
aaagctgcac gcctcatgac gctgtgccag ggagttctta aaggtgaggg agtttctttt 185040
tggtaaccta agctatgtga atcagaaggt tcattagctt gtttcttttt cttttttgta 185100
aactcctaca taattttagt aaacaggaac agtaacctaa tgtgatatcc cactggccca 185160
agacttagtg catcttcaaa gttgcttaat tatgtccgaa acagactttt gtctcttgat 185220
gagaaaagca tggttaaacg tgtgatgatt tcctattgtc ctgagctcag atctgtaatt 185280
gtggccagat tcatgcatct ctgctgcctt ctcttagaag aatcatatgt aggcttgtca 185340
gataaaacag gatgcccagg taaactggaa tttcagttaa ataacaaata acattttagc 185400
atgtcccatg caatattata ctaaaatatt atttgttgtt tatctgaaat tcaaatttaa 185460
ttgaatgtcc tgtatttttg ttggttacat ctggcagccc tagccatgct gcctttctgc 185520
ttaatgggct taattttttg aaggctggag gttttctgtt atggtgcccg tttccacctg 185580
cttttctacc aggaaaggag gcatgctgat gtagaatttg catccttatt tttgtcatta 185640
ttattgatta taacagatga cataggttta gattaaacct acaatgacat tgctgtcatt 185700
cagataattg taattattgc taattgtaaa gaaggataat tttttttgaa atgactatta 185760
tttgtttttt gtttttgttt ttgtttttct ttttttctaa ttatacttta aattctaggg 185820
tacatgtgca caatgtgcag gtttgttaca tatgtataca tgtgccatgt tggtgtgctg 185880
cacctattaa ctcatccttt acattaggta tatctcctaa tgctatccct cccccctacc 185940
cccaccccac gacaggtccc ggagtgtgat gttccccacc ctgtgtccaa ctgttctcat 186000
tgttcaattc ccacctatga gtgagaacat gcggtgtttg gttttttgtc cttgggatag 186060
tttgctgaga atgatggttt ccagcttcat ccatgtccct acaaagaaca tgaactcatc 186120
cttttttatg gctgcatagt attccatggt gtatatgtgc cacattttct taatccagtc 186180
tatcattgat ggatgtttgg gttggttcca agtctttgtt attgtgtata gtgccacaat 186240
aaacatacat gtgcatgtgt ctttatagca gcatgattta taatcctttg ggtatatacc 186300
cagtaatggg atggctgggt caaatggtat ttctagttct agatccctga ggaatcgcca 186360
cactgacttc cacaatggtt gaactagttt acagtcccac caacagtgta aaagtgttcc 186420
tgtttctcca catcctctcc agcacctgtt gtttcctgac tttttaatga ttgccattct 186480
aactggtgtg agatgatatc tcattgtggt tttgatttgc atttctctga tggccagtga 186540
tgatgagcat tttttcatgt gtctgttggc tgcataaatg tcttcttttc agaagtgtct 186600
gttcatatcc ttcgcccact tgttgatggg gttgttgttt tttttcttgt aaatttgttt 186660
gagttctttg tagattctgg atattagccc tttatcagat gagtagattg caaaaatttt 186720
ctcccatttt gtaggttgcc tgttcactct gacggtagtt tcttttgctg tgcagaagct 186780
ctttcgttta attagatccc atttgtcaat tttggctttt gttgccattg cttttggtgc 186840
tttggacatg aagtccttgc ccatacctat gtcctgaatg gtattgcctg ggttttcttc 186900
tagggttttt atggttttag gtctaacatt taagaagaag gatacttaaa gtataaggga 186960
aaatgttaca atgtatgaag ggaacatgaa gaaatagaat ctggtaaaaa agagttcttg 187020
cttttgggag gccaaggcct cctggctaac atgatgaaac ctcatctcta ctaaaaatac 187080
aaaaaattag ccgggcgtgg tggcacacgc ctgcagtccc agctgcttgg gaggctgagg 187140
caggagaacc acttgaaccc aggaggtgta ggttgcagtg agccaagctt gcaccactgc 187200
actccaggct gggcaacaga gcgagactcc atctcaaaaa aaaaaagaaa aaaaagagtt 187260
cttgctttca aaactatgga ttaggtaact tttgtgaatg agtaagatca tgagtattat 187320
aaaaatagca cctttctttt ttgtcttggg gaaattatct tattttttaa ttggatttca 187380
gaaaagagta tttcagagaa ataaatctct gaaatgcttt ttgaagtgtg aaagatttag 187440
aagacaaaag caaacctcct gtctagataa acattaaaga gatctgccct cccctcctct 187500
acctattcag gttgcaacac tttgggggtg gctgccttgg tagagcttga tcgtgactct 187560
ggtggcttgg gagatggcat gctgcacaag ggattcatgg ttacagcggg cttgtgggac 187620
tggggctctc caatacgtgg ttgggtttgt aaagaaatca gagctatggt gtgaacaaaa 187680
ggatatgcat gggagacagt gagacaagga aatgctccag aaattattgg aatataggtc 187740
agataactaa ctgtacttgt gccattttct gggggaaaat tctctgaagg ctttttggga 187800
aaagaatgga agtgagaatt ctcaggtcct caaaatattt ccttttactc agtcctaacc 187860
tgaggccgtt aaagaattcc cagagtcacg atggaaggca tgtttgggag taagagccag 187920
agtgagggtt agaaatgtgt tgttggccag gtatggtgga tcatgcctgt aatcccagca 187980
ctttgggagg ccaaggcagg tggaccacct gaggtcagga gtttgagacc agcctggcca 188040
aaatggagaa acctcgtctc taccaaaaat acaaaaatta gccaagtgtg gtgacacgtg 188100
cctgtaatcg agctcttcgg gaggctgaga caggagaatc acttggaccc aggaggtgga 188160
ggttgcagtg agccaagatc atgccactgc actccagcct gggtggcaga gcaagactcc 188220
atctcaaaaa aaaaaaaaaa aaaaaagaaa gaaatgtgtt ttccagggtt ctgggtactt 188280
aggaatttgg ttgcttttgc aggtggaagt ggaggtgact aggtaacagc tgagtgattt 188340
tgccccagtt ggacatgagc caggttgagc agaaagccct gggatgcggg gaggggggtg 188400
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gcggggaagg aattgaaagt tggttgtgtg gtttggcttt ggcttcatgg catgctcaca 188460
ccttgcttcg catagcatgc ttagactaca gcaggagcat caggaagtgg atttctgagc 188520
tcaatacaaa aagttataaa taccacctat aagggcaata aagatatata gttgattttc 188580
ttctttgcaa ggccaaatct tataggaaca taagagcgaa tgagttacag cctgggaatt 188640
tgagccttat attcagagat tttaggttgc ttctgattcc gctgtctaga caaaaccatg 188700
agaggatagt gtctagaaat gagaggaagc tcttccaatg cagaggctag aatgtgtcag 188760
cctgtgctgc gaggcctggg atagatgttt ctgaaaagta aaagggcagc tttcctactg 188820
gatacttgat cctcaggctc tagaaaactc tgctttatta actttgttga cttcctaggc 188880
accacatggg atccttgttc ttcctccttg taagcagtaa ttgaaatcag tttggcagcc 188940
tggtttacag tgaccatggt ggcttgtctc ccgtgctctt acctcactct gttgatgttg 189000
taaaacctcc agctaacttc atggggtggc tgacccacgt tgctcattta ttcattcaac 189060
acatattcat tgaccatcta ctctatgcca ggtattgtta tcagcactgg gaatagatca 189120
gtgaactatt gatctatttg tctaatggga caaattgaca aattgggaaa gattccatta 189180
cacaggtgac atttaagcaa agtcttgaat aagggaggga atagtaccat gagatatcct 189240
ggtgaaaagc aatttaggct gagggcacag cagggaagag gccctgatgt gggaacatcc 189300
ctggtgtctt gaggtacaga ggccagcatg gctggcacgg agtaagaagt tggaggtgcc 189360
gggcatggtg actcacacct gtaatcccag cactttgggt ggctgaggca gatgggtcac 189420
ctgagcccag gagcttgaga ccagcctggg caacatggtg agaccccatc tctacaaaaa 189480
aatacaaaga aaattagcca gatgtggtag catgcatctg tagtcccaat tgcttgggag 189540
gctgagatgg gaggatcaaa ttacttggga ggctgagatg ggaggatcac ttgagtccag 189600
gaggtggagg ttgcagtgag ctgagatcat gtcagggtga cagagcgaga ccctgtctca 189660
aaaaaaaaaa aaaagaaaaa gaaaaaagaa aaaaaaagaa gttggaggtg agtaaggaga 189720
ggaacgtggg ggacagagtc ctcaggactc tggcttttac tctgagtgag tcgaaaatcc 189780
aattaaaggt ttgaaagaga ggaatgacct gatctgacat tttattgtga acgttttcaa 189840
atctttacag aagtggaaga gcataacgat ccttcatgta cacatcgccc agcttcaact 189900
atgatgtttc atttgtaaat atttccgtct acacttccaa aggatgatga ctatttttaa 189960
aagtccaact ataataccat tatattttaa aagttaaaac actatgtctt taaatatcaa 190020
gagtttgtat tgattcgcac tttgaaggtc gagctgatga aatttcctga ggggttggat 190080
gtgacatgag agaggagtca agtattgcat ggtaattaaa aacctttgca gcatagtcca 190140
tttaccgaaa gactatatgt atgcacttca aagcaggttt taaagattaa catcaagcat 190200
ctggcttcat gagttttaac ttcttttcat aaatgttata caatgtcatc atctctccag 190260
ctagagaaaa tgctattatt cttattttca aatgaggaaa atgacgcaga attatttaca 190320
tattatgtaa cttggtccca agtcccttag atactggttt agaaaatcct agtaaactgg 190380
aagtgactta tccaaaatta aaatttattt tgctctattg tcttttgttg cctatgggaa 190440
ctttgtgcag gtaactaggc acatgtcagg actgatttac tgacctctca aggtatcttt 190500
aattattttg ggggatatca cggaatgagt tctacacaat tcatttgaat cgaattgaac 190560
ttaagaaaat tcaaatgatg cattggctgc ctcctattta ttacatgctg ctcataggca 190620
taacagcata gtctaacaag tataaaacct gtgtaactgt agctttcagt gcagtgtgat 190680
gagggctgag aagatagtgg tacaaagaag agaggtagca gagtgaagct gagtcaatat 190740
gatgaagatt tctctagact tgaaagggct agaaaaggtt attcttggca ggaaaaaaac 190800
atgagccaag gcataaggat aagcacaggc atggcagatt tgggaatgtc atgtaatttg 190860
ttgctgggct gcaaagtaca tggaagggga gtgaaggaac agaaggagat gaatctggag 190920
ggagaggtta aagtgttcca gagagcaata tgtaggtgtt actctaagtc aaagaggtcg 190980
taatagcatg tccagactcc aaaactctaa acaagtcata gaattgctgc cttggtaggg 191040
catatcacac acatcaaccc aatcctctgt caccatgaca tccatataac tgcaactcta 191100
tacatttccc agcctatgtt cccagagtct ccagatgaca ttgtctgcaa actgcactgc 191160
agaaggctct gctatgtctt cttaaaagta agcaagactg ttttcctttg ttacatgagc 191220
agcaaaagga tagggtgctc tttgacctca cttactgtag ggtggatagg aaagtcaagg 191280
aagagtaacc cagaagattt agttttaact ttcgcatcaa agaggtccct tagcatctgc 191340
tcagagatgt cacaatttct ggtgtgtgat tatgtttaag aattcggcct tgccactgtt 191400
gaagttgttc tgtggaaaaa gaacctctct taattttaca tgatgcccaa cttctctttt 191460
attccagaat cactcatatg ctgttggact ctttccagcc atgtgtgcta acctaggcaa 191520
tgtcataata gatgaattat gtttactttg tctttgatat ctcagctctt ttatcttcta 191580
ttcaagttcc cacctccatc attactgata gtgttcgttg aacaaagaat atgtcagata 191640
tacagaagtg tttctcccct tttctctgtc tctcttttcc ttcctttcct ttagtttcct 191700
ttctctgtct gttttctgat gcctcatttt agaaaagtga ttttttttgt gggaaaatca 191760
ttttagcatt agaaacgcaa tggctatcac tgacagcttc ctctgatgaa acggccattt 191820
gtcatcatta cacggtcatg ggagtgctaa gaagacttaa atgcagggct accacccctt 191880
cccaattcat cttttatcca ttttatttct ctaaggaaag ggtttgaaaa atgggctttg 191940
ccctcttgga tgcagtgaag aaattctagc tggctacaga tgttattgtt ggtcggaggc 192000
aagggataaa atcatggtca caccattgta gcgccagatg gggaatgtag caaacatagt 192060
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tgtaatttct cattttacag atgaagaaac tgaggtgcag aggggttcgg tgacttgttt 192120
aaggcatgta attgttattg gcagctttct gttcagaact taagagtatg agtcagtcta 192180
gatcttttca tcacaatact ctgctcctct tactttttcc tgaaatttgt cacattgaca 192240
gcaatgtgat ccctaatgac acacagattc ccaaataatt tttgtagtaa aaatttccat 192300
ttgcaattct ggacatgtgt gtgtgtggaa ttttatgtga tgacatattg gtcctatctt 192360
ttgaatagga tcataaatga aatgacttat ggatcacatt caaaagcagg ccaggggcca 192420
atgtgtaagc a,ggtgggttt tcatatttgg agttctgtac ttttgtgtta gtcagtgggt 192480
ctaggactct tgtagtgtat ttcccaaggg ccaaagtctt ctgccttgag gtgtcagctt 192540
tccaaggcag aggctggatg ctttctcttc cttctgggct cctttctctt aggcttcccc 192600
cttctcttct cctccatttg tatctgtcct ttttctcggt actttccctg gctggtctca 192660
gctagatgct cactcaatgc tgttgaataa atgaatgaat ttcgtagtaa ttctgcaggt 192720
aaatcaagtt attgtctccc aatacggtgc tatgctttct gaggaaatta gactggaagt 192780
caggcttttt aaaaaagaag atgtggtgtc aaattgcagc tctctctctc tctcgactta 192840
ccttttttct atcatccata tgccttcttt cttgtatctt tgggttccca gacctcacca 192900
ttcattagca cttggaatgg attggtaaga ataaagaaag gagaggtggt gaaactcagc 192960
ttgggtcatc tggttacaca ttagtaactg acaaaagata aaaagataca gactaaatgg 193020
gtttttaggg aactttttcc agtctattct tgtttcccat tagtgtgaaa aatcaacact 193080
tgcttgtatt ttggggtgaa gacatttttc ttaagtgagt gggaaagcct cttgacattt 193140
taccgagagc cttaaatttt gaatggtgaa tgctaatgtt ctttgtgcat aaagaatttc 193200
agaacttgta tatatgagca ttaatgatgc atcattttct atttgtgagt taaactaggt 193260
attatctgta atcatatttt taggaaacat tcaaactttc atcaagtcat tctcttatat 193320
gactctcagc tccattaact ctgttttcat ggaactcaac agagttctta acgtttgcat 193380
tataaattaa attagcattt cccctcaaag aagtattgct gtccttacaa taaataattg 193440
tagacaattt cttttctttt cttttttttt tttttgagac aggttctctc tctgtcaccc 193500
atgctggagt gcagtggcac agtcacagct cactgcagcc ttgacctcct gggctcaagc 193560
aatcttccca cctcaacctc ctgagtagct agaattatag gtgcacacca gacctggcta 193620
atgtttaaat tttttgtaga gttggggtct tgctatgttg cccaggctgg tctctaactc 193680
ttgggctgaa gcattcctcc caccgcagcc ttccagagca gtgagattac aggtgtgagc 193740
taccatgccc agctaattgc aggtgatttc taatgggatt tagtatttct gggtttaagg 193800
atgagatctg aggtaatgac tttgtttcca gatgtgaaat aatttgctct tgggttgtga 193860
gccctttggg tgggctccca aggatcctgc tctcttccag gagcccaggc tctggggtca 193920
gactgcctgg gtccttgact ccctgttttc tgattgtaca actttggtga gtggcctaat 193980
tcctctgtgc cttggctacc ttggttacta tttctaaaac aactggtgtt gtagtagtac 194040
tgcttagagt actttcaagg gttaaatgaa ttaatccatg taaaacgctt aaaatagtgc 194100
ctgccacaac catcaattta gtgtgaaaat ctgctcacct gcttggccag cccctttcac 194160
tttattaaac caagggtcgt gctgggtttt ccagaagtct aagttgcggt ctaatctttg 194220
tgcagaagct gaaatagcag ccataacgtt ctccctagat gatttcgtgg agcttctttg 194280
aactgtatct atctccagtc atttttgtgg aagaaatttt cttctgtact ttttagggat 194340
gagaattacc tgccttggtt tattaactaa aagacaccat gattacaaat aaaattaaat 194400
aaatattgta tcactaaata gataatatga gatagatgta ttaagttttc agataaacag 194460
tataaaagag ctagagtaat ttgtaaaaag ttgggaggac ctattttgtc atgcaggaaa 194520
caatttttaa cttgcctacc ccagaacata gctaccacat ggttagggtt tgcccaaacc 194580
tggcccagga gtcatttacc ttgagctttc ctaaaaagga ggatcaggat tttcctctcc 194640
agactctatc attttaggta gagtccttct tgtcaattct ttttaagaac atacatttac 194700
ttttgtggaa aataaataga tacaaaataa atacatacaa aattgcatag caattagaaa 194760
tacccaggag gtatgttatg gtcacagaca caaactgcct ccaacttctg tccatccata 194820
gtgatattta aagcagagag aggtacacag gtaaccacat ttagatggac tgggatgttg 194880
ccacacatac aagcattgat aactggcttc tcattacctg aatacattct tctgtcagag 194940
caacagactc agctatgctt ctggcaaaat tgttcttaat tctctattga ttaatttatt 195000
cggtaagtat ttattgggta ttttctgtct gaaaagtgcg attccaggtg ctttatgtgt 195060
ctctgtgtgt gggtgttata taaatactta taatactgta tccatactct tgaaaagctt 195120
agttgggaag gcaaggcatg caataaggaa cacagaattt tagtcattcc acaaccatct 195180
gttgaatggc tgctattgtt agtatcgtgg tggaaactga gaagcaaaga tgactataat 195240
aggatctctt ttctggagat gcacagtgga cacgtagtta tatgatgatg ataaggactc 195300
cagaatagtt ctatacatga tgctctgggg ccacatgcag attctgatga gaaacaatta 195360
actctttttg gctgctacct gagaaggggt aattgtcact caggaggttt ttgccttttg 195420
accaacatag aaaggagtgt gagtgaaggc tagaggtgta ctaacttggt cagggcaggg 195480
tgacacataa aattaaccat cacagggaag ggtagggctg gagaggcaga ctgtggccag 195540
gttacaatgc gctgaggcta aggagactgt gtttatcctg taggccagtg ggtcttactc 195600
tgaagtcttt tgggtgggac attcatggac ttcaagagac ctgtgaatgc cctaagatta 195660
taagtaaaat ctgtgagtct gtaactaaag ctaaagctat ttttctgggg cccaccatct 195720
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aaagaagatt ctgaagcctt agggtagccg tggaggagac atgaaggtcc attttgcatg 195780
gtagaaccct gcctggctct tgctgcagtg tgggaggaca ggtttgcaat gtggaggtgt 195840
ggcaggcatg gatttgggag gattggcaga ggactcacca tgtccataca ctcactgaga 195900
tggcaaatat ttattaatca tccaactgtg tatcagacac taagaataag ctgggaggcc 195960
atggcaagtg aggtcaccac agtccctgcc acagtggagg ttatggtata caggtaaggc 196020
agggaagagc actgcaaagg gtttgcccat tgcatcagtc atttatttat gcacatgttg 196080
attcaacaat tatttctatg ccaagctgtc ttcaaggtgc tggaggaaat gaagcgtaca 196140
tttcactggg gaagacagac aataagtaaa cacattaaaa tctggcttgg cttgatgttg 196200
gggaggggtg agtgccatag agaaaacaaa ccatttatgc agccaacaaa catatgaaaa 196260
aaatctcatc atcactggcc attagagaaa tgcaaatcaa aaccacaatg atataccatc 196320
tcacgccagt tagaatggtg atcattaaaa agtcaggaaa caacagatgc tggagaggat 196380
gtggagaaat aggaacactt ttacactgtt ggtgggagtg taaattagtt cagccattgt 196440
ggaagacagt gtgatgatcc ctcaaggatc tagaaccaga aataccattt ggcccagcaa 196500
tcccattact ggctatatac ctaaaggatt ataaatcatt ctactagaaa gacacatgca 196560
cacgtatgtt tattgcagca ttgttcacaa tagcaaagac ttggaaccaa cccaaatgcc 196620
catcaatgat agactggata aagaaaatgt ggcacatata caccatggaa tactatgcag 196680
acataaaaaa ,ggatgaagta atgtcctttg cagggacatg ggtgaagctg gaaaccatca 196740
ttctcagcaa actaacacag gaacagaaaa ccacacactg catgttctca ctggtaagtg 196800
gaaattgaac aatgagaaca catggacaca gggacgggaa cattacacac ctggggtcta 196860
tcagggggtt gggggctaag ggagtgatag cattaggaga aataccaaat gtagatgacg 196920
ggctgatggg tgcagcaaac caccatggca cgtgtatacc tatgtaacaa acttgcacat 196980
tctgcacatg tatcccagaa cttaaagtat aattaaaaaa aaaagaaaag aaaacaaacc 197040
agtgtaagag gatggaaagt aataggctcg tttagaatgg tgtgagaaag ccaggcaggg 197100
agaaggcgct gagacaggga ggtcctggat gtgtttgtgg aagagctgtg gcagcacctg 197160
gaacttgggg agcaagggaa ggagtgtggg caggcaaggg tgagggtgca gggggtcatg 197220
ctgggccttc caggtcacgg aaggacttga gctttactct tgttgtggtg agaagctgct 197280
gagggcttgg agttagggga gtgaaaagat ctctactata atagggagag ttcgggatct 197340
gtaacttaac cccaggagcc agcaaagctc cctggaggaa atgcagttta agctgagaat 197400
gggaggataa acaggtgttt ttcagagaag aggaagggtg ctctaggcac agagaacaac 197460
atgctggaat gcttctacta gatcataggg gcaaaatggg agtgcaggag taggagaggg 197520
ctttctggga aagatactta ttttaatttt gcatgcattg agtttttgag gtttctttgg 197580
tttgttcatg tggaggtgca gagtgggtat ttagcacata ggtctgaagt ccaggggagg 197640
ggtgtgggac agcagttgga tgtggcagag attccacaaa gagcaaatat catctgagaa 197700
tggcagaggg ctgagggcag agccctgagg aacactggtg tttaggagcc tgctggagaa 197760
agaaaatact gcaaagggaa cggaagtgga gtggttgcca gacatagaag ctagtgtcta 197820
actagatgtc atgagatgtg gggaaggtgt tacgtatcta agaatgcaaa gttgaacccc 197880
tgtgaactgt aatacttaag ataagtcgta taaattgtct ggaactagag cttgattttc 197940
caggagagat gaaatgtgtg taggtgacag gaaacaatga atatgtgggc gagtgtagtg 198000
tgagcaattt ctcagaggtg aatttgacag cattttgctt aggaagctac aaagagacca 198060
atgctagttg gtgcaaggaa ttcaagaatt tggacttaag tctatataat gatgattttt 198120
tttttttaac ttgagtttcc cggtttatca ctcccagaat ataggcagaa gtttgagatt 198180
t'ttatgtgta ttttctggaa aagatagttt cagtgttttt tacattctca aacaggttta 198240
tgatccaaag aaaaggcagt ggtcacagat acatgaaacg acaaggtatt caaaggagaa 198300
cgttgtactt tatgacagtt ctttgggcag tggcttgcag gatgagtttg aggaatgatt 198360
ggaggcagga gagtaattct agtaattcaa atgtggagta ttgttgatct ctcagacaca 198420
aatggaaaaa caaggaattc aaagaaagat aggcagagtg ttttgaagaa ataattgatg 198480
aaatttggta atgagttaga tgtaggagat atatttagca aatatttatt aaggactgta 198540
ttaatctgtt atcatgctgc taataaagac ataccaagac tgggtaaatt ataaagaaaa 198600
agagatttaa tggactcaca gtgccacgtg gttggggagg cctcacaatc atggcataaa 198660
gcaaaggagg aacaaagtca cgtcttacat ggcaatagag tgtgtgcaag ggaactgcca 198720
tttataaaac catcagattt catgagaaat attcactatc atgagaacag cacagacaaa 198780
agcctgccac catgatttaa ttacctccca ctgagttccc ccaggacaca tggaattatg 198840
gaagctacaa ttcaagataa gatttaggtg gggatacagc caaaccatat caaggaccta 198900
ctgtatatgg ttaaaattgg gagcaaatga gacatgattc ttgccttctt ggagtttact 198960
gtttactagg ggaacataca cttgtcaata atcacccaaa tataggattg gaaattgtgg 199020
taagtgccat gaaaaacaag tatagggaat tttgagtgta catagctttg gggacttgat 199080
ttgatgaggg agccttatga agttattgca ctagaactga attaaaccac atttctagga 199140
agtggacatc tatttgttgg ttctttaaat ttagctttac agaaatattt cctttaaaaa 199200
ccaaggcttc ttaaattttt aaaactgctt ggctaatcag gggaataatg cttttggata 199260
gctggtatcg ttatttatgg ttggaaaaac aacagtattt gattacattg agctttaaac 199320
ttttcctttg attaatgaaa attttattgg cccatagttt ttattatgct ctgtttttac 199380
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ttggtccaag agattctatt ctctggaccc aatatgaata ccttcagaca tccctctttt 199440
tttttttttt tttcacccag gctggagtgc actggcacga tctaggctca ctgcaacctc 199500
tgcctcctgt gttcaagcaa ttctctgcct cagcctcccg agtagctggg attacaggca 199560
cctgccacca cacctggctt atttttgtat ttttaccaga gatggggttt caccatctcg 199620
gccaggctgg tcttgaactc ctgacctcat gattcaccca ccttggtctc ctaaagtgct 199680
gggattacag gcatgagcca ccacacccag cccagacatc cctcttaatt atgttgaata 199740
tgtaatatcg gtgatttcat ttgaaaatat ttagtagtcg aactagatca aggcagttaa 199800
gcttcctatt tccatagatg cagtggtatt gtgtcttttt tatatgatct ctcatgcttc 199860
tggacatcct tttttctgct attcttcatt ccttagctac acttggtgct tcgtggttgt 199920
aatgcattgt catagatgcg ttcatttctc attcgatctt cagctctatt tctttccaga 199980
gaatctctac aggcatctgt taggttgaag gacatctaat gtcttaatgt gtagcttggt 200040
aaaccagtca actttctatc tgagtcttaa gagaaagtgt ccaagatgag aaacggtaca 200100
ggtttggtga caactcagtg agaaaaagaa gaattttaca aggaaggagg tatcttagta 200160
attttgctaa agaagtaggt aaaccttcac ttataataaa gggatagggc tcggttaggg 200220
tttgtgaagt ctccccttag gaaagcaaac cctgaaatat tttgaatctt ttaaagaagg 200280
aaaataagag tcttttaaat aaatttttaa aatttatttt atatattttt tatagacagg 200340
ctctcactct gtctcccagg ctggaatgca gtggtgcaat catagctcac tgcagccttg 200400
aatgcctggg ctcaagcggt ccttctgtcc cagcctcctg agtagctggg actgcaggca 200460
tgagccaatg tgcccagcaa gagacattca ttttggtact gtgatggtac agaaaaacaa 200520
agggcctttg aggccgaagg agcagaagaa ggatggactt agacatggta taggcacttt 200580
ctactaaaga gctgtgaagc taaaaatgcc aggtctatga caggtgcagt gggccaaggc 200640
caggtagaga gcagcaggaa gagaggaggt ggggacctgt acctaggccc atctgctggg 200700
actgatctag ccataggtac tcagagaagc ccagattggt gcctgaccca cccttatggc 200760
ccagacatgg acacctccca gtctgttcct tcctgctgcc catggatggg ctgtgttagt 200820
ctgtattctg aggacacagc tctctgtcta gaggaagtta tgttatcttg atctgatgga 200880
tactcaacgt gaacattatt tcaacgtgcc acagggtctt ggagcccaga ggaagaccgc 200940
tcttgccttt tagtttatat tctttgtttt tttttaaata acattttgac agtctttatg 201000
gagtaagtct gggccaaaat gataattgac aatgttattt acatggattt ctaagttggc 201060
taaaaaagtt cctttatggt tagtgaatat agcccatgta gtttccccgt cttctttaga 201120
tgccttctat ttctatgccc aaagtctgca gttgattttc agtaagctgg gggtcatctt 201180
agagataaaa tgtagatgaa tggcattttg ctgacagcat acatctttgc tatttctgag 201240
gaaaatgggc tctcgctatt aaatcttttg tcaatattta taaaaatagt atttacatat 201300
tctatctata ttgtggaaac tatacattta ttgattcagt catttgatat caatgttgtt 201360
gagtccctat tccaagtgag gcactatgct ctaagcacat ggcattttaa agatgaataa 201420
gacaccaaga actttgcaga tagtaatgga aatgagaatt aatcaattga agattaatat 201480
agtaagtagc agaagagaaa taaaaaaatc ttctagagag ttcagaacag ggatgttgat 201540
tcaagtttat ggggattagg agtggctggt aagggaggca ttcaggcaaa agacataaaa 201600
atgcagtatt cccctcgcac tcattaggat ggctactata ttagaaaaag aagagagtaa 201660
gtgttggaga ggatatagag caaatagaaa ccttgtgcct tgttcatgag aatgtaaaat 201720
ggtgcagcca ctgtggaaaa cactggtgat tcctcaaaaa atcaaaatag aattatcata 201780
tgatccagta attctacttc tgggtatata tctaaaagaa ttaaaaatct gggtcttgaa 201840
gaaatatttg tatactcata gttatagcaa cattattcat aatagccaaa aagtagaagc 201900
aatccagatg tctatagatg gatgaatggg taaacaaagt ctgtgtagta tatacagaca~201960
atggcatatt agtcacatca tggaccttca ggacattatc ctaagtgaaa tatgctagac 202020
acaaaaagca aaagtagggt ttcacttaat gaggtatcta gaattgccac attcacagag 202080
aacaaaagta gattggtggc tgctagggga taggggaagg agaaaatggg gaattattgt 202140
tgaatgggta tggagtttca gttttgtgaa atgaaaatgt tctgaagact ggttgcacga 202200
tgatgtgagt atatctaaca tgattgaatt gatgaacact taagcgtggt tacgatggta 202260
aattttgtgt tatatatatc ttaccacaat ttaaaaaata tagcatttta ttatgtaggc 202320
gtgggtggga agatacttga cacattggaa cttctggcca tgcgtatact gttcactcac 202380
ttattccttc attcattcaa caaacatgta ttgaatgctt gctatgtgct gggcactgag 202440
ctagatataa caattaataa ggcttataag acattgaatc tatcaatttc atgcttgcta 202500
aatatctact cccacctcca aaggcactaa gcttctacag ttagatattc atagctgctt 202560
cctactgact tgaatcatgc ataggatatt agtaaacaag caataaaaag atttgaggtt 202620
gatgggggtg ggttcaacag catggtggtg aaatggaaag agatgggtaa cagaatatga 202680
actagaattg aaaactgtga gccagtgctc tctaatgaac attaaaaaat aaagaattcc 202740
tatttgaggc tgccaacctc agaactaagt tatttagaat ggacgaaatt ggcaaagtca 202800
gacgtactca acccaaggag ccaatatttt gtgaatatta tggcaaatgt agtttgagaa 202860
ccactaccac aaaattgtga accataataa tgactgagaa ggcagggaga ggttatacaa 202920
tttgggctaa aaggaaagac agggcttgtg aaggggagcg ccagtgaaag tcagtgtggt 202980
tcgggtattt gggtggggac tggaagcagg aagcttgagc ttcctttgcc aagagaccct 203040
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gctggaaggg ctatcatcaa ttgactttag ctcatcttag gattttcatt ttttaaaaaa 203100
tgttcacagg aaccttcact ccatctatac tttcaatgtc tgcctacctt tctttcttat 203160
acaactttga acactctctc cattcattta aatatattat ggagtgccaa ctacatgcca 203220
ggtactgtgc tgggctctta ttccaccttt atttgattgc acatgcctgc caagtcctgg 203280
gccaatataa catctactcc tatgtctggt ctggcgagag atgcaaactc atcttcctct 203340
actttcctta cctccttcct tccagtcttc ttcaagttgt cttcattgag gcaatttctt 203400
ttacctgtgt ttttaatccc aactcctcta gtttccttct tggctttatt cttttatctt 203460
cctctttgtg ctttcaaaca ttccctttct cctggcccat gcccttcagt ctacacgagg 203520
ccttctcaag tctcttcatt ctaaaaaatt cattttcttg ggtcttatat tcttcagctg 203580
ccaccctatc tgtatctttt cctattctcc tccaagttct caaaggaatg ccttccctca 203640
ttttcatctc cttacattcc atctgctgaa ttttggcttg tgcctgtacc tgtctaagga 203700
aactccttgc taagagtctg ctttgtcagg tctgaattca cttaaccagt ctttgctttg,203760
ttggacttct ctgccccatt tgccattctt gatcatcctc tccataaacc tttctactta 203820
aagcatttta cttccttatt ttcttggttt tcctagaatc tccttactgt tcattttcag 203880
cttcctttct gtgttcctct tctcttccta catttttttt tagctttcta ctttcttaaa 203940
gcattttact tccttatttt cttggttttc ctagaatttt cttactgttc attttcagtt 204000
tcctttctgt gttcctctga ttgtctctct ttctacattt tttttttctg tgttcctctg 204060
attttcacgc agtctggagt tgtcatgatc aatcatagcc tactgcagcc tcgacatcct 204120
aggctcaagt gattctccca cctcagcctt acaagtagct aggactacag tcacacatca 204180
ccattctcag ctaatttttt taagaagcat ttttatagag atggagtctt gctatattgt 204240
gcaggctggg ctcaaactac agggcttaaa caattctcct gctttggcct cccaaagtgc 204300
tgggattcca ggcatgaacc accatgctca gtctctacat gttcctaaag aggagttttg 204360
aatattgaag aacagtattt tcaaattaca ttattcaagt tataaaaact gatatccagg 204420
gttatgtggc aatgacgtaa aaatttgaat tgttattttt ttgacacatg ttctgtgttg 204480
tccatcagtt catctgagtt ccaaatgtcc cagctgtttt atgctttgtc tctgtttccc 204540
agagaccctg agtgtggtct agagttggga tgagcattgg tctctaatgg ttctgaaata 204600
attgtatatt cctgcaaaaa cattaagtct attagaaacc agctaatttc attttgtcat 204660
ttttataggt aacatattct ggtgcaggta gtatgttttt aaaacaagtt tgcaataaac 204720
aatttcccct caaggttaat ataataggca acaccttttg ctgcaacaga cggcaagagg 204780
taatgaaaga ttagcttaca ttatgattca ttatttcaaa atgtcaggat aaagtggatc 204840
tgctgcatct cccagagagt gcatgttttg cttttctaat gttaatggat ttactgtttt 204900
tttcccccca ggccaaattc agataatcga cgccagggtg gcagagaaag attggccagt 204960
accaatgaca agggaagtat ggctatggaa tctgccaagg agactcgcta ctgtgcagtg 205020
tgcaatgact atgcttcagg ctaccattat ggagtctggt cctgtgaggg ctgcaaggcc 205080
ttcttcaaga gaagtattca aggtaatagt gtgttgaaaa cgacttctat ttttgatcct 205140
atgagcagat cctaagagcc aaagcgactg aggaaggaag acatagaatc agccatttgt 205200
acaaaacatg aatccctagt aggtccacta gtatctttgg tagaaacatg gagaagagac 205260
aggatctcag gagaaggagt tgacacatgg cagggcagct gaggctgagt aattccgctt 205320
ccttcctttg gcaagactca atcagtcttg agcaactcta cagaagaatt ccactagctg 205380
gatctctgag gaaaaaagaa atgttgtctg tgccctgact ggggaatgcc agatggacat 205440
tcatgtttgg taggcaactt tgcctatatg atctggtata tgctgttaat tgtccatgca 205500
taattatctc tctactcagg ccttgtccag gcaaatattc tgttttgttc tagtttagct 205560
tgttctcccc tttctctctt ccatctcttt cttgtctcaa tggatgacag gatattttgc 205620
tatgagctga ctcagtggtt ggtgtcttgt aatggggaga tatcatcttt atcaaacagt 205680
tattaagtat ctacctgtag catttcattt tcccgcctgc ctccattgtt ttcttgtcta 205740
tagtttgcca attatagcta atatacggag agctatactt tatttctact ccagaaatgt 205800
ctctattatt gcattataat aggataccct ggggaaacac taatcatttt tactacctaa 205860
aatacctatg ctgaatatcc tttatctgat aggaacagag atctgacagc agcttaggct 205920
aaccaaattc attttttatc ttaagtgtgg ggcatttttc tctcttctta ttctttacct 205980
tttcagctta agtgaaggtt agtataaaca ctaagaatat ttctgatgga gttttcatgt 206040
gattccttct acaaaaaccc agatttaagt aacttgttga aaaccagagt ccgctaagtt 206100
aataaacact gattgaagaa gtgattctca tggactttct gtgatagctc tttcctgccc 206160
tgatatgaga tgaaagctgg gggatggtat atagtattta tttttccttc cgttgccagt 206220
gggacttttt tttttttttt aaaagctgtt catatcttaa tcgagtagca tgtgaggtca 206280
acatggtcta ttttaaaagc attttcttcg acacattgct tttaacatct tttagaactc 206340
tgctgtgaga cacatggact tttttgttgg tatttttata caattaatga tattctcaat 206400
agtaatcttt gtgtgtgtat atatatagaa ataaattcta aatgtaagtt aatatattta 206460
ttatttttct aaacatatat aaatatatat atgcacacag gctatttaat tttattagat 206520
gatgctattt taattcagaa aaaaatgaca tttatatttt gatttaggtt agtataagcc 206580
cttagaggtg ttttgacaac tctcttaatt tgtggtttta ctgtttattt gattttatat 206640
aatctaaaat accattgttt ttaccaagca tttaatttgg cagtgaaaga gcgtctgaca 206700
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gaggtatggt tagtagatag gtctaactgc acaactggat ggattgagct gagactgttt 206760
cctcatcagt aaaaatgatt tgaagcagtg gttggcaaag tttttctgta aagggccaga 206820
taataatatt ttaggcttta caagggccat gcagtctctg ttgcagctac cgaactggat 206880
tatagcctgt aaggtgacct gtaaacacat ggaagtgatt atgtgctaat aaaactttat 206940
ttatcagaat aggtaacaga tcagccctgg cccgtggccg atccctgatt taatgtttat 207000
ttatctgatc taaatacctt tatttatgga agggaatagg ggatttttaa atctaaagtt 207060
ttgattattc acattttact gagaacttac tctatacctg attagatgtt ccgagagaaa 207120
taaaaaaaaa gtgtaagaca taatccataa taccacaaaa tttaaaatgt atttaggaaa 207180
tttatttgag gaagtaaatg tacttgttct catgatacaa tcagaaagta agtcagtatt 207240
gataaagtgt tacctgtatg agaaagataa ggaaaacaat agagagatgt aagaaatgaa 207300
aataccagtt ataaattaaa attattaaga ttgaaagtgg aaatgatctt cctccgagaa 207360
acaatggcaa tattctcaca aattttttac atcatttttg ttcagcattt aagataaaat 207420
tatataaatt cccataacat ttagtattgt ctctaagcat taagaacaga aaaaacagaa 207480
ggaaaatata tttctaaaaa tcaacgaata cagtgtgaga tgtttcattg gtatggcatt 207540
atctcaagtt caaacatttt gaaaaatgtc tgcttactct ttgatagtta aaaacaagta 207600
tctcagctgg cgtggtggct caggcctgta accccagcag tttgggaggc tgaggcgagt 207660
ggatcacaag gtcaggagat cgagaccatc ctggccaaca tggtgaaacc ccatctctac 207720
taaaaatatg aa~attagct gagcgtggtg gtgcacacct gtagtcccag ctacttggga 207780
ggctgaggca ggataattgc ttgaacctgg gaggcagagg ttgcagtgag ctgagatcat 207840
gccactgccg tccagcctgg tgacagagtg agactccatc tcaaaaaaca aacaaaacaa 207900
caccaccacc actaacaaaa acctcttatc gccgtcttgt atacgcagac cagctagtag 207960
aattttactg aaacagtagc ctataaaaat gcaattccac ttggtttcag aaacttcttg 208020
tgtatcatag tgtgaagtca cttatcttag gcttttaaaa tgggataaat attgagtcca 208080
aagttctgga agaagcctag aaagaaggca gagttattaa cttttagata tagggaggaa 208140
ccttaaaatt attcagttct tcattcattc acttattcat tgactagctt tactaacaaa 208200
gccctatgca agaccctgga aatgcaatga tagaaaaacc tggtccctac cctcacagaa 208260
cttgtgaggt aaagggggat acagactgat aaaccagcaa ttagatgatg gtgtcaagat 208320
agaggtgaag gcagtgtctt ataggatcca aactccactc agtcctggtg gtggttgagt 208380
ctggctatca gaggtttcct gattaaatct ggagggtgag tcaagggagc atggtgaaga 208440
aggagggaat gcatgtttag ccatgtgaat gagtccatga gtgaagacca ggaggaaagg 208500
cagagcgcgg ggaattctat gcgtaatatt taacaaaatt aatgtactgt taaacaaaga 208560
catttctggg ccatggattt aatcctagac tgtgtaaaaa ccaaptaatt gatttccttt 208620
atactttaaa agcatttcca tgtatttgat ttgtttgtgt gtataaaagg gaaataccac 208680
aacaagttta agggtttcta gttctgcttt ctcatcatag tcttgataac ttggaactaa 208740
aaagtttttg ctgaaattgt ctgtgactct ttataaatca cactgcccct caaacacatt 208800
taaggatggt gaagggtctg acacgtaggt gggaagttct gaagatgccg cagctctccc 208860
tgttttcctt gttacttaag aagagagcta gaaatgagtg tacatcagat tattctcatg 208920
ttctaagtgt tttggttgaa gaggtaaagt gtttggcttg aaagcataca aattttcatc 208980
cactacttag tgtacaaact tgattactta agagattgag taatggcctc cagtgaaacg 209040
cattcttttt aaaaagcaaa gtgaaggatg ctatttaagt cagaaggggc aaaattggat 209100
attttatgag tttattaatc attgcaggca tagaagtagt gttccttaag atgtgtttta 209160
gacagagtcc ctgggatgag ttatataagc agatctggtt gtagcttcag cagccagata 209220
ctacctttga gtattacttc aaggaaaaag gactccactg agctcactgc ttctctttca 209280
ttattatttc agaaggttgt gtggcgtaga gggggctcag gcctacctat acaccactag 209340
ctatgttgcc attttatatt atttctataa ggtgccaaca gaagctgctc atcagatcag 209400
acagacatag cccaggcaag tattgattta cagatgatct ttggccagga agacatggta 209460
tcagggtaga gtctggttat gggtcaatgc agtggggacc ttaggtccta caggtataac 209520
tgagagcctg atccaccagg ccttagaaag cttcagggtg agacagtcca gcaccctgga 209580
tagctccttt aacagctgtg gccggtaagc aggcacttat ttgctaaaga actcaagccc 209640
atttagctgg cttcatctgc tttgtagagc tctgttaaaa agagttccta tttctccaca 209700
tcctctccag cacctgttgt ttcctgactt tttaatgatt gccattctaa ctggtgtgag 209760
atgatatctc atagtggttt tgatttgcat ttctctgatg gccagtgatg atgagcattt 209820
cttcatgtgt tttttggctg cataaatgtc ttcttttgag aagtgtctgt tcatgtcctt 209880
cgcccacttt ttgatggggt tgtttgtttt tttcttgtaa atttgtttga gttcattgta 209940
gattctggat attagccctt tgtcagatga gtaggttgcg aaaattttct cccatgttgt 210000
aggttgcctg ttcactctga tggtagtttc ttttgctgtg cagaagctct ttagtttaat 210060
tagatcccat ttgtcaattt tggcttttgt tgccattgct tttggtgttt tggacatgaa 210120
gtccttgccc acgcctatgt cctgaatggt aattcctagg ttttcttcta gggtttttat 210180
ggttttagtt ggtgggactg taaactagtt caaccattgt ggaagtcagt gtggcgattc 210240
ctcagggatc tagaactaga aataccattt gacccagcta tcccattact gggtatatac 210300
ccaaaggact ataaatcatg ctgctataaa gacacatgca catgtatgtt tattgcggca 210360
5~
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ctattcacaa tagcaaagac ttggaaccaa cccaaatgtc caacaatgat agactggatt 210420
aagaaaatgt ggcacatata caccatggaa tactatgcag ccataaaaaa tgatgagttc 210480
atgtcctttg tagggacatg gatgaaattg gaaaccatca ttctcagtaa actatcgcaa 210540
gaacaaaaaa ccaaacaccg catattctca ctcataggtg ggaattgaac aatgagatca 210600
cttggacaca ggaaggggaa tatcacactc tggggactgt ggtggggtcg ggggaggggg 210660
gagggatagc attgggagat atacctaatg ctagatgacg agttagtggg tgcagcgcac 210720
cagcatggca catgtataca tatgtaacta acctgcacaa tgtgcacatg tacactaaaa 210780
cttagagtat aataaaaaaa aaaaatttaa aaaaaaaaag agatcttagt tcttttgggc 210840
ttggggactc actcttgttc acttaaagtg gattggttct tacatttatt ttcatagttg 210900
tgtctggtca ccttctggct tgatgtatgc ccctatgtct ggaaaaggtt agagaatggg 210960
gtagaagtgg aggctgcccg cccatcatgt aactgtttta tcttttcaga gatacaattg 211020
ggatcctaac tctttggtct ccgtatttcc acacttgctc ttatacgatt cagtttccat 211080
gcaacagcag gagagatatt ttagatatat taatcaggtc ctatggtctt gagtttacag 211140
ctctcagtgt aaatcttact ctcaagagaa aaattttcct tctgcagctg aaaacattcg 211200
acatattctc tctcctattc cttctccccc attcactgta ctccaggcac accagctttt 211260
atttttattt attttttgct attcccccca acacgccaac atgttccttc ctcaggatct 211320
cagcacatgt ggttcccttt ttccctttgc ttgaaatacc cagatcttta cttggctggt 211380
ttcttgtcat tcagattctg cccaaagtca ctttctcaga agtagtgtta cccttccacg 211440
agtaatacta ctcttacttc tctttacagc tctcaaattc ttatgaagtt ttcctattta 211500
ttcatttgtt tgattattgt ctgtctgcat caggtaccgt gcaaacttgg atgtaaactc 211560
agtgatagct gatttctgtt cagcattgtt tgttgctata gctccagtgc ttttagtcat 211620
gttgggcacg tccctactaa atagtagaat atggcgaagg gtcagagtca tgatagatag 211680
ccggatgtgg tggctcatgc ctataatccc agcactttgg taggctgaga tgggcagatc 211740
acgaggtcag gagttcaaga ccagcctgac caacatggtg aaaccctgtc tctactaaaa 211800
atacaaaaat tagccagttg tgatggcatg tgcctgtaat cccagctact caggagactg 211860
aggcaggata attgcttgaa ctcgggaggt ggaggttgca gtgagctgag atcgcgacac 211920
tgcactccag cctgggcgac agagtgagac ttcatctcaa aaaaaaaaaa ataataatga 211980
tagataaaaa ctgctagagg ctctctgaga aggaagaaat gtcactgggt taggttggta 212040
agagaagtgt taatgcaagt ggtacatttg atataagcat gcaaataaat ggtagtttgg 212100
aggaaaattc cagaaatgtg aaacagtatt gagaaattga gtaagccagc tttgagagaa 212160
cacacggctt attgtcctct ccttctgttt tgctcctcag ctctctaaag tgggcattct 212220
ctagggtcct gtcttcaatc tcagcttctt tttcttcttc atccttctct ttccacctag 212280
tttcctaggg aattatatat atatatatat atatatatat aattttgtat atatatacaa 212340
aattatatat atatataatt ttatatatat ataattttat atatatataa aaaattatat 212400
atatataatt ttatatatat atacaaaatt atatatatat gtctggtaca ggctgaattg 212460
tgtctcccag aaagatatgt tgaagtccta atgctcagtg cctcagaatg tgaccttatt 212520
tggaaataat gtcattccag gtgtaattag ttaaggtgaa gttatactgt ggtgtaaccc 212580
acagtatact tccagtatat acttcagtat atgggccctt aatctaatgt gactgatatc 212640
tttagaataa gaagaaaatt tggacacaaa cacagagaag agaatgtcat atgataacag 212700
agagagagag agagaagaga gagagggagg agagagaggg aggagagaga gggaggagag 212760
agagagagag aaggagaaag aaagagagga gacagaagag aaacatctac aaagcaagga 212820
acaccaaaga ttgctggtgc ctaggaaact aatataataa cataatattt ggggcctaaa 212880
gtgttacagc tgcaccaata tctcccaaat cttgctccta gctcctgccc cagcctgatt 212940
ttctcagtga ctcccctgtg tttccctctg ccaccagccc ctccttctgc ctgctgtgtg 213000
tgacagttcc cttgccactc cctccggcat ccgtacttca aactggggag ttagttattt 213060
ccattgtttc ttattgcagc ctctggctct gacgtttcca gagctgttgc atagctctat 213120
tgagtctatc tccttaaatg cattttcatc cacttaccat tgctgagtta gctgcattac 213180
ctttcaccag gatgcttgca ataatttatt gtttccattt gccttctcct tcatctaagc 213240
cgtttgctta tgtctttttt cttgttgcga gacattctgc acattgccac tctattagtg 213300
gtcataaagc aaatcactga tcatgtcaat acgcagtaca agatccttta atgacctcca 213360
tagcccatgg aatggtcctt aaacaagagt tcaaggactg ccacaatctt gttctagcct 213420
atctttctag tcattttaaa gtcaccattt ttacttgtga aataggcact ccagacacag 213480
tgaattcctt gttcttctac aaatatgatg attccatttc tttgctggga atttctttcc 213540
agatttacct gtaaaaattc ttcgaaccct aatcaaaagt gactgttgtt aagcccctga 213600
agataatgca gaaattctct ctctcctggg acctcgatat tagtttattc cattgtattg 213660
catatatttg attgcccatg ttctgtccca tactgactgt aaagtcctta aaggtgaggg 213720
cccaatattc tcagagtcac tcaataaata aataaaagaa taaatggaaa ttaggatcag 213780
tttgtgggct ttagcaacac aaaaacatta tactttttca acatgggaga ggtatgatga 213840
aggagttttt tttttttttt gagacagagt ctcactctgt cactgaggct gcagtgcagt 213900
ggcattgtgt cagctcacaa caacctccgt ctcctgggtt caagcaattc tcctgcctca 213960
gcctcccgag tagctaggat tacaggcgtc caccaccatg cctggctagt ttttatattt 214020
59
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ttagtagaga cggggtttca ccatgttggc caggctggtc ttgaactcct gacctcaggt 214080
gatctacccg ccttggcctc ccaaagtgct gggattacag gcgtgagccg ccgcacccgg 214140
ctgatgaaag agtctttaatJ gcagattaat ctggcagagg tatataggag ggaccagaga 214200
agggaaagaa tcaaagcgtg aagaccaatt tggctgatat tcaactagct tagatgtact 214260
aaaaatctgt actttttggt atttgtgaaa tggaaagaag gggaatagaa taaaggatat 214320
tataatgaaa ggatatacat tgcttgaagg taattaaata tgggttatcc aggagataaa 214380
agagttaaag aggttcagac atagactgaa tgaactgaga aatgaatgac ttggtcacca 214440
agaggaaggc cagtcatcag ggggtaggat aagttcaatt ctagacatgc tgcatttgag 214500
atgatagctg gatgtccaga tggaattatc cagcagccac agaaacagaa tcagctctct 214560
gcggatattc caggggtggg gatttgaatt aatttcctca attaatttta aagaaacttg 214620
atgaaaagaa tggtctgaat acttcttgaa ggttgcacat tattaataat ggagaaataa 214680
ctctaaaacc ttcctcttga ttttcataat aatataagca ttccctgaat cttaccaaac 214740
cttgtaagaa acactcttat tataaaaagt gtatgtgcaa agcccttcta aacaggaaaa 214800
tgataaatta gtcctacagg gccaaatgca gctctctggg agcttacaat tcagaaagaa 214860
catcctgcta ccagcacatt aagctgtaca aatagtaaac tgcagaaaca aatataagca 214920
tttttatgat gtccaaacaa gaaccaagca ggtgtttttt tttttttttt tgcagattat 214980
ttatactgtg gcagttcata gcctcctttt cggacccaga gcttgcataa tccttccctt 215040
atttctactt acgtgtttta ctctccatca tgtgttaaca tacatactgt gcaacagaaa 215100
tgactatgga ggctgagggc agcagagttt tagtgtgtac acatatgagc tgtcatgtaa 215160
ttttcaagtg aaagcctttg caatgaaact ttttaaaaga aagtcatggc cgggtgcggt 215220
ggctcatgcc tataatccag cactttggga ggctgaggca ggcagatcat gaggtcaaga 215280
gattgagacc atcctggcca acatgatgaa accccgtctc tactaaaaat acaaaaatta 215340
gctaggcatg gtggtgtgca cctgtagtcc cagctactca ggaggtggag gcaggagaat 215400
ggcttgaact cgagaggtgg aggttgtagt gagccgagat tgcaccactg cactccagcc 215460
tggcgacaga gtgagactcg tctcaaaaaa aaaaaaaaaa aaaaaaaaaa aaagagaaag 215520
aaagaaagaa ggaaaaagaa agaaagagaa agaaaggcgg gcattaactt caggtattgg 215580
taaatttgct aggtgtttgg ctactgtttc tcatcagaga aatagaaaga cacaccatga 215640
aagtcaaggc ctgaaaacct cattccatgt aagaatgaca tccccagtgt taagtgcttg 215700
ttagtggtta atgcgatcct gtgaaactta gatgtgtttg tgcacacatg cacgcatata 215760
tttgaagaac tcagaagagt taaatcacag cctttcaacc tgtgaaatga cagtagttct 215820
tcttttttcc tctccctttg gctaagtcat ctttatcttg gagataatta agacaaaaat 215880
gcctctgaca aataaaatca gtatagaacc cctatttctt ggcagctttt gtggacacag 215940
ctgaagcttt cagaggtctt gaaaaaccat ggcaacaaat gcctttgaag ggtaagcaaa 216000
ggttccaaat gtttttaatc gctggtgttt tttctgctac cacttcaagc atttttcttc 216060
attttttgtt catctgatca aaattaaatt tccaatttcc ctactaagtg gttctgtcct 216120
ggtcatgcca ttgactattt ccattaaagt agtagagttt gtgcccacat atggttgtta 216180
agctcatcaa caattccatt agaaagcttt gtttatcagt ggcaataatt tcccataaaa 216240
attatagata ggttttaatg ggcacatttt caaaaggcat caactcgtcc tcaaaattat 216300
gtgctgacac tgttcttaca accatggttc gtggcctaat tccaccaaat ttctctcttt 216360
ttcatagaga actgttgtca gtagctttat atccttttaa agagaatggt ctgtatctct 216420
gatactcatt cagagaaatg agtattttag acgtaggttg ctaattttaa gctatatact 216480
acactatgtc agcactatat aggttatctt gtaacctgct tgcctggcta tttggctgaa 216540
aaataacaac atgtaaggaa aatctatttc ataagtctaa catttacttt gtaaaacttg 216600
ttctggctac tctgttaatt ttccacttac gtgtgggtta gagagcagat ttgatttttt 216660
tttaagcgaa agatatggct tacctgagaa aagaacatag tggggaaagc actcctatta 216720
ttttcctcat atttccattt tcctttagcg gaaataaaaa gacatttcag tttttcagtt 216780
gctaagaaat gaaggaacca aagacaaaac aacttaatta ttaaattaca atttatttct 216840
gtaataagca ctcgttctct ctgttttcct ggggaaagag tatgtggact ttcaatttta 216900
tccaaataag catcatcttt ctctgattag tgtggcagtt tcaaaatcat gtattaggaa 216960
gtacagagtg aatgagtaga gaatttctaa attagcaccc aaggttgggt ggctagatta 217020
tgtttataaa tatgaacttt tgtattaagt gcaatgattt aaaagaatgc ctgcatcact 217080
ttagggcatt tcattaagtg ctgtgcacaa tatttttcct tatacatcat aaaagataaa 217140
ttatagttca taaaatagta taaattccta attattttgt gcttttgaca cctcagagtt 217200
actaataagg gatttcgttt taaaatgata tttatttatt tatttagaga cgcagtcttt 217260
ctctgttgcc caggttggag tgcagtggtg cgatcttggc tcattgcaac ctctgcctcc 217320
caggttcaag cgattctcct gcctcagcct ccagagtagc tgggaccaca ggcatgggcc 217380
accacaccca actaattttt gtatttttgg tggagacggg gtttcactgt gttgggcaca 217440
ctagtctcta actcctgacc tcaagtggtc ctcctgcctt ggcctcccaa agtgctggga 217500
ttacaggcgt gagccactgt gcctggctcg ttttaaaata atttaaaagt atattttgcc 217560
accactatta accagttaag ccatgatggt atattataat caccatggag atggtttttc 217620
tctttatttt attttgtttg ttttctgatt gctagcatgc tgattactct tcctattcta 217680
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
caagtgcctg CaggCCagCC CCatttttgC tCtCttC3Ct tCatttttCa tttCtCCCtg 217740
tttcactctt catagcacat ttgtactctg tccacaccta gagacctccc tgttgaagtt 217800
cttcacattc tcttccctag agagggttaa cttgttgagc tcagagactt aaacttaaaa 217860
taaaatgtaa cagatatgta ttgaatgact attttatttt agctctagga gaaatgcaaa 217920
gatatatcat ccatagaccc tgaaatccag ctaagggttc tgcttataca caaggtgaaa 217980
ggttgtgata atgcacatta aacaatagaa gagttaaatt cagcactata agtgatgcct 218040
caaagcagca taatgggaaa aaggggtatt tcagaaaaaa atggtatgag ttcagaggca 218100
agagaaaaca gaatgctcta gattaaactc aaagacttta tggaggaggt ggtgtttcaa 218160
tagatacctt tccacagaac catgaagaga gttctactta attgtaagtg gcctgtgatt 218220
tgtcgttagt cattgcatgc tcaattctgc atgtgtgata actgtgtatt tttatggcaa 218280
aatcgcaatt acttttgcac caacctaata gaatagtgtg ggtttaaaaa aactatttgt 218340
aatatattcg aacatatttc ttatatatat gtttcaccat cattagcagt aaatctattt 218400
tgcatccaga gattgaataa tattttgttt ctaggatgtg agtgatgtac tattttaact 218460'
tacttttgaa gtttgacatg ggagtgatat taataaaatc taaagatgct cctaaagagg 218520
agcaatagat aatgtaggta tagataatgt agctattatg gaggtaagtg tatttgatac 218580
tttttattat gatatgaagg gaaacaacta gtcccaagct acaatttatt aaggtaggct 218640
tagcttatac gccataattt ttatgtttgc aactttcttg attttcttcc tctggcttta 218700
cttctatggg atatttatga aaggatgttt ttaaaaatgg ctagagactt ttgcttctaa 218760
gagttgacat aaacttttcc acaacatgaa caattagtag atgatacact tagatacact 218820
cttgaatttt taaaattgtg gcagtaaaac tgatctcaga gaaggaagaa aatgctttgg 218880
ccagctttta tcaattatat acaacgtgtt tggaagattc agttcctctc gccttctttc 218940
tccctatata atactttttc ttaaggttgg tactattgat gcacttggtg taaacacatg 219000
agataatagc aaaatatgaa tctaggtccc agaaatgggc ttctttcact ctgccacctg 219060
ttctgactgc atttctcctg actttctgta aatcccgggg aggagctgga agagcaaggt 219120
gtgtgctagc ataactttgg ggatgaagta cccttcttt-t tttctgattt tgttcccaca 219180
tctccttact ggaccaagta agggcatcag tgtcaaactt cctgattgaa gatacatttt 219240
tgccctacca tgaagggctc tgggtaacat ttattgctta taaaatgctt ttttggtggc 219300
tactttgttt ctgaatataa ggcaagataa aaagtttgat tcaagagttt cttgtaaaca 219360
ctttgtgtgt gcgtgtgtat tcatatatgg ctgcacacgt acataagtcc atacataagt 219420
acagtccacc ctccatgttt gtgggttcaa catccatgga ttcaaccgac tgcaaatcaa 219480
aactatttgg aaaaaaatgg atggtagtgt ctgtgctgaa cacatacaga gattttcctt 219540
gtcattattc cctaagcaat ataacaactg tttacagaga atgtacattg tattaggtat 219600
tataaataat ctagagatgt tttaagctat atgggatgat gtgcgtaggt tatatgcaaa 219660
tattatgtca ttttatataa gggacttaaa catctataga ttttggtgtc tgaggagtct 219720
tcgaacaaat cccccacaga tcctgagggg ccactgtata tatatatctt cataaacaca 219780
cccacacaca caaacacacc cacccaccca cacacacaca cacaccaatg tgtatatact 219840
tttttttctt ttttttaatt cgagaccaag tctcgctctg tcgcccaagc tggagtgcag 219900
tggcgcaaac ttgcctcatt gcaacctctg cctcccgggt tcaagtgatt ctcctgcttc 219960
agcctcccta gtagctggga ttacaggcgc ctgccaccat gcctggctaa tttttgtagt 220020
tttagtagag gcagggtttc accatgttgg ccatgctagt ctcgaactcc tgacctcaag 220080
tgatttgcct gcctcggtct cccaaagtgc tgggattaca gatgtgagct accacaccca 220140
gttgcaatgg gtatagactt ttgaaatgtg tactacaaaa tattaacagt gactatctct 220200
gaatgatagg attatggata aattttgttc tttttgcata tctgtatttt tatttttcca 220260
cagtaaacat cttttacttc tgtaataaaa acttcattaa aaaatccatg ctgcaattga 220320
ttaattatat actaactttt ttttactctt ccctcagtac agaaagatta ttctgtattt 220380
accaaatctt tacactttat ttgcaaatca ttttgactgt ctgtttgcaa gaggtcaaat 220440
ttgcactcaa gttcagcttt cgttcattat ccatgagccc aagagaaatt gtgtcaggtg 220500
gacatcaggt agctgaggcc aatacaatat tattcctttg ggttgttgag aaatcatagc 220560
agaggaaagc ctgtgttgat aatagagtac caccaggaat ctaggtcttt acagctgctg 220620
gcctgaccag caagggtaaa atatttcagt cacgcagcca gtgattatta accctagctc 220680
tatattccag agaggaagag ctagcctttt tgggttgtga tctgtcactg attgcagttg 220740
cacatatact agccatgagg tctacacaca tgtgaagagc atgctacaca catagactag 220800
atacactgac tcatcagcct ggaaacagtg cctgaccctc actttgattg tttgaatgtg 220860
tcctgaccca ttaccctgcc tttggatccg ttcctgtttt tttttttttt tttaaagcat 220920
tttatctgtg aattaaaata gtactttcca ttgcttcatt tttttttccc tgaggagttt 220980
agctttgttt aattagaaac aagacaacaa tcattactgg tctggtgcaa tcttgtttag 221040
gactcctctt ttgcttagaa ctatacctgg attagggatc actgtgattt agagtgtgca 221100
gtatgaggtt atttaaatac ttaatagtat atttgaaatg aaaagagtag aaattaaaga 221160
ctgaatcatt taccaagaaa taacagagga gaccaattta cttctgtaag atttagtaga 221220
ggctgttccc ttctttataa ttggctttgt ttcagttacc agttaagtgg ggtgaactgt 221280
tattaaaagg ctatgggtaa ggttacagta gcattcttct aagaaaaact acaggagtag 221340
61
CA 02426405 2003-04-17
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tcactgtgca gctatctgct ttgtacctgc caatatggca gtagatatgg aagggtcaga 221400
aaaacaggac ttcatgttca ataacttttc ctttttcctt tctttccctt atttttttca 221460
tgtcttgtat gcaagatagc atgcctattc tttaccttca atgtattttt gaatttttaa 221520
tccagatcat attttatcac aatttgtaac atgtagctaa taaaaatggt tattacatga 221580
gaacttgctt tacaaattat agatcaaatt tttatacaaa ttattatgtc accatagaaa 221640
aatagttacg atttatctgt ttagtcttag aaaaattatt tcacatatta gttaaggctt 221700
ttagttttga gtgagcaaaa tccaattcaa actagctttg ggtagaggtg ggggtaaaag 221760
agaggaatgg atttcaatgg aaggtttact tgcgtgtctt ggctaactgc aaacatggca 221820
gggtgcaacc agaccttagt gatcacagac ccagggactc agaccctgtg aggaccttag 221880
ccttaccgcc actcttctcc atgt.gtcagc ttcgcgttct ctgtctgcaa gtatgcattt 221940
tccctaaggt gggaagcaga gttggcaaca gctgccaggg ttgacttcct gtggcattct 222000
tgcagttagc aaatattaga gaaggactct gcttggccca gctttgggac acacctctgg 222060
accaactagc tgttctcagg aggcagtaac atgtacagag gtgatccctg gggctcgccc 222120
tgtgaaatca ttgtgagcca atcactacct ccctccctga tgctgatgtc tactatgttt 222180
gatgtctctg aacttccatt tcctcaattg tgaatggcac cctggttcct accttgctgg 222240
atagatgtag tgattagagt tcatgcttaa cctacaggtg ctctgtaaag aatcattggc 222300
atcattacct cttgttggct ctatcccatt ccctatagat atctttctgc tctgagacta 222360
agcagagaaa ataatttaac atttaattat tgtgcttcta aatccacttt tacctcttct 222420
ttctttactt ttctctttat tatttttaat tatttcaaaa ataaaattgt atatatttaa 222480
ggtgtacaag atgttttgat atacatatac at aatgaaat gattactgca gtcaagctaa 222540
ttaacatcaa tctcctcacc tagttatcat ttttgggggg catggagtga gagcacctga 222600
aatctctctt agcaaatttc cagtgtataa tacagtattg ttaaacatag tcatcatgtt 222660
gtacattaga tttctagact tgttcatgct acataactgc aactttgtac cctttgacca 222720
atacctctct attttctcca ctattccatg cctgaaattg tgggatatag gtatatagtg 222780
tgtgtgatat atatagaggg agtgatatat gtatatataa ttgtgtgata tatatgtgtg 222840
tatatacaaa cacacagaca tacacacatg tacatatgta tatacatgca cacatacaca 222900
atgggatatt attcagcttt caaaaaggac atcctgccat ttgcaacaac atggatgaac 222960
ctggatgaca ttatgttaag tgaaacaagc tggacacaaa aagaaacatg caccttactt 223020
cttagacaca aatttctttc tcatagccag cacctgaaaa tagggccaag tattttgcat 223080
gatttacaat tgactgtata aatgtagcat agccagttat atgatgtgtt accatttctg 223140
ctataaaatc aaaagaagag atcagaacat ttaaaaactt ccctgtggat ttctacctct 223200
tacctaagct ttgttcttgt ttttttaaac ctcatgaaca cgaagcttta gatagcggag 223260
gtcatgtatc cttgggctca aatatacagt ttcttagcaa tctttgattg ctacattgcc 223320
cttttttgtg tttttaactg gccttccctg acttaaaata tactttaaaa aataacaaag 223380
gtggtattta gtttgcacag tatggaatta aaggtaaaca actttaaatt aaatttggtt 223440
ggatgtataa attattaaaa tatcctttct ctcatggctg ggtaagtctg cattttccat 223500
tcagcctgct atgtctcttt ccatgagaac actcccgaag aatggggccc tgcttccaaa 223560
caagccaagc attttgtagt aaattttaaa aagctaaatt tcataataac ctttataatt 223620
gctacctgaa aatggagttt ggaatggcac caaattatta atcagtagaa ggagaataga 223680
ttgcaaaaag gtaattatat caaattgaat gcttcttgaa atatattctg ttaaataaaa 223740
tacagttcct cttccctgtt ctcatttgta agcaatgagg acaattcagg tagcatgaat 223800
caggaatcag agtacttttc tgttccgcag attggcttaa tcattttggg ctcacttcaa 223860
actgtagatg agcattgtcc tttaacctgc cgggcagcag aggtgaccac gttcactgca 223920
aagcccagaa gtgagttgtt catctgggtt agggtctcag gaagaggcat gttatgactt 223980
ccccacattc ctggacagtt tagactgtaa ttcttggttg tttaaaaagg tgtttgaatg 224040
tattttgttc agaggcttga gtaaatggct cttattctta cacttttttt tttgcctgct 224100
ttttccagca ttagaatagt ttcagccctg acaattagcc ttatgctgac tggagtggat 224160
tttttgcgta ggaccaagtg ttttgcatga tttacaatgg actgcataaa tgtagcctaa 224220
caagttatat gatgtgaaga aaattactta agggtaaaaa tggattgttt actgagaaaa 224280
tgatgttatt ataaactggt ttgagggtat tgtggtttag atgctgtcct tacaaatttg 224340
agctctgttg gtttggagat ttaatatcta ataataatag ttaatgtgta atgaatactt 224400
gccctgctcc aggctctatg ttacgtgtcc tgaatgcatc atctcattta atcctccata 224460
aaatttgaag cagtcagcat tgtaattaat ctcacttttc agatgaggaa accaaggtat 224520
gtaagaaaca aaaccagtgt tgaatctgac tagtacgact gcaaagcctg actcttaacc 224580
attgtgttct gttgccttct ccaagggaaa ggagtgcttc cagaaaggcc attggaagtg 224640
aggagtgtca cctgataata gctggctcct catcccacta ggttaacagg caacagatgg 224700
gggccacaga gttggctgga gttagtcctg gttgccaagg gtaaatgggg ctgttaccat 224760
gcaatggata gaaactagga tgctcctgtg tgtctcctta tatcctacca ggtgtagcat 224820
gaaggttaag gacaattccg tcctcttatt tggagaggag accaaggccc tgtaggacta 224880
aaggtttggg tgagctgaaa gccaagggca attggcccag cttggggagg agagttacaa 224940
atacatttgt gactatcaga ccagaaacag actgcggtgt tcacctgcgg tttgggtacc 225000
62
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tgctgcttgt tctttgctgg ggtatctgaa gactgaaaac acagctcaca cttagccttt 225060
ttcctattct gtgtgaaaga actgtagtag ttttctcttg cttaacaagg ttctagtggt 225120
gaagtttatt gcttagtctg tgagttgtag ggaaataacc acaggatggg atggtagcag 225180
aacgagaaaa gaaaagaaga ttgtagatgc caggctggtg tcggcttgaa atttttaaag 225240
tatacagttc ttctttatgg attattaaaa aaaaacagca aatgaataca caagattaaa 225300
tgttaagcag tacaacattg tacatgatga aaggttaaag tctttctctg gtctcattca 225360
aaaatctaca gtctcttgta gtatagtttg aagtcaggta gcgtggtgcc tccagctttg 225420
ttcttttggc ttaggattga cttggcaatg cgggctcttt tttggttcca tatgaacttt 225480
aaaattctgt gatgaaagtc attggtagct tgatggggat ggcattgaat ctataaatta 225540
ccttgggcag tatggccatt ttcacgatat tgattcttcc tatccatgag cgtggaatgt 225600
tcttccattt gtctgtgtcc tcttttattt cattgagcag tggttttgtg gttctccttg 225660
aagaggtcct tcacatccct tgtaaggtgg attcctaggt attttattct cattgaagca 225720
attgtgaatg ggacttcact catgatttgg ctctctgttt gtctgttatt ggtgtataga 225780
atgcttatga tttttgcaca ttgattttgt atcctgagac tttgctgaag ttgcttatca 225840
gcttaaggag attttgggct gagacgatgg agttttctag atatacaatc atgtcatctg 225900
caaacaggga caatttgact tcctcttttg ctaattgaat actctttatt tctttctcct 225960
gcctaattgc cctgtccaga acttccaaca ctatgttgaa taggatggta ctggtaccaa 226020
aacagagata tagaccaatg gaacagaaca gagccctcag aaataatacc acacatctac 226080
aaccatctga tctttgacaa acgtgacaaa aacaagaaat ggggaaagga ttccctattt 226140
aataaatagt gctgggaaaa ctggctagcc atatgtagaa agctgaaact ggatcacttc 226200
cttacacctt atacaaaaat taattcaaga tggattaaag acttaaatgt tagaactaaa 226260
accataaaaa ccctagaaga aaacctaggc aataccattc aggacatagg catgggcaag 226320
gacttcatgt ctaaaacacc aaaagcaatg gcaacaaaag ccaaaattga caaatgggat 226380
ctaattaaac taaagagctt ctgttctttg ctggggtatc tgaagactga aaacacagca 226440
aaagaaacta ccatcagact gaacaggcaa cctacagaat gggagaaaat ttttgcaatc 226500
tactcatctg acaaagggct aatatccaga atctacaaag aactcaaaca aatttacaag 226560
aaaaaaggaa ccccatcaac aagtgggtga aggatatgaa cagacacttc tcaaaagaag 226620
acatttatgc agccaacaga cacatgaaaa aatgctcatc atcattggcc atcagagaaa 226680
tgcaaatcaa aaccacaatg agataccatc tcacaccagt tagaatggtg atcattagaa 226740
agtcaggaaa cgacaggtgc tggagaggat gtggagaaat aggaacactt ttacactgtt 226800
ggtgggactg taaactggtt caaccattgt ggaagacagt gtggcgattc ctcagggatc 226860
tacaactaga aataccattt gacccagcca tcccattact gggtatatac ccaaaggatt 226920
ataaatcatg ctgctataaa gacacatgca cacgtatgtt tattgcggca ctattcacaa 226980
tagcaaagac ttggaaccaa cctaaatatc caacaacaat aggctagatt aagaaaatgt 227040
ggcacatata caccatggaa tactatgcag ccataaaaaa ggatgagttc atatactttg 227100
tagggacatg gatgaagctg gaaaccatca ttctcagcaa actattgcaa ggacaaaaaa 227160
ccaaacactg catgttctca ctcataggtg ggaattgaac aataagaaca cttggacaca 227220
gggtggggaa cattacacac tggggcctgt tgtggggtgg ggggaggggg gagggatagc 227280
attaggagat ataactaatg taaatgatga gttaatgggt gcagcacacc aacatggcac 227340
atgtatacat atgtaacaaa cctgcacatt gtgcacatgt accctagaac ttaaagtata 227400
ataaaaaata tttaaaaaat ctacagtccc tttctcaata ggtaaacact attaacaatt 227460
tcttctgaaa attacatatg tacacacaca cacaccccac acatagatat tttgttaaca 227520
tacattacct tatgctctac acattattct gtgcctagct tttctcatcg aataatgtgt 227580
attggagatc tttccatata agtacatatt ggtctcactc attcattttt aatggctgta 227640
tattagtcca tagtatggag taataatacc ttttattggc acaaagtttt gcagttgaca 227700
aagggtttgc atatattgtt tcattgggtt gtatagcagt catcaacgga catatcaaga 227760
atcccagaag ggtaacctgg gcttcaccca ggatcgcatg gagcttggga ctcaaacagc 227820
taacattccc taaacaggcc catattcctg caatttagtg cagctgctac aacatttagg 227880
taaactcttt gaaagcagta aaaagatcac caatctggga catcaagaag ccagacgaca 227940
aggagacata gacctcaggt gagtgagaaa agagaataat tgaagtttag aactgaatgg 228000
gcactaacga acaacagata catctctttc ctttcaccga tgaggacctg ggtgtggcct 228060
gtggatgtta agtagcatgt ttaggccaca cagctggatt gttttctttc ctgaggctag 228120
ctctggagag gggaggaaac ggagatgcta gatttttccg ggctctcttt tctcatcagc 228180
tagaatggga tgtggatgga atgcagcttg agaagccaaa cacccttgag aaatgagaac 228240
tctgctttct gatgtggggc gcatcctatc tgagataact ctcctgccag cgcagtatga 228300
ccattgcgac ttgagctgtg tgggtgccca ggtggtgtag accttaaaac cactcctgct 228360
tttgtttact gaatgtctaa tattcacaca gttctttgtc tgagtgcagg gccaaagcag 228420
caaataacga agaagctgtg cccaaccata agaactatga aatgctccag atcatctacg 228480
ctagtttgag ttaaatttac catgcaaata aatatagaac atttcttctt atgcatagat 228540
tgtatttgtt ctattaaaca accatcctgt aaaggtttta ttcattcatt tatttttatt 228600
tgttaggaga aattgttatt taagctaaga aagtagacta gtagttattt cttttttttt 228660
63
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gcttattata ctttacgttt ggggatacat gtgcaggtta gttacgtagg tatacacgtg 228720
ccatggtggt ttgctgcacc catcaacctg tcatctaaat taggtatttc ttctaatgct 228780
atCCCttCCC tagCCCCCCa CCCCCtgaCa ggccccagtg tgtgatgttc ccctccctgt 228840
gtccatgtat tctcattgtt cagctcccac ttatgagcga gaacatgcag tgtttggttt 228900
tctgttcctg tgttagtttg ctgagaatga tggtttccag cttcatccat gtccctataa 228960
aggacatgat tgcatccttt tttatggctg catagtattc catggtgtat atgtgccaca 229020
ttttctttat ccagtctatc attgatgggc atttgggttg gtttcaagtc tttgctattg 229080
tgaatagtgc tgcagtaaac atacgtgtgc gtgtgttttt agaatagaat gatttataat 229140
cctttgggta tatacccagt aatgggatgg ctgggtcaaa tactagaagg ctacagtaac 229200
caaaacagca tggtactggt accaaaacag atatctagac cactggaaca gatcagaggc 229260
ctcagaaata atgctacaca tgtacaaccc tctgatcttt gataaacctg acaaaacaag 229320
caatggggaa aggattccct atttaataaa tggtgttggg aaaactgact agccatatgc 229380
agaaaactga aactggaccc cttccttaca ccttataaga aaattaactc aagatggatt 229440
aaagacttaa atgtaagacc taaaaccata aaaaccctag aagaaaacct aggcaataca 229500
attcaggaca taggcatggg caaagagttc atgactaaaa taccaaaagc aatggcaaca 229560
aaagctataa ttgacaaatg ggatctaatt aaactaaaga acaactgcac agcaaaagaa 229620
actatcatca gagtgaacag gcaacctaca gaatgggaga aaatttttgc aatctatcca 229680
tctaacaaag ggctaatatc cagaatgtag aaggaacttc aacaaattta cacacacaca 229740
cacacacaca cacacacaaa caaccccatc aaaaagtggg tgaaggatat gaacagacag 229800
ttctcaaaag aagacattta cactgccaac aacataaata tgctgccaac aagcatatga 229860
aaaaaagctc atcatcactg gtcaagagaa atgcaaatca aaaccacaat gacatactat 229920
ctcacaccag ttagaatggc aatcattaag aagtcaggaa acaacagatg ctagagagga 229980
tgtggggaaa taggaacgtt tttacactgt tggtgggagt gtaaattagt tcaaccattg 230040
tggaagacag tgtggcgatt cctcaaggac ctacaattag tagttatttc taggtctgac 230100
gggctgtctt ttagtttgtt ttcttattct gaggtggact taaaccaatt ttaaaaacag 230160
ggatgactga attcgtgtgt taatcttgta ctacaggaac cctttgacat tgattcagaa 230220
gcacccaagt gtttgttcat taatcctttt ttatttttgc atattattta tttttcaact 230280
tttattttaa aaatcagggg tacatatgca ggtttgttac aaaggtatat tgagtgatgc 230340
tgaggtctgg catatggatg aatctgtcac tcaggtaatg agcatagtac ccaatgatag 230400
ttttttgtac ccaatgatag 'ttttttgttt tctttgtttt tttttgtttg tttgtttttt 230460
gagatggagt ctcgctctgt cacccaggct agagtgcaat ggcttgatct cggctcaatg 230520
caacctccgc ctcccagatt ccagcaattc tcctgcctca gcctcccaag tagctgggac 230580
tacaggcgta caccaccatg cccggctaat ttttgtattt ttagtagaga tggggtttta 230640
ccatattggc caggctggtt ttgaactcct gacctcaggt gatctgccca cctcggcctc 230700
ccaaagtggt gggattacag gcgtcagcca ctgtgcctgg ccccaataga tagtttttca 230760
gtccttgccc ctgttcctcc ttcccacttc tagttatcac cagtgtctat tgtttctgtc 230820
tttatgttca tgtgtaccaa atatttagct cccacttata agtgagaaca catggtattt 230880
ggttttctgt ttctatgtta gtttgcttag atagacctcc agctgcatcc acgttgctgc 230940
aaatgacacg atttcattct tttttatggc tgtgtagtat tccgtggtgt agatatacca 231000
tatattcttt atctaggata actgatgggc aattgggttg attccatgtc tttgctattt 231060
tgagtagtgt tctgatgacc atatgggtgc atgtgtcttt tcaatagaac aatttatttt 231120
cattactctt atcaggatac ctgggaggaa cttctcctac gaagttaatt tggggggact 231180
cctgaagatg agtgaaaccc cttattaagc acttagaggg tcgaaagtgt acaagggaac 231240
gttcaggtgt gacagcttga gagacatgca tattccaccc ccacaccaga gcttagtgaa 231300
ccgtcttttc tattttctcc caaagcacca aaatggccca gaaattggaa gatggaaaat 231360
ggacttattt atgagtctgg gaaggcaggg cagtaagcac agtcctgttc agggttctga 231420
gttttaccct cttgctctga ttgcgagatc attttcctct tccttgcttc ttcagcttag 231480
gacaagaaca gtttggaaat tgtttctact actttggaca ccatagttta gatttcaaat 231540
gagtacaagt gggaggaaag cttggataat tctctggaaa taatcgaaca gagtgaagga 231600
gaggggtcta caggtgagct gaatgctgca tggcattgaa gtaatcacac cagtcgtcac 231660
aattctctcc tctttgatgg ttatctgttg tcccagaagg aacaatttca gaaagtcctt 231720
ttctggactg tagaatagca cttgcttatt tgatgagccc tgagaagcat tactgaaagc 231780
ggttcattgt ccctgaggta ttacaatgag atggtggtca ctgatttcat tatgttttcc 231840
tttattgcag ctgttggttt gatcctttgc caggtgctta aaacaattgt ggttttgcag 231900
atggtaagtt agaggttgga caaaaaaagg gatcatgtca ctgccctggc caaaatttca 231960
acagactggg gtctagtgag ggcaaataga tagaggcttt. cctcttcact ttgtgttatt 232020
tagaaaaaga aactttccag gacaaatttc tttcctagaa ttcctttttt aaaaattttt 232080
tttctttgaa aatttactta gatgcaaata atatattttt cttcctttta aataataaaa 232140
gtaagatgtc tcttggaggt ggtggttgtc actgacaaga ttaactagaa ctgactagct 232200
gtaaaaatat aatttgggat gcattattaa ggcatgccat ttttatttgc atgccattgt 232260
gtacagatgt ggttgtgaaa tagttcaaat catggcacat tgaatgtcct cactggattt 232320
64
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ttaggaatgt gttcactgag acagccaaat cctatttcat tttctttggc tcattgcatt 232380
ggctgtaaat tggagatatt cactttaata tgtgagtcaa aatttatttc caaacataat 232440
actgcagttg ttctgtcaca gaatataaat ttcttattta tttccttaat acgttgcttt 232500
ctactttttc tttttttctt tattttattc tggagtatgt ggaaaggttt tccagaaaga 232560
tttgcatatg ccataatcta ctgatgaata ctttttttgg gttactcttt catattttgg 232620
gagatataac tatggaagtg ttaggaatca tgggttctgg aaatagtttt attactgctt 232680
ctgaaatgcc ctcccaatga taccatatag taattccatc agggaataat atttttatta 232740
tagtttaaaa tataacttaa tatttaggtg ctcttgttca gtcatcgtca agttcttttt 232800
atttcaccaa ccctaccatg gcactcctga aagacttgtg aatgcgacag acctggattt 232860
aatcatggct ttgccatctg ctagccaaga gaacttgaac aagtgagtca acttcttgga 232920
gtctcatttt ctgcttctgt aacatgggaa ctagggtaat ctaactcatt gcttgtgatg 232980
attagatgag gcaaaatgct gagttcacct agcccagcac ctggtccatg ggaagcatgt 233040
gggttctgct gctacccagt ccttggccca gtgcatggtg cacagaaggg aatctgaaca 233100
ggccaacttt attcctattc ttgacccacc ccatgtagat gcttcctaca tcttcagctt 233160
cttcttcttc ttcttt.tttt ttttaaggca gggtctcact ctgtccccca ggctgaagtg 233220
cagtggcaca accacagctc agggcaacct cgacctccta ggatcaagtg atcctcccac 233280
ctcagcctcc tgagtaactg ggatgacagg accacactac cacacttggc taatttaaaa 233340
acttttgtag agctggggtc ttgctatgtt gcccaggctg gtctcaaact cctggattca 233400
agtgatgccc tcacctcagc ctcccaaagt gcctggaaaa caggcctcca cacccagcct 233460
tcaacttcat tttaaaaaat tgtggt,aaac tatacaattc atccatgaaa gcagaaacca 233520
cttgtacccc aaaagctatt gaaatttaaa aatatatata ttaaaaataa aaataaaatt 233580
gtgataagat atacataata tgaaatttac tactttaatc atttttaagt gtacggttca 233640
gtggcattga gtacattcac atttttgtgc aaccggaact tttcatcctc ccaaagtgaa 233700
gctctgtact tattttttat tttattttat tttttgagat ggagtttcac tctagtcgcc 233760
caggctggag tgcagtggtg caatctcggc tcactgcaac ctctgcttcc tgggttcaag 233820
agattctcct gcctcagcct cccaagtagc tgggattaca ggtgcccacc accacaccca 233880
gctaagtttt tgtattttta gtagagacgg ggttttgcta tgttgggcag gctggtctct 233940
aactcctgat ctcaggtgat ctgcccgcct cagcctccca aaatgctggg attacaggca 234000
tgagccactg tgcccggcca gctctgtgct cattaaacaa tgactccaag ttccccttcc 234060
ccacatctcc tgctgacctc tcttctactt tctgtctctg tgagtttaac tattctaggt 234120
acgtcatgta agtgcatcta tgtgatattt gtccttttgt gtctggctta tttcacttag 234180
cataatgtct tcatgattca ttcatgttgt agcatgtgtc agagtttcct tcctttttaa 234240
ggctgaataa tactccactg tatggataga ccacacttta tttatccatt tgtctgttga 234300
tggacatttg gatgatttcc atcttgtggg tatactgagt aattttgcta tgaacatggg 234360
tataaaaata tctatttgag tttctgcttt caattatttt gggtctacac ctcaaagcgg 234420
aattgttgga agtggaattg ctttccactt gttggaagtg gaacatggtc tcccacttca 234480
ttttgacaca acttccaagc ttcagaactg tatttacaac agcgtgctgg gaggtcgctt 234540
tgagtttatg acggaaatct catatcaaca ggttttaaat tgttccatac gacttcttgc 234600
cacccctgtc ccaattcaga tctttttttt gattaatggt atgaacaatt ttcaaaatat 234660
cctggcacaa tctattagaa tatttgactt tctcctcctc ctccctttag ccctaactat 234720
ttggcaaagc tgttgaaaac ttcttcacat cttctctctg cctcatctac tttgctactc 234780
aaagatg.att agtagatgtt ttggtatgat tttttttcct tggcataact gtgaatactt 234840
ttaatccttc atgttttatg acaatcatac attcccactt ttgtgtaaaa acattttgaa 234900
ttcttctttc tataacaaat tctttgccag tcttcctttt ctttttgctt ttagtgagtt 234960
ccaatgatat cattgtttga acctgttttc taattctatg ctgctattcc catactccct 235020
ctttgctttg gttacagtag ataatgtggg tggtcctacc aagacaaagc atcactcagg 235080
agtcaagggc tggggtagat acagacacta ggtactgcag aaagtcaata tctttctcag 235140
agtgtaaggc aggacaagac ttctgttccc ttgtaccgtt gtggctgggg agttggactg 235200
tgcatttcat ccttgtcata taagtcaaag tattgcccaa ataacttaat tttggtgtgg 235260
tcttagtaag tatttgtctc gtagatatgt taaatagaag acagtaacat tgggttggct 235320
gtgttaattc ctcacttttt ctttcctata catgagcttc ctaagaagcg gaacacttgg 235380
tggtcagaca gttgcagaga ttccttgcat gattgcaatc tggaaagtag ataccattct 235440
tgaatgaaga gcttgccctt tggagaagct gggctttcca tatatggagg ttgttagaat 235500
gcataagagt tcagcttctg gaatgaaagg agaccttggt tcaaaaccca tctgccactt 235560
gcttgctgtg tggcttaaat caggctttta aacttcaatt ataattttgc atctgtataa 235620
taggattaat ataattcctt cctcataaag ttcctagggg gttaaatgaa acaatcaatg 235680
tataacacac ttcctggcat gtgatgttca gtacctagaa gactcggttt ccttggtaga 235740
gagaatattt ggctagacaa gcttatggaa ttacccccag ataggaagtg agcacaagtg 235800
tgaaatgaac aagccagagc aggaacggct cttggaagcg tctactcagg cctgggcagt 235860
tgctggttta tataacagtg ctttgaaaat tcacgtgcag attcttacta ttttcccaaa 235920
tgttacagct caaaactatg ttgtctgtac cttaacacct aaaggataat atagtctttc 235980
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
actgataaaa ctaaaatgtc ataggttttc ctttggccaa atatgtatag aaacttgtga 236040
tttcacatca gatttaaagc tgtatttaac actctatgaa aacatactga tgcttagaag 236100
tagaaaggaa gtcagatttt gacatcttac ttgtcaactt aaattattta tagttcctgg 236160
atgcttcaaa atgtgataaa ccatagttaa ttttatgtaa atattcgatg agtgccttta 236220
ataaggagac tgtaaaggta gccaagcttt atatatgtta gctacattta tgggtcaatc 236280
gggtataaaa aataggactt cgaaaataaa atattatttt gtcggactcc tccaatgagg 236340
ctttttcgca ggattagcta aaattggctc ttatttgatg tgtgagtgct taaacattgg 236400
agaattcatt tttcttttag aattcatttt tatttctgag ccttaaaata tgaacagtta 236460
gctaaatgtt tgtatatgtt gataaggaat gctaagtgtt tattccttaa tgggacgaca 236520
ccttttcccg gtttacataa cttgcctttt aatctaacct tatgaaagtc tccttgactt 236580
taattttttt tcagagtact gtatatctct ttagggaatg catttattta aaaaattata 236640
aagcaagaat agatgtgata tattttgaag ttttctagtc acaaattaaa tccctagatg 236700
tgttgtagtt tgtggagcac tttgaaatgt gccaattcaa gatggaaata gcaggaaaga 236760
accattcaag tacgatttct gactccataa agttaggaag ttatgataaa ggaaaaataa 236820
ctacaccaca tacttatggc acagaattgc attattggga caaattgatc ttcaaatttg 236880
taggctatga tggaagcaaa tatttgtagt atcttaatat tcaactgtta agccaggaga 236940
cgagtactct gaacttcagc ttctcataaa atcagtcagt tacatgacag tttatgtagt 237000
ttatatgtaa gaaacccttt gatcaagata tgccttttct tcagccttgt taatacttca 237060
tttataagga tttttatttc taggaaaata ataccataga cctattttat ttaaagctaa 237120
agtgtttcct ggtgatggtg gtgaatgggg agatgattca aggaaactgc taatcttgta 237180
gagtttagta aaatcttgga atagaaattt taaaaagtta aaacacacta tgaaaacaaa 237240
tcattattag taaaatgaac catattaaaa tgtctccata accaacgtat tatagcaggg 237300
gaaaatggca ttttaattca gaaaaacatt tctatataaa acaagctttg gaataatttg 237360
aatatgttga tttttctttg gggcaatcat gaaatacagt catattagga aagaggcaag 237420
gcctcaaaac ggaaagagta gtgaggataa ttcatgagca atgcgtggct tcatggatcc 237480
cttcctggcc ctcttcatct atgaacatct gctttatgtt catgtctggc ctcacccagt 237540
gctgaagagc agactgcccc tgcttagaac caagccttgt tcttgtggat ttgagttttg 237600
gggtcctgag gtagaatggc catcatattg ttcagggtcc tcaccttccc actcattact 237660
tcctttatag aaccccagtc atccccctca ggaggcctgc gctccacaaa tgaagttggg 237720
ggtgagggga gctttagcat ctcagtattg ttcagatatt ggatacttgt tgagctccac 237780
tatgtgtgtg agaatgcgct gggctcagga tcaatagcca taaatgagac agatatggcc 237840
catcccttgc catgcctaaa ctgatctggg cattgagaca agcagttaaa acccaacata 237900
gtaagtccta tgatgagaca caaactaagc atggctggaa gggcagataa gatttcacag 237960
aggaactgac atcttgactg gcacacttag aagatgagta ggagtcagtt gggccaagag 238020
gagaaaaagt gtgtttccat gaagaagaag agcatgtgcc aagtcctggg ggtgagaagc 238080
atggcatgtg tcaacagaaa gacatgatca gagcttggat gggagttaga gcggggagag 238140
aaggcaagga aaaacataag agctttgcaa actgtgaagg cattgcattt agatgtcatt 238200
tttagagctt ggaggagcct caggacattg aggcaggata gtggcctgat ggcgtatgat 238260
tttaggaaaa atcactgtgg ccaccctgtg gggaaggatt ggcgggggaa ggctggaggc 238320
aaagggtcct gcggtgggct gtggtaatga tctgggctgg agaaggtatg gtggtgccca 238380
gcgcaaaatt ggtttcgctt tgaaaaataa ttagaaaata tttgttttga tctgtgtgcc 238440
tgtggtggga ggtggggagg gagggtcaag tgaggaagga gattgaatct agaataatgc 238500
ccatgtttca ggcttcacgt gcagacattt cttggttcag ctgggaagtg aataggaaca 238560
gactggcgag gaaagaagac agtcgtcagt tctgtctggg gcacatccat cttgacgagt 238620
gtgagagagt caagtcttga tgga.cagggg caggtggaca ttcaggaaac tcaggaaaga 238680
gatttgatct gaagtgacca ccagaaaata ctgacggaaa agaggtgaca aaaggagaga 238740
cctgcaatat tatattggct ttctctcagg caactgcttg gcctgtcttt atattccttt 238800
tgaatctctg catatgtacg ggccattatt tattttcaca actaacaaat gcagactttc 238860
tgtgtaatga caacaaagcc aaaccagctg ctaccaaagg agggaaaatc agaagagaag 238920
gaaaaagaac aagggaagct tggggaaaag ctgaatgtgg gtccttctgt tgctgcaggg 238980
gctggggtgg gcccggtgat tcctactgag aggcgttttc tctccccgct tcctgtcttt 239040
ctggttccat ctcattcacc tcctgtcccc tccacttcct gccagtcaaa ccttagattc 239100
ctccagaggc tttttatttt tatcttttga tgggcaagaa aatagtgcgg attatttttc 239160
caaaccttca cctgaacatc acatcgtggc tttggcccta tgggcttggt tcatccgggc 239220
ctgcacagaa ggacttttcg ggccagtctg gtcacataca tcgagtcctg tcttttcagt 239280
taaaaaaaaa cacacacaca cacactgcta tgtttcacta agacaactgg tgtgagttgt 239340
tttttagaaa atcaactcta cttcagtaag attttctcaa gcattatctt gagaagacca 239400
gataataaaa tttaaaaaga atttcttctt ttttttttat tatactttaa gttttagggt 239460
acatgtgcac attgtgcagg ttagttacat atgtatacat gtgccatgct ggtgagctgc 239520
acccactaac tcgtcatcta gcattaggta tatctcccga tgctatctta atgcaactta 239580
aatcaattgc tttaataaca catattgacc aagttacact cattaaggaa aaaaaactac 239640
66
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tttgttgttt ttcttcttct gacgtgagct gaagacttag aaatagttgt taatagtgtt 239700
tggttaataa gaatttgttt taattgcata tatcaaatat gtatttatta aacttttctt 239760
tttgtcagtt tatcaattct agctttgtca caaaaggttt gccgtatgaa catgattctg 239820
ttgtacatct atttccattt ttgttaagag acgaattcaa ttgtaaaaat ctagtacctt 239880
ttattcatta aacatgttag ttcaggaatt tcacttggtt ctacaaagat acatatctac 239940
agtggatggc cagtgcaaac atgagactca gccaactggt ctctgaccca attcagttct 240000
cctgtcttct tctggcttac aaagtaactg gctctgggga gaaagtgagt caaagtaata 240060
tttggtttga atggttattg actattttct tctgaaactt aatgtatact aattaatttt 240120
ttattttatt cttttttttt tagagatagg gtctcgctct gttgtccatg ctggagtgca 240180
gtggtgctat cacagctcac tgcagccttg acctcctggg ctcaagcgat tctcctgtct 240240
cagcctcccg agtagctagg attacaggca tgtgccatca tgccaggcta atatttaatt 240300
tttttttttt gtagagacaa gatattgtta tgttgcccag gctggtctaa aactcctggt 240360
ctcaaactat cctcccacct cagcttcctg aagtactgga attataggca tgagctgcca 240420
cacctggcca tatactcatt ttttgttaaa agctgaaata tatcagcata tactgcataa 240480
ataccacagg agactaaaca ctgaaagttt ctttagggta tcagaagaat acactttttg 240540
cttgcagtta gcatctgcac agataagttt tgtttctggt tctattactt cttcagtttg 240600
accctattaa taaggacaat tctaaaaata ataactgtgt ctggatatct gaatccgtgt 240660
gtggtctttt actgaagtta caggtttata actctgctga ctagtttgct ggtttctgtt 240720
atgcaataga agagtgcaaa tgttaatttg atctgaagcc cgtgtataca gtgactttta 240780
taatgtatat ttaaagatgg aaagccaagt tttatgaggc cagcatttct tgtcaagtcc 240840
tcactccacc ctcttctaat tgggcctgac ccttaagttg aataaagaac aaagagctct 240900
gtagttaaaa catttcactg catgttgcat cttgccctta gtaaatggaa aaaaatagag 240960
acttaagcag agaatctgaa ctagggtgtg aaatatatat tcagttttgg ggtgggagaa 241020
tgagaaccat gttttacaat agtatacata acttccttag tctaaattca ggacatttcc 241080
ccaagatatg taagaattta gacttatgca gacagacttt ataaaaacat gccaatattt 241140
attagtttgt gaattttaat attctgctcc ctataaacca gatttatttt gagggataaa 241200
gggatggagg tgacttctaa atcttagagc agaaacttcc tgtgggcagc tggacatatg 241260
taccaggagc tcagagaaga gggttgtgtt gggagcgtac attctgagtg atctgcattt 241320
ggtgatgatg gaagccatgg acatgcacta gattgtcttg tgggagaata tggagtagta 241380
agagaagaag aagacctagg attgagccct gagcacctct ggcttaatgt tggatggagg 241440
aaattgaatc tgtaaacaat accgggaggc tgcagcctga gaggcagaag gaactggggt 241500
gtttgggatt atggaagcca agggaaaaag cctgtctcac agcgggaagg gaggtatcaa 241560
cattgtaagc tgcttcagat aggttatgta ggatgtggac tgaaaaatac ctgtaaaatt 241620
tggcaacgcg attcattggt aatcctaggg aagttgcttt tttggggtaa ctaaggtgga 241680
aaacagattg gtgtgggttg agcaatgcaa gagaggtgaa gaaaaggaga tttcatgtgc 241740
agacgtttct gagttcagct gggaacaagg gataagatag aagatggaag ttagagagca 241800
tgtggggcaa gggagactct tttatgggac agtctcgcat gtgatcaaag ccaatgagta 241860
aggagcattt gagggagaga gagtcaatca acaagagaga aaagaaagag ggttcatcat 241920
aaaataacgg taacaacaac gaacatcttt tgagtgtttt ctatatccgg ggaactatgg 241980
taaactccta acctgcattc tcacattcaa ttcttagaat cgttggatgt ggtgggttcc 242040
atgatttcct ctagattagc gaggaggaaa gagagatcta gaaatgtcag gtagcttgct 242100
cagagttctc caggtagtca gtcatggact aatttgtgaa ctgaaggact gaacttcgtc 242160
accacccagc ccaccaagcc ggcttgactt taggtattct gtgctgcatg tgagtaccga 242220
cttaaattat attttaagaa gggctacttt gaaactctct ctctgaaaac tctatttcta 242280
aaagctctac cctcacaaca attttggcaa gcagtcttgg taaaaccaaa ccaaaccaaa 242340
ccaaaaccaa aaaaccttat ctgctgagaa aatataacca cataaaatat ggtgctacaa 242400
aatatagact gtgtgaactg aaggtgactt gcccaaagga ctcctgaagc aattggctgc 242460
tgtagaaatt aagtccacgg gaggtttttt gttctgtttt tttttttttt tttttgagat 242520
ggattctcac tctgttgcct aggctggagt gcagtggcgc aatctcggct cactgcaacc 242580
tccgcctccc gggttcaagc gattctcctg cctcagcttc ctgagtagct gggattacag 242640
gtgtacacca ccatacccag gttttttttg tatttttagt agagacgggg tttcaccatg 242700
ttggtcaggc tggtcttgaa ctcctgacgt cgtgatccac ctgcctcggc ctcccaaagt 242760
tctgggatta caggcatgag ccaccgtgcc cggcccatga gaggttttgt ttgcacttca 242820
agaaggacag aaaaaggcag gcaggctggg gagcaacata gtaaggctga ggaagtgata 242880
ggaaaacagc ctccaaaagg tttccctgta gattctgact ggctaagttt cctgaaataa 242940
tattaattct gtcctcttgc ttttaatagg acataacgac tatatgtgtc cagccaccaa 243000
ccagtgcacc attgataaaa acaggaggaa gagctgccag gcctgccggc tccgtaaatg 243060
ctacgaagtg ggaatgatga aaggtggtag gtacatctct cccaggggcc cttggggatg 243120
gccctggcca ccgcccagtg ctggctctac ccattggaat aacaccatgg gaattttgtg 243180
tttttttctt ttaattgttt tttttctatt cttatttttc tttgcaacaa aagtattttc 243240
ataatccatt ttattttaaa aaggtggaag tgtctggaac tggaaattct aacatggcat 243300
67
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tttgtgtttt ggattttcaa tgtaaataat tatattttaa atcaaaggtg tgtgggaggc 243360
ggtgatggaa ggaaacgaag agtgcttagt aaattattct agaaatattt ttcagttact 243420
gtttatgttg caaatgctag aaaa.tgatat ctgaggataa actttcccta aattgagact 243480
tgtaaatgtg aaagctgagt agctaattta tagccttcca gtctgttatc atcccttaag 243540
gaatgtgaat ttcaatcaaa aggcagtttt ctcctttaga acctgagtga accagccact 243600
ttcttaacct cagtgtctag catggtgctg gcatagttga ttactgagca ctacactaac 243660
aagtgtcaga gcatgcatgg tttgtgactg tgggtttgtg tttttgtggt ctttgtggct 243720
gtgtgtgtgt gtggttttct gtcttctcat gtatccgatc ttccagtttt gtcatacagg 243780
aatctggaaa ctgaatccca gttctgggaa tattaggagc cccataaatg tggttgcctg 243840
attgacctca ttgtattctt gggagtctca tcttgaggaa cattgcttct agtcttggat 243900
agccttcagt gtagtggaag agaacaagta gaaaatgtgt aattaaaata aagtcatgag 243960
gctgaggtgg gcagatcatc tgaggtcagg agttcgagac cagcttggcc aacaaggtga 244020
aaccctgtct ctattgaaaa tacaaaaatt agctgggtat ggtggcgagt gccagtaggc 244080
ccagctactt gggaggtgga ggcaggagaa tcacttgaac ctggcaggtg gagggggcag 244140
tgaactgaga tggcgccact gcactccagc ctgggtgata gagtgagact ctgtctcaat 244200
aaataaataa ataaataaat aaataaataa ataaataaat aaataaagta acggattcat 244260
ttagtgtttc agaaggatac tgaagggagg gaagggctga tgatggtgct acctgctgat 244320
tgtaataggg aaaagcccgt ttcttttctg aaggaggtga agcttggggt gatttaagga 244380
gaacaaaatt tcaatgaaaa ggaatagtga, ttttgcaaat agtgggcagc taacctttaa 244440
atcattctta ctgggacgca ggaggaagga gaggaaagac caagaatgga gattatgatg 244500
aagacaagct tgattgttaa caagcttaca gtgacaggtt tcatagtccc ggggtcataa 244560
atacgccaga caggttgagg tttggaatgc agcatttgga ataaattctc ctggtgaaga 244620
gatgcaatgt tgaatttacg cattctgtga gctgtgacta tgactataca tcttgaacat 244680
ctgaaaaagc agctttaatt caaagggtaa ttaattccaa gaatttaaca gctacattca 244740
gaaaatgaca cttgagtcat atggattaaa tatttaagga attcatcttt ctttgtactg 244800
ttggagaatt agtcaggctt aattaaactt acaaaatgcg tcttaaggta acttggtaag 244860
tgacaggaat ataacagctg cataagaaaa gctttatttg aaacagtgga gtcgaggttt 244920
aatattcttc tttggcgatt atatgtaggt taagcacagg ctcttccata cattctcctt 244980
gaaagctgaa ataatcaagt catgaatatg tccaaaacaa tttttaaaat gtgaggggta 245040
cccatgcatt gaccccattt cataaaaccg attctgtttt tttttttgta attaatatcc 245100
agatacggtc tggctgcatg aatataaatt acgcattctc atttttaatc taacaaaaat 245160
tcatatatgc aaagacataa taaaagtctc cccactgttt tctcctagga atctagataa 245220
tttgactgta cacaacagac tgtggatggc tccatacaca cttgcacatg tatattgatg 245280
actgtaaaat atatatctgt attagttttc tagggctgcc ataatgaaat accacaggct 245340
gggtggctta aacaacggaa attaattttc tcccaattct ggaagctgga catgcataat 245400
caaagtgctg gaatatttgg tttctagtga gccctccctt tttttttttt gagagatgga 245460
gtcttgctct gttggccagg atggagtgca gtggcactat ctcagctcac tgaaaccttc 245520
acctcccagg ttcaggcgat tctcctgctt caacttccca agtagctggg actacaggtg 245580
tgtgccacca tacccagcta atttttgtgt tttttttttt tgtagagacg gagtttcact 245640
ctatgttggc caggctggtc ttgaactctt gacctcaggt gatccgccca cctcggcttc 245700
ctaaagtgct gggattatag gcgtgagcca ccatgcccgg cctgtgaggc ctctcttcta 245760
ggcttgtggc tagccgtctt ctgcctgtgt cctcacatgg cctttcctct gcgtccgagc 245820
actcttggta tctctttctc ttctcacaag ccctgttgga ttaggagtcc acccttatga 245880
cctcatttaa ccttagttac cgccaaaaag gccctatttc caaatatagt cataccaggg 245940
gctagggctt caacatacaa gttttgtggg gacacagttc ataacaggct gccctcccaa 246000
aataccatag actgggtggc ttaagtaacg gaagtcaatt gcctcatagc tctggaggct 246060
gaagtctgag actaaggtgt tggcaggttt gatttttccc gaggcctctc tccttggctt 246120
gaagatggct gccttctctc tgtgtcccca catggccttt tctcggggca tccacagctt 246180
cttcttcttc ttacgaagac accagtcata tcggattagg gccccacaca caggacctca 246240
ttgaatctta atcacctcac ttaaggtaca atttccaaat acagtcacat tctgacjgccc 246300
agggggtaag atttcaacat atgagtttta agggtacaca attcagtatg tggcaatatc 246360
ccataggggt tactcagtga ttgttcagta tttctttaca tgtaaggaaa acatgtatct 246420
ttctggcagt ttttatatgt acataagttt taaatgaagc tttaaattca taaaattata 246480
gcccgtgaga acatcttatt ttaatgatat gtataaagta cttgccataa atcaatataa 246540
tttattgtat tttctacaac atggaatacc acacatggcc acaggatacc ctctataaca 246600
actccttgaa aaatcccatt gaataaagcc ttaatttaca actggaagta caatgataac 246660
taactataaa atgtgcagtc acatggcaaa ggccagctgt gactgaataa atctttacaa 246720
catgttttca accattaggg ttcacaacaa tccactttct taaccaggct ggttaccaac 246780
taggatattg aaactctacc tatgaaataa aaagtttagt ttcagttaaa agagaaccac 246840
agacctactc cctattttca tagcaaggct gaaaaaattc actgaagatc tattgtaaag 246900
atccaaaaga gtgcatgatt tgtctccatg aactaacaat tttaatctgt tataatactt 246960
68
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
actgcctctg aaaatcccag catcattatt agatttggtt ctgaatcatg gtagttctat 247020
aagatgcagg atttgaattg cactttcggg aatgtgcttt tctatcctag tacatgtgct 247080
ggtttctctg cattgctttt tcctcttcat ttgtctcctt cctcttgaac tttaggttgt 247140
agattacatg tctcttcttc aggaaggcct acacagttac ctgacagttc ctgaggctcg 247200
aagttcaaaa tcaaggtgct ggaaaattca tgttctagct ttaatggcaa acagctcttc 247260
tcttagctct tatcaccatt attattagtc attcaatgtc tgtctttaca tatggtccat 247320
aaactccatg atggcgcggg ggtggggggt ctctgtgtct.tgtttaccga tcttgcatga 247380
aacaagtcac aaggtaggtg ttcaagaagt atttttttgc actaattaat gaattgattc 247440
aattcattta aatagttatt tgtgtagggc ttcttatatg caaacccttg ggaataaagc 247500
aaatatgaat aagattgtag tcccttccct caatgtcctc acagtataaa gagaacattt 247560
gcatgggaag cggcaaataa aaatctcaac ggcaagtgga gactgggttg caagatggct 247620
caaatattga atgatcagaa tgggagtcta gagctttaaa caaccactcc caggtttagt 247680
ccaactcaga gtattactca gacacctgac atccaagaca tatattatta ctcaagaatg 247740
tggccttttt gctgagtttg gtagaaagag gaactcttcc aaagataaat gtgttcaaat 247800
gctggctcct cctcaaactt gctgaacaac cttgttaaag tcacttttat gagcttcact 247860
aatttcaaat atgaaatgga gataaataaa ttttattgtc caagcacggt ggcttacgcc 247920
tgtaatccca gcactttggg aggctgaggt gggcggatca cctgaggtca ggagttcaag 247980
accagcctgg ccaacaaggt gaaacctcgt ctctacaaaa ttagccaggt gtgatggcag 248040
aagcctgtaa tcccagctac tcaggaggag gaggcaggag aatcacttga acccagtagg 248100
cacaggttgc agtgagccga gattgcacca ctgcattcca gcctgggcaa cagagtgaga 248160
ctctgtctca aaaataaata tataaataaa caaataaata aattttactt aatgagtttg 248220
tcatgaagat gacaaatcgt aacatgggaa aatataaatc taaagtgcca cacaagtgtt 248280
agctattaca tatctttttt gtcttaaaaa taattactat cttagttaaa aatttcatca 248340
tatacgagca ctgctgggtt ttttttttca gctgaaagaa agagaatggc aatttcatca 248400
cttctacaag atataaattt ctaatttctt tgtggagaat aaaaacttgg cttaaacacc 248460
taagcttttt tttcttttct gatctcatat gctgaatata gctgaatgac aagtgagatg 248520
tgttatttat cattttatga tgccagagat ttacacgaat ttgtgaaagg ttttttctta 248580
ccatagattc agaggcgtgt ttgaggcaag gttttcattg tgcagtgagg aaattggcac 248640
atagaaatca attgatgtgc aggactcttg gactgactat tctggttatg tttccttata 248700
acacattaag aagaaatttg agataaagta gtaattgtca actagtcttt atttatttta 248760
ataacaaatg ttgcagtata atttttagaa atattccaaa ataacaaata aatccaaaaa 248820
ttaacgggat aattttaaag tgagaaaata acatactact aatatagaca gggaaatata 248880
catgtgtcca gaatgattca gaagcccaat gaaacactgg aaaataaaat attttcctgt 248940
tgcttgggtt taatatttat cactatgagt tatcgtaatt tgctttattg atggataaac 249000
tcccaacctg gggactgcga ttggaatcct ctttaatcct acattggcta tcctttatca 249060
aaagtaaaca accggctggc catggtggct cacacctgta atcccagcat tttgggaggc 249120
cgaggcgggt ggatcacctg agatcaggag tttgagacca gcctgaccaa catggtataa 249180
cctcgtctct actaaggata caaaaattag ctgggtgtag ttgtgcccac ctgtaatccc 249240
agctatttgg gagcctgagg caggagaatt gcttgaactc aggagacgga ggttgcagta 249300
ggccaaaatc acaccactgc actccagcct gggtgacgga atgagactcc atctcaaaaa 249360
aaaaaaaaaa agtatacaac caattattaa tgttcatgat ggtagaatca aattaataaa 249420
ttaaaaatgt agatgtgaat tacttttttt ggattgccga ataattgtgg aagatttgta 249480
gctgcatgtg aatccaagtt tcctcaaaag gtaggttggg gtgctcctat ttaggattga 249540
atttaagaaa aatgttaaag aaaagctagc tgctctttac caaagagaga ctggttgttt 249600
taagcagtaa tctaatctat atatttatga tattgaaact attattttat taattcatat 249660
aatagatatt tattaaaaac tccccatatt ataatttttt atttgcaaac aaatatactg 249720
aatcaagtaa gtgaatcaca tatggacctt aaagactaat gaatccaatg tttgacagta 249780
ttttatatca atcaagctct ggtttccaca agcagaagca gatcgtcatc tatgaaacag 249840
ataaaagttg atttggcata ccctctcttt attcattatg atgttcatga gaaaccttct 249900
tagaacccta gggctccaag gaacacagtt tgcaagccac tgatctaatc taactccttc 249960
atcctctagg tatgaaaatc aaggccctcc attacctatt agggatgaag gcaggtcagc 250020
ctctgtgact gtcagttcag ctggaggaag catgagtgta ggcagcacaa caatccctat 250080
aaggaccatg ttcttaagct ggtttttttt ttcctagtag tttttacagt ttcaggtcta 250140
acatttaagt ctttaatcca ggttgagttg atttttgtat acggcatgag ataagtgtcc 250200
aatttcattg ttcggtgtgt agatatccag tttctctaga aacatttatc aaagaaactg 250260
tcctttctcc attgtgtgct tttagcagct ttgtcaaaaa ttaattggct ctaaatgaat 250320
gaatttattt ctgggttctc tattctgttc cattggtcaa tacatgctgt tttaattact 250380
atagctttat agtatatttt gagtcaggta gtgttatgcc tctagctttg ttcttctagc 250440
tccagattgt tttggctatt cagggttttt ttgtggttcc atacaaattt ttggattgtt 250500
tttccacttt tgtaaaaaat gtcattgcaa ttttgatagg cattgcattg aatctgtaga 250560
ttgatttgtg tcatatggat atttttaaca atattaattc ttccagtcta tgtatggtat 250620
69
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atctttccat ttatttgtgt cttcttcagt ttcttttatt gatgtctata gcttttagca 250680
tacaattctt tcacttcctt ggttaaattt attcccaaat attttgtttt atttttatag 250740
ctattataaa tgaaatttct tcttgatttc tttttttgga tagtttgctg ttagtgtata 250800
gaaacactac tgatttctgt atgttgattt tctcttctga aactttactg aatttgttta 250860
ttagttctaa tagttttttg tgtggagtct atacttacat gatctatgtg taagatcatg 250920
tcatcagcaa acacgggcaa tttaacttct tctttttcaa tttgcatgcc tttatttttt 250980
ttcttgcata attgctctgg caggaactct cagtactatg ttgaatagaa gtggtgagag 251040
tgggcatcct tgtcttgtta ttgatcttag gggaagactt ttcaaatttt caccattgag 251100
tatgatgtta gctgtaggct tgtcatatat ggcctttatt gtgttgaggt acactctttc 251160
tatatttaat ttgttgagag tttttgatat gaaaggattt tgaattttgt caaatgcatt 251220
ttttcctcta ttgagatgat tgtatggttt ttgtccttca ttctgttaat gtgtgtacca 251280
tagttataga tttgcatatg ttgaaccatc gttgcatccc tgggcaaatc ccactcgatc 251340
atggtgaatg attctttttc atgtcatgac aatcaatttt gctagtattt tgttgtggat 251400
ttttgcatct atattcatca gggatattgg catgacattt aattttcttg taataccctt 251460
gtctggcttt agtatcacag taatgctggc cttgtaaaat gagtttggaa gtattccctc 251520
ctcttcaatt tttgggaaga gtttgaggat tggtattagt tctttaaata tttggtagag 251580
ttcagcaata aagcccatta ggtcctgggc ttttcttcca tagaggactt tttattgctg 251640
attcagtctt ctttctagct attggtctgg tcagactttc tatttcttca tgattcagac 251700
ttgctaggtt tatgtgtcta agactttatc catttattcc aagttatcca agttgttggt 251760
gtgtaattca tcatagtact cttataattt tttgcatttc tgtgctatca gttgtaatgt 251820
ctcctctttt atttctgatt cagtttattt gtgtcttctc actttttttc ttagtctagt 251880
taaaggttaa tcaattttgt ttatcttttt aaaaacaaat tcgtagtttc actgatcttt 251940
tgttttgtgt ttttagtctc aattttattt atttttcctc cgatctttat tattttcttc 252000
cttctactaa cttggggctt agtttatttt tatttttcta gttatttgtg gtataacatt 252060
agattgtttg agatcttctt ctttgatgaa gacatttatt gctataaact tccctcttga 252120
aaatactctt gctgcatccc acaaattttg gtatgttgtg tgtccatttt catttgtttc 252180
aagatatttt tcaacttttc tttttatttc ttctttgacc cactggttgg ttctgagtat 252240
gttgttttat tttcaagtat ttgtgaattt tccaaaatta ttcttgttga tttatagttt 252300
catattattt atggttggaa aaaatacttg atatggtgtc aatgttctta aatttattaa 252360
gacttatttt gtgtcctaac atatgaacta tactgttttt tttctttttt tttttttgag 252420
acagagtctc actgtgttgc ccaggctgga gtgcactggc tcaatcttgg ttgactgcaa 252480
cctccgcctc ctgggttcaa gctattctca tacctcagcc tcccgagcag ctgggaatac 252540
aggagcacac cgccatgcct ggctaacttt ttgtattttt tagtagagat ggggtttcac 252600
catttgggtc aggctgctct caaactcctg acttcaaatg atctgcccac cttagcctcc 252660
caaagtgctg ggattacagg agtgagccac cgtgccaggc catgatctat actgttttat 252720
ctaacattca gtggataatg ttccatgtgt attt.gagaag aatgtgtgtt ctgttgctgt 252780
tggatgaaat attctgtatg tatctgttaa gtccatctgt gctaaagtat agtttaagtt 252840
tgaactttca ttattgattt tctgtccgaa taatctgtcc attgctaaaa gtggggtact 252900
gagttcccca atattattgt attacagtct atcttccctt tcatatcaat taatatttgt 252960
ttcattcatt taggtactcc aatgttgggt gcatatgtat gttcacctgt tatatcctct 253020
taatgaattg accctcttgt cattatttaa tggccttctt tgtcttattt tatagtttgt 253080
gacttaaagc ctattttatt tgatataaat atagctgtct ctgctttctt ttggcttcta 253140
ttttcataga atgccttttt tggtcccttc gccttcattc tctgtgtttt cttaaccatg 253200
cattgaatct cttctagaca tcatataaca gggtcttgtt tttttaaatc catttactca 253260
ctgtatctct ttcttcctat cttgctgtct tcctttgtga ttaggcgatt ttctatagtg 253320
gtatcctttg aattcttact ttttgccttt tgtatatttg ctacaggatt ttgctttgtg 253380
attaccataa ggcttacata aaagatctta tagttatacc aggctatgtt caactgttta 253440
taacataact ttgattaatt ttttaatact caatttattt gattgcttat ttagagataa 253500
ttttgattcc tatcagaaga aaactgaggt atctttatgt accttttcag gaatgaccac 253560
gtctcacctt accttgaatg ttacaagaaa tgctggcagt gactcaaggc caggcaaaaa 253620
tttcagaaag ggtttatctt gtttgtacaa ttttcttttg caaaaataaa tgattcttga 253680
tatgatgtaa ggactttttc cgtagataga acctataaaa tgcagaactt tggggcagta 253740
attatatgaa tgaattgcta ctttaaaatt ctgtaagtcc ccaggaattt ccatatgctt 253800
ttttttgttt gtttcagtgg ttgtgatcag gctaatgggt agtttttaga gctgaaaaga 253860
acttaaagat catctagtgc acctttttgt ttttcagttg gattgttctt .gtccaaatca 253920
ctaagctaag ttaactgctc agacaggaaa ccaagtctcc tgacccatgg tttaatgctc 253980
ctttcattgt tatgcgtctg cctggctgac ctgttagtaa cataaagtgt catgagagat 254040
agacatatgc atgagtaaga tattaatatc ccataaacca aaactgtgac ttaggaaatg 254100
ttacggtggg cacaggatat tactcctctt caacaaaaac atcaatcata tgttggctta 254160
gttgcacagc agaagtacca aaataaattt atatagacgg tgtcacagat actttaaaaa 254220
gacctactta agatttaatt acctaatatt atttaatatt taatataatt taaaaggggc 254280
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
atttttatct ttcagccaag gttttaattg tttttagata attctatttt tgaaagtctg 254340
attttgtttt aaaatgccca ttctggtata taaaaacatc attttgtcaa ataggagtcc 254400
cagctaaggg ccaagcgtgc aattaaactt gactctttac ctactaccta ggaaccttgg 254460
gcagatcaca tactttttct tcactcagtt tttacttctg aaaaatgcca gctgaagtat 254520
gtttcaaatc ttaaatttta tgttttatga tctaagttca gattaacaat ggaatggtta 254580
gaatccaaag ctaaaggtag tatatacaag tgtatattgg gggttgggag caactgccgc 254640
agctatcata tttacatttc aagctcaatt tagaacaact gcgggcaact gtaaaaaccg 254700
gtaggaatgg gcagagttat tgtcttcact agtcattgtg gaaagtgaat ctcttctgaa 254760
tggagagtca caaaaatgag tttgatgctt tcatgatagt gaaatgagaa gatggccata 254820
tattgctata aatcaccagc aacataaaag aaaaaattca aaaatcaagt ttgttgaggc 254880
aggactctga aaagataact aagctttttt tttttttttt ttctgttaga gatgtaataa 254940
tcatgactaa gactggaatc ccaagagctg gtgagacttt ctagtttctg ccttgtggaa 255000
agagaaagga agaggccaaa aaagataatg aattttggaa agttcctgat taaatatcgc 255060
ataggctagt ctggttatgt ctgcttgaaa acttatccag taggtataaa ccaacacact 255120
tgaggccagt ctttttggaa attacagaaa tatatgtcag ccttaagaga catcctatga 255180
tgaagagcag agggagttgt ttataaagaa atgttctcat tggctgggca tgatggctca 255240
cgcctgtaat cccagcactt tgggaggccg agctgggtgg atcacttgag atcagaagtt 255300
ccagagcagc ctggctaaca tggtgaaacc ccgtctctac taaaaatata aaaaaattag 255360
ccgggcatgg tggcgggcgc ctgtagtcgc agctactcgg gatactgagg caggagaatg 255420
gcgtgaacct gggaggcgga gcttgcagtg agccaagatc gtgccactgc actccagact 255480
gggcgacaga gcaagactct gtctcaaaaa aaaattagcc aggcatggcg gggagcgcct 255540
gtaatcccag ctactcagga ggctgaggca gggaaattgc ttgaacccag gaggtggagg 255600
ttacagtgag ttaagatggc accattgcac tccagcctgg gtaacagagc tagactccat 255660
ctcaaaaaaa gaaaagaaat gttctggtca tgcctggaga taatacatgg tttagtttat 255720
gcttgattca gcaaataaaa attggtgagg aacatacaga attatattta ggtgattata 255780
ttttttatat tttatatata aaatttatat tttttatatt ttaggtgatt atatttttaa 255840
acgcttgctt tacaagacta atcattatta cttttttaag ttttgtgata tattttattt 255900
aactaatata ccccaaatag tatttcaata cagaatcaac atttaaaaat tattgataca 255960
ttatgtatgt ttttttcctt cactaagact tccaaatcct ccaagtgttt cacacttaca 256020
tcttattttg gaccagccag attttagtgc tcatttgacc atgtgatctg tgcttaagga 256080
ggctgctgga gctgaggctg ggctgcagta ccaacataga agtctttatc tgtcaaacca 256140
ggagtttgag atccctgagg gatatgggaa ccataaagga tcttaagcag agaagtgact 256200
ttcttaattt tgaacctatc ctggtgttct catagattag aggagagaga tttaggagtg 256260
agggatcaag caagaaggtg gctccacatt gttttccata gtagttgtac tagtttacat 256320
tcccaccagc agtatagaaa tgttcgcttt tcactacatc cacaccaacg tctattattt 256380
tttgattttt tgaaaatggc cattcttgtg ggagtaaggt ggtattgcat tgtggttttg 256440
agttgcattt ccctgatctt tggtgatgtt gagtattttt tcatatgttt gttggccact 256500
ttgtatcttc ttttgagaac tgtctattca tgtccttagc ccactttttg atgggattgt 256560
ttgttttttt tcttgctaat ttgtttgagt tccttgtaga ttctggatct taatcctttg 256620
ttagatgtat agattatgtc tccttctctg tgggttgttt gtttactctg ctgctgctcc 256680
ttttgtgcaa aagctcttta gtttaactaa gtcccactta tttatctttg tttttgttgc 256740
atttgctttt gggtttttgg tcataaaatc cttgcctaag cccatgtcta gaagggtttt 256800
tctgacgtta acttctagaa ttttatggtt ccaggtctta gatttaagtc cttgatccat 256860
cttgagttga tttttgtgta aagtgagaga tgaagatcca gttgcattct cctacatgtg 25920
gtttggcaat tatcccagta ccatttgttg aatagggtgt cctttcccca ctttatgttt 256980
ttgttggctt tggcaaagag cagttggctg taagtatttg ggtttatttc tcggttctct 257040
actctgttcc tttggtctac atgcctattt ttataccagt accatgctgt ttcggtgact 257100
atggccttat agtatagttt gaaatcaggt aatgtgatgc ctccagattt gttctttttg 257160
cttagtctta ctttggctat gtgggctctt ttttggttcc atattaattt taggattttt 257220
tttctagttc tgtgaagaat gatggtggta ttttgatggg aattgcattg aagttgtaga 257280
ttgcttttgg cagtatgatc attttcacaa tattgattct actcatccat gagcatgaga 257340
tgtgtttcca tttgtttgtg tcatctatga tttatttctt tgagaggtgt tttgtagttt 257400
tctttgtaga ggtccttcac cttcttggtt agtttttgtt ttttttggtt tttttttttt 257460
tttgcaacta ttgtgaaaag gagtgagttc ttgatttgat tctcaccttg gttgctgctg 257520
ttggtgtata gcagagctac tgatttgtgt acattaattt tgtatcctga aactctgctg 257580
aattcattaa tcagttctag gagctttttg ggggagtctt tagggttttc tagttataaa 257640
atcatatcat cagcaaacag cgacagtttg aattcctctt tactaatttg gatgtccttt 257700
atttctttct cttgtctgct ccggctagga cttctggtac tgtgttgaat agtgagagtg 257760
ggcatctttg ttttgttcca gttctcagag gaaatgcttt caacttttcc ccattcagta 257820
ttatgttggc tgtgggttta tcatagatgc cttttattac agtgaggtac cttgtatacc 257880
gattttgctg aaggttttaa tcataaaggg atgctggatt ttgtcaaatg ctttttctgt 257940
71
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atctattgcg attattgcga tggtcatgcg atttttgttt ttaattttgt tcaggtggtg 258000
tgtcacattt attgacttgc atatgttaaa ccatccctgc atccctggta tgaaacccac 258060
ttgatcattg tggattatct ttttgatatg ctgtttgatt tggttagcta gtatttcgtt 258120
aaggatattt ttttgagatg gagttttgct cttgttgccc aggctggagt gtagtggcac 258180
tgcaacttcc actttctggt ttccagcgat tctcctgcct cagctccctg agtcgctagg 258240
attacaggca cctgccacca cacccagcta atttttgtat ttttagtaga gatagggttt 258300
cgctatgttg gccaggcggg tcttgaactc ctgacctcgt gatccacctg ccttggcctc 258360
tcaaaggact ctcaaagtgt tgggattaca ggcgtgagcc acagcgcccg gccagatttt 258420
tgcatctatg ttcattagga atattggcct gtaggtttct ttttttgttt tgttctttct 258480
tggttttggt acaagggtga tactggcttc atcgaatgat ttagggagga ttccctcttt 258540
cttcatcttg tggaatagtg tcaataggat tggtaccaat tcttctttga gtgtctggta 258600
gaattcagct gtgaattcat ctggtcctgg actttttgtg ttgttggtaa tttttaaatt 258660
accatttcaa tcttgctgct tgttattggc ctgttcagga tttctaattc ttcctgactt 258720
aagctaggag gtttgtatct ttccaggaat ttacctatct cttctaggtt ttctagttta 258780
tgtgtgtaaa ggtgttcata gtagccttga atgatctttt gtatttctgt ggggttggtt 258840
gtaatatctc ctgtttgttt ctaattgagc ttatttggac cttctctctt cttttcttgg 258900
ttaatcttgc taatggtcta tcaatttcat ttatcttttc aaataaccag cttctttttg 258960
tttcatttat cttttgtatt tttttttcaa tttcctttag ctctgctctg atcttggtat 259020
tttctttctt ctgctggctt tgggtttcgt ttgtttttat ttctgtagtt ccttgatttg 259080
tgaccttaga ttgtctattt gtgctctttc agagtttttg agtaggcatt taaggctgtg 259140
aactttcctc ttcgcattgc ttttgctgta tcccagaggt ttggatggtt gtgtcactat 259200
tattgttcaa ttcgaagaat tttaaaattt tcatcttgat ttcattgttg acccaatgat 259260
cattcaggag caggttattt cacttccatg tatttgcatg ttttggaagg ttccttttgg 259320
agtcgatttc cagttttatt ccactgtgga ctgagagagt agttgacata gttttaattt 259380
tcttagtttt tttgacactt gtttgtggca tatcatatgg tctatcctag agaaagttgc 259440
atacgctgat gaatagaatg tatattctgt ggttgttggg tagaatgtta tgtaaagatc 259500
tgttaagtcc atttgttcca gggtacaatt taaatccatt gtttctttgt tgactttctg 259560
tcttgatgac ctgtctagta ttgtcagtgg agtattgaag tcccccacta ttattgtatt 259620
gctgtctgtc tcattactta ggtgtagtag taattgttct atacatttgg gagttccagt 259680
gttaggtgca tatatattta ggattatggt attttccttt tggacaaggc cttttatcat 259740
tatataatgc tcttctttgt cttttttaac tgctgttgtt ttaaagtttg ttttgtctga 259800
tataagaata gctactccta cttgcttttg gtgtccattt gcatggaatg tctttttcca 259860
cacccttacc ttaagtttat gtgagtcctt atgtgttagg tgagtttctt gaaggcagca 259920
gatacttggt tggtgattgc ttatccattc tgcaattctg tatcttttaa gtggagcatt 259980
taggctattt aaattcaatg ttagtattga gatgtgaggt actattctgt tcatcatgcc 260040
atttgttgcc tgtatacctt ggattttttt tagtagtatt tttgttttat acctccaatg 260100
agatttacac attaaggagg ttctgttttg atgtgtttcc agcatttgtt tcaagatttg 260160
gagctccttt tagcagttcg tgtagtcatg tagtgctggc ttggtagtgg cgaattctct 260220
tagcgttgtt tttatctgaa aaagactgta tctgtccttc atttaagaag cttagttttg 260280
ctggatacaa aattcttggc tgctaattgt tttctttaaa gaagctgaag atagggcccc 260340
aatcccttct agtttatagg gtttctgctg agaaatctgt taacttgatg ggttttcctt 260400
tataggttac ctggtgcttt tgcctcacag ctcttaagat tatttttctt atcttaactt 260460
tagataacct tatgacaatg tgcctaggca atgatctttt tgtgatgaat ttttcaggtg 260520
ttatttgagc ttcttgtatt tggatgtcta ggtctctaat aaggctaagg aagttttcct 260580
caattatccc cccagatatg ttttccaaac ttttagattt ctcttctttc tcaggaacac 260640
caattattct taggtttggt tgtttaattc tgtcccaaac ttcttggagg ttttgttcat 260700
tttttttttt ttttcttttc tttttttttt ttaattgatc attcttgggt gtttctcgca 260760
gagggggatt tggcaggatc acaggacaat agtggaggga aggtcagcag ataaacaagt 260820
gcacaaaggt ctctggtttt cctaggcaga ggaccctgcg gccttctgca gtttttgtgt 260880
ccctgggtac ttgagattag ggagtggtga tgactcttaa cgagcatgct gccttcaagc 260940
atctgtttaa caaagcacat cttgcaccgc ccttaatcca ttcaaccctg agtggataca 261000
ccacatgttt cagagagcac agggttgggg gtaaggtcac agatcaacag gatcccaagg 261060
cagaagaatt tttcttagta cagaacaaaa tgaaaagtct cccacgtcta cctctttcta 261120
cacagacacg gcaaccatcc gatttctcaa tcttttcccc acctttcccc cctttctatt 261180
ccacaaaact gccattgtca tcatggcccg ttctcaatga gctgttgggc acacctccca 261240
gacggggtgg tggccgggca gagcggctcc tcacttccca gtaggggcgg ccgggcagag 261300
gcgcccctca cctcccggac ggggcggctg gccaggcggg gggctgaacc cccacctccc 261360
tcccggacgg ggcggctggc cgggcagagg ggctcctcac ttcccagtag gggcggctgg 261420
gcagaggcgc ccctcacctc ccggactggg cagctggcca ggcggggggc tgaccccccc 261480
acctccctcc cggacggggc ggctggccgg gcggggggct gaccccccca cctccctccc 261540
ggacggggcg gctggccggg cggggagctg acccccccac ctccctcccg gacggggtgg 261600
72
CA 02426405 2003-04-17
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ctgccgggcg gagacgctcc tcacttccca gacggggtgg ctgccgggct gaggggctcc 261660
tcacttctca gacagggcgg ttgccaggca gagggtctcc tcacttctca gacggggcgg 261720
cccggcagag acgctcctca catcccagac ggggcggcag ggcagaggcg ctccccacat 261780
ctcagacgat gggcggcagg geagagacgc tcctcacttc ctagatggga tggcggccgg 261840
gaagaggcgc tcctcacttc ctagatggga tggcggctgg gcagagacac tcctcacttt 261900
ccagactggg cagccaggca gaggggctcc tcacatccca gacgatggcg gccaggcaga 261960
gacgctcctc acttcccaga cggggtggcc ccgggcagag gctgcaatct cggcactttg 262020
ggaggccaag gcaggctgct gggaggtgga ggttgtagcg agctgagatc acgccactgc 262080
actccagcct gggcaccatt gagcactgag tgcggttttg ttcatttttt aaattctttt 262140
ttctttgtct ttgttggatt gagttaattt gaaaaccttg tctttgagct ctgaagttct 262200
ttcttatgct tgttttattc tattgctgag actttcaaga acattttgca tttctctaag 26226D
tgtgtccttc atttcctgaa gttgtgattg ttttttattt atactaacta tttcactgaa 262320
gatttctccc ctcatttctt gtatcatttt tttgacttcc ttaaattgga cttcaccttt 262380
ctctggtgcc tccttaatta gcttaacaat cgaccttctg aattcttttt caggtgactc 262440
agggatttct tcttggcttg gatccattgc tggtgagcta gtgtgatttt ttgaggggta 262500
ttaaagaacc ttgttttgtc gtattactgg gattgttttt ctggttcctt ctcatttggt 262560
aggctatgtc tgagggaagt actagggctc aaggctgctg ttcagattct tttgtcccac 262620
aggttgtttt cttgatgtag tactctcccc cttttcttag agatgtggct tcctgggaac 262680
cgacctgtag tgactgttat ttctcttctg gatctagcca ttcagcaggg ctaccaggct 262740
ccaggctagt actgggggct gtctgctcag agtcctgtgc tatgggctgt tttcaggtct 262800
cacagcgttg gattccagca cctgctctga tagaggtggc aggggagtga aatggactct 262860
gcaggggtcc ttagcttttg ttgtttaatg cactattttt gtgctggttg gcctcctgcc 262920
aggaggtggc actttcaaga cagcgtcagc tgtggtagta tagggaggat caggcagtgg 262980
ccagggcctt agaactccca agagtatatg acctttgcct tcagctacca ggatggatag 263040
ggaatgacca tcaggtgggg caaggctagg actgtctgag ctcagactct cctcgggtga 263100
gtcttgctga ggctgtgctg tggggcaggg gggtgaggtt cccaggtcaa tggagttatg 263160
ttcccagagg attatggctg cctctgctgc gtcatgcagg ctgtcaggaa tgtgggggaa 263220
agccggcagt tacaggcctc acccagctcc cttgcaaccc ccaaaaccgg tctcactcct 263280
gtgccctacc aacagcatca agtttgtttg caggcagcgg atgagcaagg ctaagaactt 263340
gccgcaggct accagcctcc cagcaaagaa tgtaagtagg gctttcatgc ctcccttcct 263400
gttgaatctg tacaccaaat tcactccctc ccccaagttc tggccaggtg acttcatgtt 263460
tggttggaat tgttacaaag ttcagctgga ggtttccttc tcgctgtggt cttttcccag 263520
ttcctctggc caccctcccc aaggacccct gtgagacaag gtagaaatgg cttattaggg 263580
gacccagaga gcccacaggg cttttcccct tgctttctct accctttatt tcactcagct 263640
gtctaattaa atcagctcca ggtaagttca tatccttctc ccatgatctg gagctgcaga 263700
ttccccagtg agggtgtgtg ttcgggggtg ggctatcccc ctttcctact ttcacagctt 263760
gggcactcac agtatttggg gtgtctcctg ggtcctgtag gagcaaactg cttccttcac 263820
agggtctgtg gattctcttg gctttcctgg tatattcctg tagtagttct ggagcagaag 263880
tttatggtgt gagtttccac acactgctct gttcatccaa gtgagagctg caatctagtc 263940
CtgCCtCCtt tCCdCCattt tttggCCttg acgtattaca tttattttat gtttgaagtt 264000
ttggcagttt tattttgaaa attttacata acaaatgcca agccaaatcc aaacttcttg 264060
gcctaaatca tttacagata acctttactg agcatttact acatgaaggt gttgttgaca 264120
caggggattt aagatgtgat cactgaccac aacatccagg caacctaaaa gtgaaaagag 264180
gtcattcaca aaaaatagga ccaaacttcc tccattcctc aagggaccta ggactggagt 264240
tggcctaaaa attcctgctg tatcacctca cccaccagtt ttgatcttgc tctcagggat 264300
caaggaagct caaggtttct ggcccttttg gctcatgttc ttggaggtat attctattgt 264360
caagttaaag tcgtacccat cctagatctg tttctctctc tttgtggttc cagtctcata 264420
gaaaacataa ctatgtgaaa acaccaacta ccccataaag ctattctgag actcaaagac 264480
atgaactcta ttttgataat cacaaattga tgtatagatg tcagatatca ttcatgtatt 264540
atgtagcatt gtggtttaag tcttagctgt tggaatcaga ctacttgcat tcaaatttta 264600
gctctgttga taggtgtgta accttgaaca agatacgtaa cctcttcaga cctttgtctc 264660
tttgtttgtc aaataacgac aataataata ctaacttagt aagtatgtat aaggaggcat 264720
gtaaagcttc tattgtattt ggcttatggt gagcccttca tataaattgg ttacaatggg 264780
taatgaaaag tacgttcaat ttttcccaca aggatttaat ctaatctcta aataaaatgc 264840
cagttttagt atactgtcat cattataagg aaactataat tcttaagtaa ttaattactt 264900
tggttccctt tggataatta gtgatacata aaatgcagta ccttgccctg aggaacctac 264960
aagttagcct ccctctaatc ctggcattca aagtcctcca ccttccgaat tacacctgtt 265020
ttttcaggca ttgtctccca ctttcctagc aagcctttgg ctccaggaaa ctgttctgtt 265080
cattgacgac agaatgtatt ttgtcccgta tgcctccctt caatctgaag ttcattttta 265140
gtaatttttt ttattagtag tgactttccc catttactaa tgcctttctc tttagctcat 265200
ttagaattcc ctggaagtca tcatgttttc cttctgaatt gctatcatat tctgtctctg 265260
73
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tgtctaatca gaaagttagg tgagctgctg tctcagctcc tgtgttaatc caggtactga 265320
gctctttgta ccctgccagc ttgagggcaa cttggatgcg ctggtgtgta gtgatttgca 265380
actgtgagag agccgtttcc atcaacaagt gacagctttt ggttctaaac actgcttgac 265440
ctcattctgg tttgaacata tactttggcc tctgccctct acctcacctc cagttctgat 265500
cttgggcatg ccacagaacc ccatctacac taggctttca ttttggactt ctaagtcctt 265560
tacttgacca cttattttct ttaattgcta gacttaatca tccatgcata tgacagccac 265620
tcagctctga ccccaatact tcattgaggc tcatgccagt ctgacctctc acagggaaga 265680
gcacccctgc cggtgagccc ctggcccttg gattatgctg tcccaccagt gcccagctgg 265740
ctgcttggca ctgcatgtga tgtatctttg tttattgatc gcttaattga atgggatata 265800
ggattatatt ccatgttcca gatcaagttg agccaagctg acaacttagt attaaaaaaa 265860
tatatttatc tcctatctgt ccaattaaaa ttttaatttc tagaggtaga gacagtcaca 265920
ttgctattta attcctagca cagcagtatt tttgtcaata tttgttatta gtggtgagtt 265980
taaattataa aggaaaaaag agaagtggtg atttatgtca gcgcttggct aaactattcc 266040
cttgatataa gtctattatt caggtcacat aagcatgact gaagtaatat cacaaccata 266100
atatcataat tatctctctt gctgtctctg tcactttctc acttttgttt gtgcatagtg 266160
catagacctg tagaaaattt attagtaatc tgaagcataa aaccaaatat tacaactatc 266220
ataacaaata aataaaactg tgcactcctt tagggagtag taaagccatt tctaaaatta 266280
agtcaaagta agattccctt attattgaga tattttagtg gtatacacta tcataagtaa 266340
gatgaataat tttgttagca gctgacactg ctatatagat atttatcttg ggaagttctc 266400
agtgtaacat ctttactgtg tttttctctt tagattatac ttttatgttt attattttgt 266460
ttcgtggggg attcaaaaat atgcatttta tgccatactt ggggattccc tataaattat 266520
tagttgtaat atgacagttc catcatgaat tttccaggta ttcttttatg caagcagata 266580
atagctcatt ttggttttta acacattcat gcatattctt tctctctcaa taaatatggt 266640
tttaatttat taaatgaaag atttaaaaat gtgctaagca ttttaataat aatcgatttt 266700
ggattaactt gttatgttta ctctagggct gtagttcacc atttattcag ttaagtcctt 266760
ccccaaattc aatattgaac atgtggaatt gattcgtttc acgtggatgt atcatttact 266820
cccaagatgt tggtttttgg catttagtac tggtaatggg ccaggaaagt gctcatctat 266880
atttgttgtt attcactgat tgcatcttgc ccttgcaccc actgagacga tgggaaagta 266940
gcaacaatac taggtgattt ctttgattta aacccaatta aaagaattag agagttgtct 267000
gatacaaggc caaagaacta agaacagaaa caaaagcaaa acaacaaaca gcagcacaaa 267060
ctccagtgag ataaattttt aaaacattgg gaatatttaa aaaataaaaa cactccaatg 267120
aaccacccag gttttattaa agagtagaga actcaaacag cagaaggcag agctggtgga 267180
ggaaactcag caactgctca gaaatgaaac aacctaggaa ggaggtgcga gtgacctgaa 267240
actcctttta aaaacagaaa ggacaaaaag aggtatgggc tgacaaaagg aaagtggtag 267300
attactgatg tattgcatta tgcttagaat gtctcagaat gcgagaggca gtaaacacac 267360
cagaagagga tacaatatcc ggaccatgtg caactgcaaa taaatgtttg ggttaaaact 267420
tggttgattc taaattacat gaagagctga tgataattga ggcagaactg atagacctaa 267480
caatagaaaa aaatcgattt aaattcagag aagaggtcat ttaagaaagt ataatgaagc 267540
cacttaataa aaggaaatat tcctctaact aaagtttgag atttagggca taatcctcaa 267600
agacaggcta atataatcta ttttttgatt aaaaaaagga acttttggtt taaagtaaga 267660
tgttcagctg ctcttagagt ttatttctcc atatttgggc atataagaat ttaaggaaaa 267720
atatagaaat ataagaaaga tttcatgaga atcacaagca tagtttatag gcaagatagc 267780
cttttctgtt tgaaagcgaa aaatactatt tcaacatgta aaaacctaag tcagttttca 267840
ctggcatgtc ccacaatcat gcctgaaata atggttgaag acagatgtga gacatttcaa 267900
gggcaataga ttaatacatg aaacccactt atgcctagcg ttccattatt ggaacgctaa 267960
gcatgtggga gttatttata tcctattgct caaggtcatc tccaaggtct gagttttcac 268020
tcatgcaaaa attcaaaaaa ttgcaacctc ggcgtaaatg ggttaacaaa aagttaatgc 268080
tggacagtaa aataaactac taaattagac acaccatatt ttttaaatta taagagatta 268140
agaactatga gatatttaaa aagccaccca cagaagtagt aggacaggta gagaaggata 268200
aattctaaca atcaactgta tctccacccc accttgtaaa tgacaaatta gtttacttag 268260
tcaattcagg aaattaaacg tatacatttt gtgttaaaac agaagacttt ttttaaaaaa 268320
agtgtgttag ttaaggttaa ttttgaccta gttaagaaaa agcagtttag agtcttgaaa 268380
tggaaatgag aaatacataa ttacccttaa aaataagttg atagtgaatt ttatctagga 268440
ttcttaagac atttttaata tttaatgaaa atgaactaca caattattaa aaaatagttg 268500
cctgggttta gaaaaatgat cccttaataa gacatataca acagcctgaa tttttatttc 268560
caaatactat agcaacaaaa taccggcaag aaaaatgcac agaaacattg gatagtctct 268620
tcttactaat cttttacaga tatttatata ttctgaattc taacttttaa tttattttat 268680
gtattataaa tgtcatctag tatgcagctt gactttgctt tatggtatca tctgtttcac 268740
agaaaatttt aagttgtgga atttatcgta ttttttcttt atagtttgtg ctttaagacc 268800
tgtctaataa atctttcctt ccctggacgc tataaagtta tttgtctata ttctgttaaa 268860
aggaataaaa ctttgctttt tttcacattt tgttacttat ttcacctgaa agagaatttt 268920
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gtttattatg tgaggtagga atataactta atttttttcc attgaataac caaattgtcc 268980
cagagcaatt aagcaataca ttctttccct gttgatctgt gaagctacct ccattaggca 269040
tgaagttgtc ctgttgaaga gaatctgatt ctgagctctc ttcactattt ctttatttgt 269100
ctatgtctac actaaaagca atttaatttc tgtgtcttta taattacttt gactttataa 269160
tccttgaaag ggactttgtt cttcttcaaa attgttttgg ctatttatgg ctacttttgc 269220
tttcaaatga gtttttaaat caaactttaa tgagattgca ttaaacttat aaattaatct 269280
gaggaggatt gacatcttca tgatatttag tcttcctacc cattaacatt atataactct 269340
ccatttattt taggtctttt tgaatgactt ctaataaagt ttttcaattt tctccaaaat 269400
atcttacata ttaaaattta ctcatagctg tctcatctta ctgatatttt aaagacatat 269460
ctttttaaaa attatattat taaattgttt caggtatgtc tttttttttg aagttttaca 269520
aatttgggat tatactgcct cttcattcaa cattttccca tgctgttggg gatccttcaa 269580
gtcaaaatta ttagaggagc tgcattaata ttccagcatg gacatactat aatttattta 269640
attatttccc gaattgtatg tttttgtttc taacttcaca gttttcaaca tgactgggaa 269700
cagcttttct tgctaaatcc ttgcacgcca cagtaattat ctcactgggc caaaagatag 269760
gtactttttc atgactttcg ccatatattg tcaaaatgga accaatggtg atttgttcag 269820
aaatcatggt acatcatata aaaagattac tctgcaagca tcacaaactg tgatatatag 269880
aaatgtgttt attgacatga aatagatcat gaagaaagtg attacaaatg gtatttaagc 269940
attttaagtt atataggctt atactgagca ataacaaaga gggtgaataa atgaatgaat 270000
atgtgattct ggaagggtat gtaacaaaag gttaacaatg gttagccctg ggtaagggga 270060
ttatgtatga cttttatttc cttctttttt tcttcctttc cccttatgtt tttaacaatg 270120
tacatgaatc gtttatgaat aaaataaaaa actttgatat tcttatatag gtttagtagg 270180
ataacatttc tccttcattt ctttcatttt tagaaatctt tcttcacgga aattcttttt 270240
tttaaatgtt tatttctgtc tttgaggagt gagattgact ggctatcttt taatacctgt 270300
gtgtattatc attattgtat cttgctgata aatttcacaa cagttaatta ttttattccc 270360
catttcatac ttagctctat tttaggcaag ttcacaaata tcattgaatg agttcattca 270420
atgtcatcat gatgatattg aaatgtcaat agcagatgac ttgtttctgg ggtgttaata 270480
tgcctgttgg ttacatttgt gttttttggt gatggaaggc agccactgag gcaaacagca 2'70540
agaatacagc taagcctcta actgcatact cttctcactc gttgcttaaa actgaagcgt 270600
ggataattgg tgtgcattcc ctaaaaagtt atgtcatgat gcagtagaga aataagttaa 270660
ctttcctatc cctgtatcaa agtttctttt gaaggtaact gagacagcgc caaataagga 270720
gcagagtttc tgtgaatcat gaaatctttc taaacaattg agaaaaaaaa aactgttctg 270780
aaacaaaaac ttgtgcccta tccttttatt tgaatgtgtt ttcttaaggc cacaactggc 270840
agagatttga tgattttatg tttaaagcaa tttttttttt ttttcatagc aaggagtccc 270900
actgccatca ggttttgttt ttggagagat tctgtaactg acatagggta acttactctg 270960
atggcttgct ccacattcac tacaagtaca tactgttctg aaaaatctca aagttgaaat 271020
atttttattt gggcaacttc tgcaatcaag gtaattcact ctatctttgg agaataaaat 271080
ggaaaagggc aacccaatct ctgtgacctt aaacttccac tgaaacttag agacggttag 271140
cttagctggt gagagcgtgc tgctaataac accaaggtcg tggtttctat cccattacag 271200
ggcagtcaag ctcaagggaa aaaccctgtt ctttggcaca gcttccatgg cctgctagcc 271260
gtttacagcg aggcaaaaga gtagagatgt tttagtgaac taggccatga cttggggagt 271320
ctccaccttg aatctggttg tgggaccaag gaagagaatc tgctgaggct gggtagagag 271380
actctagagc accttaggcc acaggacagc agaggatgag aataacagaa ctggcttcag 271440
aaagtaggtg tcagtccaag gcactgtatt caatacatgt agcaaagaat gagcttctga 271500
caccaggaaa gtcttcagat ggcagtgact gcataaaccg gtgtcaggat gtctgactat 271560
aaaggatggg acaccttcca tcaggtgaga gctctggagg tggagtctgt tcctggaaga 271620
agcatgggta aatgtcatca aaggttccct cagccaccac tgggttcagg gctgaggtgc 271680
acctaggaag gcttgggcag aagcatgacc cctggaactt ggccaactga gccatcagag 271740
agtggtgcag gtgaggagtg gtagatgtgt agtgaaccac tcagctgtct gcccaggcct 271800
tgggtgtgga agtagagtct tctgtgtctt tgggcagact gaattataag cttcaccaga 271860
tcgccaagct aggaatgttg acatacctgg cttggggtca gggagggact gaactgtagg 271920
tggggggccc caacaaatct aatcataaga atctatgagc gtggagacag aaggaccaaa 271980
gaagggatgc tgtaaccaat tatcattatt gaaaaactag gcagagatta cattcaattg 272040
gcagtaccac cctttttatc tctgacatag ttccagaagg atatactatg tatctagtgt 272100
gacactgtct gatagaattg tctgaaatga tggaagtgtt ctgtggctac ccattttgat 272160
agccactagc cacaggtggc tattgagcac ttgatatgtt gttggtgtga ctgaggaact 272220
aaatttttaa ttcaatttaa attaaattta atttaaattt aagtagcaac atgtggctgg 272280
tggttactgg attgaaccga acagatctag atactagagt aagtggtagc agcaaatcct 272340
atattggaac aatgtaaatt aacaattata aatatatgag caggacaaag cccaaatggg 272400
cctgtactct tagttttgct atatattcaa ccataactag cactcatttt ttaaacttat 272460
aaaatgcaaa ctcatttggt tgtgatgatg aatgctcagg taattgttga gtttcaacac 272520
agtgacagcc aggaactcat tttggagact tggattgtgc cacagtttgt ccctctataa 272580
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
aatgatgatg aaaattttat cagtatctgt ctcaagctgt agttaatggg ccaatttcta 272640
aatattcctg tcaaattgta tagccattgt tttcaaagta gttttgaaag taggccattg 272700
gtaaagcaat ctattaaagt gcaggaagaa agtaatagaa tctcttactt tttaaagtct 272760
cattatgaaa attatatttc agtttgtatg ccttcgatgt acataatata ttaatacaca 272820
aatatattaa tgcagcggtc cccaaacttt ttctcaccag ggactggttt cctggacgac 272880
agtatttcca tggattgcag cggggatggt ttcaggatga aactgaccca cctcagatca 272940
tcaggcatta ttaggttctc ataaggagca cacagccttg agcaggtgca gttcacatat 273000
agggtttgcg cacctatgag aatctaatgc tgccgctgat ctgacaggaa atggggctca 273060
ggcagtaatg ctcgctcact gctcacctcc tgctgtgtgg cccagttcct aacaggccat 273120
gaactggtac cagtctgtgg cctgggggct ggggagtcct gcattaatgt aattaaatat 273180
gtacatttct tgagagtgtt tgttcaaata ttttttccta atagagacgt ataacttaga 273240
aagtatggaa ccctctggtc agtagcatat tttatcaaaa aggctatccg tcgtgctaac 273300
caatgtgatt aaatgttcat tttagtctca gatattttga taacataata atagggaagt 273360
tatggttatt gcatggcttt tctttactgt attttcaata actatattaa tgggttcagt 273420
tgttactagt tttataattc tgttttattc tcaatgagtc ttcctgtttc tccccacgtc 273480
tttcctatgg ttcatttccc tgcatcttta cagctccctg gaacattctc tcaaatcaat 273540
cagaggcttc aaaactgggc agtctcattt tgtaacctgc tctgactcgc ctctgggagg 273600
cctccctccc cactcacagc tgccttcctg catgatgtaa aatgaataca gtgccagaaa 273660
gactgatcct tggaacctct tccttactta gtttctttat agttctgatt ttagaaatga 273720
ccattttact tccagtgccc ttccccacac cagttagctg agactctatg caggaagttc 273780
ccagtgatca gaactgttcc catagctccc aggtgattct gacatgcacc cggcattgag 273840
caccatggac atggctgctg tttgttatcc tcgagctctg caaagcagtg tcggatattg 273900
cttgattgtt gcacattaat ctactgcacg gtccggtagg tagccactag ccacatgtgg 273960
ccatttagat gtaaatgaat ttaaattaaa tagtattata agttcaacac ctcagttgca 274020
ctctctgtat tcaagtgctc agtagctaca agtggttggt ggctaccatt ttgggcagtg 274080
ctactataca acatttctat caccacagag agtgctgatg aataatagta ctaacaactg 274140
gaaacattga aatggagagg tgaaggagag aaggcagaat ataagagaaa cttcaaagca 274200
ttcagcgtgt ctgataggcg ctgtatctta cattatgttt ggagcatagt ttttgaattt~274260
cttaattttc aaattcggtt gaaacagatt ttggtcaatt gaagtgaagg actatgcctg 274320
ctttaatttg cgtagcttac ctttgtttca cgtgtctccc ttattacagt gtttgtagca 274380
gcatctaact caatccctaa cttctttttg gtgcagggac catttaaaaa caatttgatc 274440
atagaggtta tctcctttgc aatccatatt gttttatgga acaggtgaac agctggtgac 274500
aatagcctca aggtttctaa tcccaccaaa ggaaaatatg gtgtcagtaa ttaccttgta 274560
ctatgatatt tgtgaaatcc aagagagggc tagatctcag gctctaataa tacatccgta 274620
taaacatctc agtagggcac cacggaagag tcttaggata tcaggaacaa taagagcggg 274680
agaatatcga ccttaatatt ctttacactt attaaaaagt gaaaagacag ccataaagca 274740
gaatgagttc ctgtcctttg cagggacatg gatgaagcca gaagccatca ttctcagcaa 274800
actaacacag gaacagaaaa ccaaacacct catgttcgca ctcataagtg ggagttgaac 274860
aatgagaaca catggacaca gggagtggag catcacacaa cggggcctgt cgggagttgg 274920
gggactaggg gagggagagc attaggacaa atacctaatg catgtggggc ttaaaaccta 274980
gatgacgggt tgataggtgt agcaaaccac catggcacat gtatacctat gtaacaaacc 275040
tgcacgttct gcacatatat cccagaacta aaagtaaaat aaatgaaaaa gaaataaaaa 275100
ataataaaat aaaataaaat aaatgaaaag tagccatttt accagttgag tatttactga 275160
cttttggtga aaatcacttt ctaagattac tagaaacctt atgaccctcg gcctctactc 275220
ccaccacgtg cggattttca cctccaccta ctttgtcacg tcacatgccc ttctgctctt 275280
taggacactt gtattgggtt cctcccccac acgtaaacag aacacacagg tctgtgaatg 275340
gacctcatta tgctcatttg tctttgccaa gaactattga aaatgatcac aaatgactat 275400
gtaattataa ttaagatttt gtacatgcat acactttatt tttaacaagt ttgtcctgtt 275460
aaatgtcacc ccattttgaa tagtaacatt cactggtgca aggaagaatt attaaaatga 275520
caatttaact gatatccttg acaggtaagc cagttattgt atttcataat tgtgattatt 275580
acaataccta tgaagattaa ttaggacaat ttattctata ggacttggtt atcaaaatga 275640
tcttttttcc cattttagtc catacatctt cagttttaat ttccttcttc caaagaactc 275700
tgagtcttgc ccagtgtgat acttcagatt ttgtaaaaat ataatgaaga agaataacat 275760
gtatcagatc ttttttttaa tgtactgggc taaaaattat aagcaccatc aaattactag 275820
aaaattcttt taacactctg cttcttagtt aaaaaatgat tcctttttgt gataatctta 275880
taattttcaa agtatcattt tagaaatttt aaaaaattat tcttgttttc attcagtcca 275940
tttcatcaga acttagattt tttcttccct ctacagtatg tggtcttgat gtgctttctc 276000
cttgcaaaat aaaatcttta gtttcaggat ctctgtgttc tattccttca atttaaaatc 276060
ataggaaaaa taactatcat ttccttatgt ctgtctccaa ttcccccatc attttctgtg 276120
agccaatttt cttctttttc ttctgtctac tgtaaggaac tttttactct gctctattct 276180
ctgcaattca gggctcacaa tttctttgac ttctcagatt atcctttgta cttgtgtcta 276240
76
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ctttttcatt aaaaaaaaaa aggcttcggt cttattttga ctttatcatc tttatattgc 276300
catatttaaa acccatctgc ttattgattg aaccaaactt ttcatcttac ttcatcatac 276360
tgaatgtata acttctgaat gacttaaaaa tcatcacata atgtgagaga attttctatc 276420
atattcaggt gactgcattg taagcaatga agttgaagaa aaatagctta taatggatat 276480
aataccaaga aataataaga atgagaatct gcgtatatca tatactgggt taacaagctc 276540
acaaggcaaa tcaccatttt attagatatt taacaaatca tactagtact ggaggaagta 276600
tagcagaaaa aaggagtatg gacattggga ttagctgcct tgctaatctt ttgtcagtcc 276660
ctagtgacat gcttttgggt tgagtcattg ttacctccct gagctgtttg tttataaaat 276720
gggggtaaat atctcagatg tttcagtgtt gtgacatata aagcgtcctc catagtacat 276780
aataccgtaa gcactccata aggtaattct tgtcctttta aaaagtatac acttttgagt 276840
tcaggacacg tacactgtaa cctagttgta accattttaa taaaagaagg ttttgatcat 276900
ttttgataaa tgtactacat gaatagttaa cttgcctttc acttcctata ccaacggaaa 276960
ttttggtaac aaatttaaag aaagcattag gttgaatatc ccatctgatt aaatgtcaac 277020
taaatattgt ttctggcttt taaaatattt ctaattcagt tataaaacag gtctattact 27.7080
caggaggctg aggcaggaaa attgcttgaa ccagggagtc ggaggttgca gtgagccgag 277140
atcatgccat tgcactccag cctggcgaca gagtgagatt ccgtctcaaa aaaaaaaaag 277200
gtgaaatgaa aaacaaaaaa gaggggtgaa atttctctgc attctccctt tctgctgttg 277260
ggaaagccct ttcattacca agaatgcatg gaattctgct tattaatttc tccatctatg 277320
tgtctctgtg aaaaatacta attatttaca attttgtaag ctatgaataa ggtctatgtt 2773'80
ttctctgaaa ttatagcaac aggagcattt cccccttatt tgggccgcaa tcttttcatt 277440
ctgattctta ccataacttc tgacttctga ctttatcatg tcttctgatt tctactaaac 277500
atgaacagaa tgaatgactt ctagaaatgg atacaggtgt aatacatata aggccaggga 277560
accacttaat tatctttaca aagtactagg acttcagaaa aatcaaatga tgaaatggag 277620
ctagctttag tatgttctac ttatcattgg actattaatc atgtctgtct gatgagttac 277680
ctaggacttc aactgttttt atagatttaa agaaaatatt ataaatgtat cttacctgga 277740
tttaagactg gacagctgat tttggatttt tttctgctac cctgttgttg atatcactga 277800
catcagcctt tgcattttga ctggaggctc ctttctctct ttctctctct ctctctctct 277860
ctctatagga aaccagtagt tatgtcaggt tgctaagtat tttcccactg aaggacaaat 277920
attctggagc agtatatatt tagcatttga catttgataa acaagcttgt ttgagatatt 277980
ttcaatacaa tttcagcttt ggcaattgta agcaaaggat ccagttggta attggtgaaa 278040
tgaacagatg tggacacgct gcctgcatcg agatgcatta atttttctga aaagtggata 278100
agatcttgtg agaatgaata atggaattca aatcagatgg ggtgagatat ttgatattca 278160
ggaacaaatc acagtataat agatctgcta ctttgtttgg ttttaatggg gagttgctaa 278220
tgctgaaata tagtcagaga aaaggaacgt ggaatttcta tagaggagag cctggctctg 278280
gggtaatact actgtccttg gtggaatgtt gtcttttctg aagacattgg ttcaattcaa 278340
tacatgaaac attcatcgat tattatttag aaaagctaat ctactgacaa gacacagagt 278400
taagtagtga aaatacagag acctagacac agttcttatt aagaaatttt ttaatttagg 278460
tggcatattt cagagagaaa ttctctgctt ggggcaatag gtacctcctt tggaataagc 278520
atggtgagaa agaattgctt ctggcagatt agtgagaaga gtgagatatt ttctttcgat 278580
gacctctcta ttaaaatttg agtggtaaaa ctttgtgatg attcaggctc ttcataattc 278640
ttaattttat catcctctaa taccaggact tgcccagatc aatattttag gaaacagtca 278700
tgcttgctaa acccagggat ttctattaac cactagataa gacataagtt tgtcatgcaa 278760
caagtattta ttgagtccat aatttgccca gcactgggct ttggtactct gggccttgat 278820
actctaggtt gtgtcagaga tgtctaatat atttaaggtg acagagttca caaatgagac 278880
tttatgaaaa tgaatatccc tttttaagtc tcgagaaata tgatgtgcac ccgcttgagg 278940
ctttattaaa tctccagcga gcatgaactt gtttgtgacc caattgtaga attgttgtat 279000
gatgactatc ccactggcag gcacttcttg tccaagagaa tgtaattgga tgttggtgac 279060
tcaagcaatc ctgggaagac tcctccatga ccaaattaaa gacaacaggg gcttggtttg 279120
tactcagctc tacaccaatc agcatgagac aaagaagaga tccatggcaa agtggggaga 279180
ctactgttta ttttacaagc tagagaagga aaactgcagt tcctgagttg caaaactgct 279240
aagaaatggg agaacacaga actttacagg ctgaaccttg gtgtcttagt tattcctctt 279300
ggctacagaa tgccaaccag taggagattc atcactgaga tattacaggg aaatgaagcc 279360
aggcaagaaa aatatgtatt ccctttcttc tcagcccata aattttgtta ttaataaatc 279420
agactcttat agaacagctt gccacggctg tctctagaaa tgtttttatt agcagaattt 279480
ttattaaaat aaaatacaca gtagttttaa gagtgaacat tatagtttta ggtcataagg 279540
ggtgtcatgg agaacacatg tggatgctac ttgccagtta cttgatctag gccttgactc 279600
ttggttttct gttgctcgga taagttagca tgatttgaca tgcagttaaa ggtgtggtaa 279660
cctgtgattg atttcccatt cttgatgctc cctgcctgga cttctcggaa aatttcaaaa 279720
caattcattc ttctatgagg gctgcctcct tggttgcttc ggctaaacag tgttgagcaa 279780
caagttggga aaggaacgtt gcagtaactt ttaaaaatta agttagaaac aaatgtcatc 279840
aaagtaaatg ataatttgcc aatatgattg agcaaaaaga tgaagatgca cgctccctac 279900
77
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gtatttgctt tgcagaagaa ttaatttgaa aaataataac atattttaaa atgaattgta 279960
aatataaaca catgctaatt gcagagggga atccctgtga ttattcagca gtttgtgttt 280020
gtcaagtgct tttcagtcag tccattccag ctcagcaggg cagaggcttg ggctgttgta 280080
aacttgtggg cagataccca gtgatggggc agacatgagc aggtagggct gacagcatgt 280140
gaattgagtt ttcttcagtc atgctgttgc agctgctccc ttccctcatt gctgagtttg 280200
ccacagcagg taggaaccta actctggagc ctgggatgaa ggagaaccca cattgggctt 280260
gaggaacaag atctgccacc ctggtaggcc ctggttaaat ctcatgcaag tgtagcaatg 280320
agagagggta tgattgagtt ctaatttagg aggaaagggg ataatgtgcc ctttgcaccc 280380
ccaggagaaa tcattgctca tctgtgccta agtagactta tcaagggcag ttggttcaca 280440
atggtgtatc accccaaagg actatagtgt tatgagaact tgccagtgta tttgaatttg 280500
ggtgctggca gatgacatca tgaggtatta tggttaccca taaatatgct agtttattga 280560
gaaggtggta gacatgctag tggatgagag ggaaggacag aagcagttag taaacagcat 280620
ctgcaacaat tcagttaact ggtggttgtc acagtagcat ggtggaaaag ttggcaatta 280680
ataacttcta agaaaactga actaatgaac caatcctgcg tgtgctatgt gtataacctc 280740
cttctcacta ttaacagatt tgttccaaac ttatataaga caatgaaaat aaagcttggc 280800
aatataggga agggatggag ggataaagct gtaaatcacg tcacaggcaa attaagatat 280860
accactggat caagggattt aatgcagaaa gactgatcct aacttatttc ttttatttag 280920
caataagatt tgttacttac attgattatt taaaatgagt tgcattatta gaaaggacta 280980
ttttgaagac aactataata aaatgtcagt aactgatagt agccaagata ttttaaatat 281040
atcaaagttg tgtcattaat attaatgtgt cccttaatat gaagtcctgc ccaggcttat 281100
ttatgtattc aacagacaca tacctgttga agtgtaacag atattctgga cacaagcaat 281160
ggtaaacaag acagatgcag tccctgcttt catgcaattt gcaattgaat ggtctttgac 281220
attttattgt gattgtttta gttatttaat tggagaagtt tttaatttaa atttgtgtta 281280
tattcagtgt taaggaacaa aaatgtaatg tgcatttctg agactcagta acacttctgg 281340
tttttccttt ttcatttaaa gaaaaattta gtgcccaaga taagctagaa tttttggaat 281400
caagtaattg atgacctggg agccaatttt attacaatag tgtttttagt ggtcttagaa 281460
cttttcagag gtggtagctc tgaaaataac actgtaataa attcacacat acatctatca 281520
tccaataaat gttaattgag gcccactaca gcattgtgtt agattctgag gttacaaatt 281580
gttgacccca tgtcgaacat gttgacccca tcaatgtaat cagtttgaca ttacacagtc 281640
atttaaacat taaagtgtca gcggatattt tagttgtaat tttgataagt gctctgaagg 281700
agaaaacagt gggtgttgtg aaaagcagta tttggttgat tgattattat agaggatctg 281760
agaaaactta cttgaggaag gaacatttgg ctgaactcaa agagatgagt aggagttaag 281820
taagcaagga agaaaagaag acacatgaag gaggaagaat gttctagaaa cacacacaca 281880
caggtatatg tatatgtaca tgtatatgta tatgcatatg tcttccttag aaacatataa 281940
acagctgcaa catgattgaa cttatttacc caattaccaa agcttatttt gcaccatgaa 282000
ggtggagata aaggcttttt aagcagcaag gatagaatct ttgtagtttt tatttatagg 282060
ctggttcttc tgacaacttt aatttttcat ctttaccaac ttcatggtct tcagtacata 282120
caatgcaatc attattataa aattatattt tgactcaaac tctaaggtag gatgattcag 282180
ctgtgcgcca tcaacatagc agcatgaatg gtagagacta gtcattccaa acagtgaagg 282240
ggcaacgtaa aactaatttt aatattatat gaaagtactt cttgcccttg actgcttttt 282300
tttttttttg aagaaagcaa actttaaaaa tttattttag atttacagaa ttattgcaag 282360
gatagtaaga gagttctcat atatgcctca cccagtttcc tctattatcg acatcttaca 282420
ttatatggta catctatcat aactaatgaa ccaatattgt ttcattatta gtaactaaat 282480
ctatacttta ttcagatttt ctaagttttc ctctaatgtt ctttttctgt cccaggaccc 282540
catcaggata tggtatgtat agttgtcatg tcttcccagg ctcgccatgg ttgtgacagt 282600
ttctgagact ttcattgttt ttgatacccc aggtagttta ggcattttgt agaatgcctc 282660
ccagtctgaa tttgtctgat gttttcctca tggtttgact ggctttaatg tgttttgggg 282720
aggaagacca cagaggttaa gtgtgattgt catcacatcg tatcaagggt acatgccatc 282780
aatatgactt atcactgttg atattaacct tgatcatctg gcttgagata gtatttgtca 282840
ggtttctgta ttatacagtt actcttctcc ctgtccatac agtacttttt ggaagaagcc 282900
attttgtgca gctcattttt tttttaattt taattttaag ttctggggta catgtgcagc 282960
atgtgcatgt ttgttacata gttaaacgtg tgccatggtg gtttgctgca cccgtcagct 283020
catcacctag gcattaaagc caacatgcat tagttgtttt tcctaatgct ctccctcccc 283080
caaccccaat ctgacaggtc ccagtgtgtg ttgttcccct ccctgtgtcc atgtgttctc 283140
attgttcagc tcccacttct aagtgagaac atgtggtgtt tgggtctctg ttcctgcatt 283200
agtttgctga ggataatggc ttccagctcc atccatgtct ctgcaaagga tttgatatcc 283260
ttccttttta tggctgcata gtattccatg gggtttatgt accacatttt ctttatccag 283320
tctatcactg ataggcattt ggtttgattc catgccttta ctattgtgaa tagtgctgca 283380
gtgaacatat gcatacatgt atctttgtaa tagagtgatt tatatttcac tgggtatata 283440
cccagtaatg ggattgccag gttgaatggt atttctagtt ctagatcttt gaggaattgc 283500
tacaccatct tcctcaatgg ttgaactaat taatttacat tccgaccaac agtgtaaaag 283560
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tgttcctatt tctttgcaac ctcgccagca tctgttgttt cttggctttt taatgatcac 283620
cattctgact ggtgtgagat ggtatctcat tgtggttttg atttgcattt ctctaatgat 283680
cagtgatgtt g,agctttttt catatgttct ttggcctcat gaatgtcttc ttttgaaaag 283740
tgtctgttca tgtcctcttc caacttttta atagggttgt ttgtcttttc ttgcaaattt 283800
gtctaagttc cttgtagatt ctggatatta aacctttgtc agatgtatag attgcaaaaa 283860
atttccccca gtctgtaggt tgcctgtttt ctctgatgat tgtttctttt gctgtacaga 283920
agatctttag tttaattaga tcccatttgt caattttggc ttttttttgc aattgctttt 283980
ggcagttttg tcatgaaatc tttgcctgtg cctatatatt tattgcatag attttcttct 284040
aggggacttc aaactatgct acaaaacttc aataaccaaa acagcatggt actggtacaa 284100
atacagacac atagaccaat ggaacagaat agagaactca gaaataagac cacacatcta 284160
caacgatttg accttcgaga aacatgacca aaacaagcaa tggggaaagg attgcctatt 284220
taataaatgg tgctgggaga actggctagc cacatacaga aaattgaaac tggacccctt 284280
ccttacacct tatacaaaaa ttaattcaag atggattaaa gacttaagtg gagctcatat 284340
ttaaggagtg agaagatatg ctctacctct ttaagggtgg agtagctcta taaattattt 284400
ggaagtgtct attctcctcc attaatttat ttagtcaaca attagtatca gccatctaga 284460
acccatgaat atttatgctt tgggtacagt ccaatactat tttattttgt agctcatctt 284520
gttccagctt tggccatttg gagatttttc agttggctcc tgtatctctt tggcttctta 284580
catatcattg tagggttttt taaaagcctt ttcttacttt ctgtcactac aagatagttc 284640
agacttatct tctgtatttt ttgccccagt tctatgatca gccacttctc caaggagcaa 284700
taatttcctt caatgaaaac caagatatgg gctgttggtg tacttgttgt tattgtgtgt 284760
tgttacttct agatcctcta agctgatagt gcaaagagat atatgtgtgt gtaccaacct 284820
atatatctac acacatataa aaatatttct atttgtaacc atctgtatct atcttaggct 284880
aaacctgagt acctactgat gtctccaatt ctaacctgca acagcatgga acattctagc 284940
cttctcctct tacttatctg tcacttccta taccaatagt gagaaacctg gctcctacca 285000
tctgctattt atttacttaa ttatttaatt ccactatact tctatggaag tttcagaatt 285060
gttaatctgt actcatgtac gaaacaactt tatcaactag agtatagtgt ttatatacag 285120
ttcctttgcc tttattctaa cagattccac ttactcattt tccgagtcac ttaggttagc 285180
gccttatttt cctaagtcca ttagtgagtt tgcttcatgt atttgtcata catttaaatt 285240
cttttgtaat attgtgcatt ccatcccagt ttcccctgac atcctaaatt aactttttaa 285300
gtttggatac attgtggtct attctttgtt ctgtaaagct ttatggattt tgacaagtat 285360
ttaatgtatt gtatcaccat tatagtaata tagttcctat ggaatagaat agtttctatc 285420
gctgtagcat agaatagttt ctctactcta taaaatatcc tgtgtttctc taattcaacc 285480
cctccttccc accttgaact cctgacaacc cctggtctgt ttaatatctt tcttttgtct 285540
cttctagaat atcatataat tgaaatcata caatatgtag ctttttcaga ctggctactt 285600
tcacttagca atattcatgt aagtttcatc tatatatttt catggtctga tagctcattt 285660
ctttttaatc actgaataat acttttattt atccactcac tggtgaagaa tctcttgatt 285720
gcttctaaat tcatggcaat tatgaatgaa actgctctaa acatttttgt gcaggttttt 285780
gtgtgcatgt gtattttcaa attagttggg taaatatcta ggaattcaat'ttctgcatca 285840
ttgtggtaat aatgtgttta gcttcataag aaattgccaa cctatcttcc aaaatagctg 285900
taccattttg cattcccacc agcaatgaat gagagttctt gatgctcgac atccttgtca 285960
gcatttgatt tttgtcagtg ttttggattt taactattgt aatagatgtg tagtagtgtt 286020
tgattgtttt aatttgcaat ttctttttct tttttgagat ggagtctcgc tctgtcgccc 286080
aggctggagt gcagtggcac gatcttcgct cattgcaacc tctgcctcct gggttcaagc 286140
aattctctgc ctcaagctcc caagtacctg ggattacagg cgcctgccac catacccggc 286200
taattgttgt atttttagta gagatggggt ttcaccatat tggccaggct ggtcttgaac 286260
tcctgacctt gtgatccacc cgccctggcc tcccaaagtg ctgggattac agacataagc 286320
cacggcgtcc ggcctgcaat ttcttaatga caaaaaatat tgaggatatt ttcacatact 286380
ttttttgcca actgtatttt ttttaattaa tttttatttt tattttattt tgtaactttt 286440
attttagatt tggggtacat atgtacattt gttaatacag gcaaatttgt gtcacagggg 286500
tttggtgtac agatcatctc gtcacccagg tactaagcat agttcttgat agttcttttt 286560
cctgatcctc tccccactcc cactctgttc cctcacgtag gccccagtgt ctcttgttcc 286620
cctctttatg cccattggtt ctcattattt atctctcact taaaagtgag aacatgcagt 286680
atttggtttt ccactcctgc attagtttgc taaggataat gtcctccagc tccatccttg 286740
ttcctgtaca ggacatgctc tcgtgttttt tttctttctt tttattttaa tggctgaata 286800
gtattccacg gtgtctatgt actacattgt ttttttttaa accctgcata ccattgatgg 286860
gcatttaggt tgattccatg tttttgctat tgtgaatggt gttgcaatga acctacatgt 286920
gcatgtgtct ttatggtaga acaatttata ttccactggg catataccca ggaatgggat 286980
tgctgggttg aatggtaatt ctccttttag gtctttgagg gatttccaca ctgctttcca 287040
caatgggtga actaatttac actcccacca gcagtgtata agtcttccct tttctccata 287100
acctccccag catctggttt tttttgtttg tttgtttgtt tttttagtat ttaataatag 287160
ccattctgac tggtgtgaga tgatatctca tcatggcttt aatttacatt tctctaatga 287220
79
CA 02426405 2003-04-17
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ttagtgatat gtagcatttt ttcatttgtt gccaactgta tgtatttttc aatgaggtgt 287280
acatcagatc ttttgcccat tttaaaagtg gggttttggg ctgggcgcag tggctcacgc 287340
ctgtaatccc agcactttgg gaagctgagg caggcagatc acctgaggtc aggagttcga 287400
gaccattctg gccaacatgg tgaaaccctg tctctactaa aaatacaaaa attagtcgga 287460
catggtgtcg ggcacttgta atcccagcta cttgggaggc tgaggcagga gaatcactgg 287520
aacccaggag gtggaggttg cagtcagctg agactgaacc attgcactcc agtctgggca 287580
acaagaatga aactccatct caaaatacat acatacatac atacgtacat acataaaatt 287640
gggtttttgt tttctttttg ttgagtttga ggagtttttt tgtatatttt gattacaagt 287700
cttttatcag ccatgtgttt cacaaataat ttctcccagt ttgtggctta tcttttcact 287760
ctcttaattg tttttttcaa agtagaaatt taaattttaa tgaagcccaa tttattaatt 287820
tttttcttcc atattgtgct attggtgttg tatataaaaa cttactacca aattcaatat 287880
catatagaat tttttctgtt ttcttcaaga agtagtttta taattttgca ttatatgttt 287940
agatcaatga ttcaccttaa gttttgttta aggtgtaagg tttgtgtata agtttttctt 288000
tttccacatc aatgtccagt tgcttcagca acattttctt tttatatata tcttaagggt 288060
aatcagcgca atattttctg aaaagatgac ctttttctca tttaattggc tcttctttgt 288120
caaagatcag ttgaccttat ttgtgtggat ctatttctgg acttcttact ctgtttcact 288180
agtccatctg tttatacttt aaccagtacc atactgcctt tattactgta gcctttatgg 288240
taagtcttga aatgaaatag tgcaagtgct ccaccttctt cagaattttg ttcttcttca 288300
gtattaaagg ctattctagg tcttttgccc ttctttaaac atgttggaat caattgtcaa 288360
tatctacaaa atagattatt gggatttgga tttagattac tctgaatctg ttaattaagt 288420
tgggaagaat tgacatttta tcaatattga ataatatgaa catgtaataa tattgaactt 288480
tcaatctcta ttatctcttc atcattttaa gatcttcttt catttttcat tgttttatag 288540
atttttacat ataggccttg tacatacttt gttaatttat atcttagtat tgaatgtact 288600
attataaatg gtattttcta aactttgaat tcctgttatt catgatgata tgtaggaaag 288660
aaattgactt ttgtatattg acattagatc ctttaaccgt ggcatcatta cttattagtt 288720
ccaggggaga ttttgttgtt gttgttgatt cattggaatt ttctgcatag ataatcatgc 288780
catctgtgaa taaagatgtt ttatttcttc cttcccaatc tatatatctt ttatttcttt 288840
ttttgcctta ttgcacttgc tggtatttct agcataatgt ataataggag gaatgagata 288900
agatatctta gaattatcct catcttcagg ggaaagtggt tagttttttg tcattaagaa 288960
taatgttagc tattgttttt ttaaatttcc tatatgaaat tgaggaaatt tctgtctatt 289020
ctgaatttgc tgagttttta atcataaata gctgttgaat tttgtcaaat agttttcctg 289080
tgtcaattaa tatgatcata tgacttttcc cgttttcact gttaatgtgg cagattatat 289140
tgatttattt tcaaatgttg aatttgccat cagacatgga ataaatccca tttgttcatg 289200
atgtataatt tattttatgc atcgtttgtt ctgtcttgct aacattttgt tgagattttg 289260
tgccagtgct caggagagat attggtctct agttttactt tcttataata tctttatctg 289320
atttgggtat taggataatt ctagactcag aatgagttag gatgtgtttt ctctgcctgt 289380
ttactaacac agattgtaga gaattggcac aatttctttc ttgaagattt gttagaagta 289440
atcttgccac cacctgagcc agatgatttc tttagaaggt aattagttat tgaatcaata 289500
tatttaatat atatagagat atttaggcta tttatttctc catgtgtgag ttttggtagt 289560
ttgtgtattt caaggaattg gtccatttca tccaaattat caaattcgtg agcatagagt 289620
tgttcataat attcctttat tatcctttta atctccaaga gaccagtcgt ggtgacttct 289680
ctttcattta tgatattggt aatttatgtt ttctgtctct cttttttttt tgccagagtc 289740
taactctgcc acccaggctg gagtgcaatg gtgtgatctc tgctcactgc aacctctgcc 289800
tcttgggttc aagtgattct catgtgtcag cctcccgagt agctggtatt acaggcatgc 289860
tccaatacac ttggctaatt tttttttttg tatttttagt agagatgaag ttttaccatg 289920
ctggccaggt tggtcttgaa ctcctggcct caagtgctct gcctgcctcg gcctcccaaa 289980
gtgctaggat tacaggcgtg agccaccgtg cccggcttct ttttcttaat tagcctgaat 290040
agaagtttat caattttatt gctcttttaa aataaccagt ttttgtttca ctgagtttct 290100
ttatcatgtt tctgttttca attttattgg catctgctct aatttcagat gctccttgac 290160
ttatgatggg gttgtgtccc agtacatcca ctgtaatttg aaaatatcat aagtcttttg 290220
acttatgtaa tgcatctaac ctaccaaaca ttatcgctta gcctaacctc ccttaaatgt 290280
gctcagaaca catacattag cctacagttg agcaaaatga tctggcaaca aaacacacta 290340
tagagtattg atggtttacc ccgatgatca catagctgac tgagagctgc ggcttgctgc 290400
tgctgcccag cattaagtga gagtattgtt ccatatattg ctagcacaga agatctaaat 290460
tgaaaattca aaatacagtt tctactgaat gcatgcatat tacttttgca ccattgtgaa 290520
gtcaaaaaaa ataataaatc aaaccatctt aagttgggaa ctgtctatat tattctttct 290580
cttctgcttg ctttaagctt atctagtttt tttcttctct agtttcctta ggtggtggct 290640
taggttggtt attgatatta tatatttttc ttatctaata tatttactta atgctatgaa 290700
tttttctcta agcactgctt ttcctgcatc ccacaaattt tgatgttcta tttttatctt 290760
catttagctc aaaatagttt accatttatt ttgaggcttt ttctttgact catacgttct 290820
ttaaaagtgt gttgttcaat ctctaaatat ttcgatattt tccagctatc tttctgttga 290880
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tttctaattt atttccaatt tggtgtgaga gcctactttg tacactttct gttcttttaa 290940
atttgttaag ggtgttttgt gacccagaat gtggtctatc ttggtgcgta ttccatcaga 291000
acttgagaag aatgtgtatt aagttgtggt ttgatggagt attctataaa tattaattag 291060
accatgttga ttcatcatac cgtttaggtc aactatatct gtatta~attt tctgcctgct 291120
tgcactagca attactgaca gcggaatggt gaggtttcta agtataataa tggtttgggc 291180
ttgtctattt ccccttttag tttcaatcat tttgcttcat gtgttttgat tcacttttgt 291240
taggtataca catatataca catatttatg attgttgtat catcttgaac aactgacccc 291300
tttatcatca tctttatcct tggtactttt ccttctttgg tagtctgctt tgcatgaaat 291360
taatatagcc actccagctt tatttttgtg aatgttagca tggtgtatct ttctccattc 291420
ctttactttt aacatatcag agttattaca tttaaagtgg gcattattac taggataaat 291480
accaaataaa gtattttgca tgctgggctt aaaacctaga tgacaggtta ataggtgcag 291540
caaaccacca tggcacatgt atacttatgg aacaaaactg cacattctgc acatgtatcc 291600
cagaatttaa agtaaaataa aaaataaata aataaaaatt aaaaagtaaa aataaattag 291660
ctgggtgtgg aggcagccag ctactcaggg ggctgaggca ggagaatcaa aataaataaa 291720
tcaataagtg gggctttttg taga.caacat atagtttggt ctttcttaaa attcaatctg 291780
acaatttcca tcttttaact ggtatattta aacaatttat atttaaagca agtgttgata 291840
tatttgaata aaaataaacc tgtgtttatt aactatttca tatttgttgc caaacgcttc 291900
tttttggtct ttcgtagttt tatttgagca atgtatgtca taccatttta tcttttctct 291960
tagagtatta actatacttc tttttttttt ttttgagaca gagttttcct cttgttgccc 292020
aggcgggagt gcaatggtgc gatcttggct taccgcaacc tctgcctcct gggttcaagc 292080
gattctcctg cctcagtctc ccgaatagct ggaattacag gcatgtgcca ccatgcccgg 292140
ctaattttgt atttttagta gagacggagt ttctccatgt tggtcaggct ggggtcttaa 292200
actcctgacc tcaggtgatc caccggcctc tgcctcccaa agtgctgggt ttacaggagt 292260
gagccaccgc acccggctta actatacttc tttaaagaat ttttgtagtg gtgccgctaa 292320
agttcacagt atacattttt aagtattcta aatacacctt caaataacac tattcctttt 292380
tacatgaaat atagggatat tataacatag tattctcaat tcctccttac tgtcccttgt 292440
gacatagctg tcatttattt catttcactt acctatatac tataatcacc tatacattgc 292500
tgctattatg attttaaaca ggcagttatt gtttacgtca attaagaatt tagaaagaat 292560
ttagaatcct gtgtaaaata aatttccttt tattttacct taattcatgc attctctgat 292620
tatcttccat gctttatgta gatccaagtt tctgacttat atcaccttcc tcttgcttga 292680
agaacatctt ttaacatatt ctgcagggca agtcagctgg tgatgaattc tctgaatttt 292740
tgtctgattt ttttttaata tttccttcac ttttgaagga taatttccct gcatctagaa 292800
ttctaaattg gtcacttttt tcaacatttt atatatttta cttcactttc tttattaatg 292860
tacggtttct gaagagaaat ctgctgtatt tcatcctgtt ctctatggtt aggtgcttcc 292920
ctgccctggc tctggctttt tcaagatttt ctccctgtct ttggtttttc tacagtttga 292980
atacaatatg cctaggtgtt gtttgttttg tttttttgta aggagtggca tgtatttatc 293040
ttcttgatac tccctgagct tcctggatct gtggtttggt gtctgtcatt aattttgaaa 293100
agttctcagc cattactacc tcaaatattt cttcttcgcc tttctttttt tttctttctg 293160
gtattccaat tatgcatatg cttgttatac cttttgcttt ttcattcttt tgattcttta 293220
catttcagtt ggggacgttt ctgttgactt atctttcagc tcactgatta tttccttggc 293280
cgtgttgaat caattgatta gtcctcaaag acatttttca tttctgttac accattttta 293340
catttctagc atttgctttt gattctttct taaaatttct atctttctgc ttatattacc 293400
catcttttat tgtatgttgt cttctttttc cattagagcc ctcaaactct ttttttttat 293460
tatactttaa gttttagggt acatgtgcac attgtgcagg ttagttacat atgtatacat 293520
gtgccatgct tgtgcgctgc acccactaac tcgtcatcta gcattaggta tatctcccaa 293580
tgCtatCCCt CCCCCCtCCC CCCdCCCCdC aaCaCtCCCC agagtgtgat attCCCCttc 293640
ctgtgtccat gtgatctcat tgttcagttc ccacctatga gtgagaatat gcggtgtttg 293700
gttttttgtt cttgcgatag tttactgaga atgatgattt ccaatttcat ccatgtccct 293760
acaaaggaca tgaactcatc attttttatg gctgcatagt attccgtggt gtatatgtgc 293820
cacattttct taatccagtc tatcattgtt ggacatttgg gttggttcca agtctttgct 293880
attgtgaata atgccgcaat aaacatacgt gtgcatgtgt ctttatagca gcatgattta 293940
tagtcatttg ggcatatacc cagtaatggg atagctgggt caaatggtat ttctagttct 294000
agatccctga ggaatcgcca cactgacttc cacaatggtt gaactagttt acagtcccac 294060
caacagtgta aaagtcttcc tatttctcca catcctctcc agcacctgtt gtttcctgac 294120
tttttaatga ttgccattct aactggtgtg agatggtatc tcattgtggt tttgatttgc 294180
atttctctga tggctagtga tgatgagcat tttttcatgt gtctgttggc tgcataaatg 294240
tcttcttttg agaagtgtct gttcatgtcc tttgcccact ttttgatggg gttgtttgtt 294300
tttttcttgt aaatttgttt gagttcattg tagattctgg atattagccc tttgtcagat 294360
gagtaggttg cgaaaatttt ctcccatttt gtaggttgcc tgttcactct gatggtagtt 294420
tcttttgctg tgcagaagct ctttagttta attagatccc atttgtcaat tttggctttt 294480
gttgccattg cttttggtgt tttggacatg aagtccttgc ccatgcctat gtcctgaatg 294540
8~
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gtaatgccta ggttttcttc tagggttttt atggttttag gtctaacgtt taaatcttta 294600
atccatcttg aattgatttt tgtataaggt gtaaggaagg gatccagttt cagctttcta 294660
catatggcta gccagttttc ccagcaccat ttattaaata gggaatcctt tccctgttgc 294720
ttgtttttct caggtttgtc aaagatcaga tagttgtagg tatgcggcgt tatttctgag 294780
ggctctgttc tgttccattg atctatatct ctgttttggt accagtacca tgctgttttg 294840
gttactgtag ccttgtagta tagtttgaag tcaggtagtg tgatgcctcc agctttgttc 294900
ttttggctta ggattgactt ggcgatgtgg gctctttttt ggttccatat gaactttaaa 294960
gtagtttttt ccaattctgt gaagaaagat attggtagct tgatggggat ggcattgaat 295020
ctgtaaatta ccttgggcag tatggccatt ttcacgatat tgattcttcc tacccatgag 295080
catggaatgt tcttccgttt gtttgtatcc tcttttattt cattgagcag tggtttgtag 295140
ttctccttga agaggtcctt cacatccctt gtaagttgta ttcctaggta ttttattctc 295200
tttgaagcaa ttgtgaatgg gagttcactc atgatttggc tctctgtttg tctgttgttg 295260
gtgtataaga atgcttgtga tttttgtaca ttgattttgt atcctgagac tttgctgaag 295320
ttgcttatca gctgaaggag attttgggct gagacaatgg ggttttctag atatacaatc 295380
atgtcgtctg caaacaggga caatttgact tcctct~tttc ctaattgaat accctttatt 295440
tccttctcct gcctaattgc cctggccaga acttccaaca ctatgttgaa taggagcggt 295500
gagagagggc atccctgtct tgtgccagtt ttcaaaggga atgcttccag tttttgccca 295560
ttcagtatga tattggctgt gggtttgtca tagatagctc ttattatttt gacatacgtc 295620
ccatcaatac ctaatttatt gggagttttt agcatgaaga gttgttgaat tttgtcaaag 295680
gctttttctg catctattga gataatcatg tggtttttgt ctttgtagag ccctcaaatt 295740
cctaatcaca attgtttatc tctttcctga cattccacat ccaatccatc agcatgtctt 295800
attggcttta ctttcaaaat aaattaaact cagccacttc tcagcatttt taaaatcacc 295860
ctaatacaaa ccccctgcta cctcatcaac tgcaatggct tcctaactta ttttgtaact 295920
tttgatcttt gagttcttcc aagagccaag agttcttcca aagctataaa ccctatcatt 295980
ggcactcctc tgctctatgg aaagcagtgg cttctcatct ctttcagagt ataatgcaaa 296040
gctctcacct tagctggcat ggccctgtgg gattggcctc ccttgtctta ctttttcctt 296100
gttcaggctg ctgtgacctc tctggtcttt ggctcttact agaaaccttt gaacccgttt 296160
ccttcccagt gtcagtattt gtgtgttgtt cgttcaccct tctcacttca ttctggtttc 296220
tacagcacag agaagtagta gtccctgatc taaacaccct ctccacctgc tttccacttt 296280
gttttttccc ctagcactta ccattatcag atatcatata tttatttgtt tattgtctaa 296340
cttcctcaca aaaatatgac gttgtgagga tagggatttg gctttttgcc ccagagcagt 296400
gcctgactct caataacttt gttgtattaa gtgaatgaat aaaataaaat taaaattgat 296460
tcaaagtgta tgagcatgtg tacattttac ataagtgata catgacattc ttccattcct 296520
tgggggctct tttaaccatt ctcaaccagt tgtagtacct ttaaaaaatc atgatgaaga 296580
tgattttgag agctaatttt ggtaggagac agcagtttta gcctgtccgc tccatgtgca 296640
gaataatagc ctattttatt acatctgata ttcaagcact agaatctatc aataggtaaa 296700
taatttccaa aaataaaagc atcagtggga aaacagggaa attattttta aaaaagaatt 296760
tctagaccag gatgtgtgca atttgtaatc tctaataaga aacgttatag ctgataattc 296820
cagcaattac agaatcatga tcatatccat aatggatcag tagaggctct ggcttatata 296880
atagcttgcc ctctcaggat tctagagccc catatgtaaa cacagaacac atttatattg 296940
attgacagtg catgtaggtt tctacagatt gtgccagtca gtgttttcta aggcagttat 297000
gccatggtaa ttaaaattat gggctctgaa atcagcctgc ctgggttcaa accccagctt 297060
catgtgtcag cttccttggc tgtaataagg aatactaata gcacctgcct tgtggctttg 297120
aaaattacat gatgtaactt tgtcaagagc ttagatgagc acttgggata tggcgagtgc 297180
tcaataaatg ttagtttacc atcatcatca tcattattat tattactgat tgcaagcaag 297240
acaaactggt tctcacttca gcagaaaaag aaattactga agtaattttg gttagatcac 297300
agatttaacg tgaaggatga ataaccagac ttggaaaaca ggtggaaacc aagaggcagt 297360
cagcatggca tagcagccag cacttcacca gtgtggtgcc ttgggggcag cctggcagga 297420
gccactgcct tcactcctgg actgcagatc taccacagga cagcagactg aattgtccta 297480
tgtccagact tcacagtcac agggagcagg ctgcatgcag gtggggccca ggtcacctac 297540
cttcacccta gagtctggag ccacagaaaa cagtaattgt ccttgtagct tttgtgatgg 297600
aaagcaagtc ctgacaccca ccaactcaca tactagggaa ttcaccaaat gtaggacggc 297660
agctaagatg ctgggaaacc aagaattaac aaatgagtat tacaccaatt agttaattca 297720
ttacagattt caatattttc caaaaaacat cctacaaaga acagctcact ttaatatact 297780
ccaacaaatg atgaaatctc tccttggtca tcagcttttc taaatttctg taactttagg 297840
tgattctgaa tttcttagtg attctgaact tctagaagat tctgaaacag aacagtctta 297900
ctttgggatg tattcaaatc ctagagatca gtcacatcaa tctgtgccct ttttcattat 297960
gtaacatgaa acaggaggac ctttccaact tgccttggga acctgctcct acaacagggt 298020
atattatcac atttaataaa gaaagagtaa tatttgcatt gtgacccttc atctgaggtc 298080
atcgggactg tgctgtcctc ccaagctcca ctgtaaaggg atagacaaca accttgtctc 298140
ccagtcattg taatctgtat cagagagcat cattagatga atgaagatgg aaatgttctc 298200
82
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
acggtcagca ggtggggaag gcaagacttg ctgattggaa gcaatgaacc atagttcatt 298260
ctaaggcttg gggagagcaa ctttgaggaa atgaggcccc taaacttgcc atgtaggaga 298320
agttgggggg tggtaaattg ggcacccttt atctactaaa cgtaatcttt acttccccac 298380
cctctaattt ttctcagttg ggcttgaaat tgtttttgct tgttacactt tatgggaaaa 298440
gaaagggaaa tcctaataag gtccatgcca gcaaaactct agaagaagaa actaagaatt 298500
tcaaattgac agtttgttaa tgagaaaaga caaggttaaa ggattttgtt aaacagatga 298560
ccaaaataat tattggaaac ttctgcttct ggccaaggtg gaataataag ggctacattt 298620
accttcccac cagaaaatat aataacaaac aaaaactgga caaaacactg gacatgacac 298680
tgttgtcttt aaaccttgga catcaatcag tgcaggatgt tattttgtaa gaaagggaaa 298740
aaaattgggg tgagccttct gattgtttcc agactggaga gaagtttcag gccacagcaa 298800
gtggggagga acctaggtgt aagtatatgt ataaggtagc acatcatagt ggccaaatga 298860
atggcacagg aaagaaaaac tacaagaaca gaggaggtag ggccacaaaa ctagagtggg 298920
gtccaagatt cactatggat aaaatggggt gttaatttgg ttttcaaggc caatacaaga 298980
ggaggcatag aaaaagaaca aggtggtgtt gggaagtagt ataaaaaggg gcacaggctt 299040
atccttgttt tataaaaaac aaaggttttt ggaagggatt tgtagagata agtttgaaaa 299100
gtagtttgag actatgtgtg gaaattcatg aatcttagag tttgatttta ttcaggagat 299160
cagtagcttt taaaatgtaa aataaaacca gtaaactcta tctaaaataa attcttcccc 299220
taatcccaat ataaaaaata catataaaag cgtagctgct ctagacaaaa tggcgggtat 299280
gagatgacca gaaacctcaa cagcactacc tctggtagcc ccatagaact gccaagagtt 299340
ttcagagtat agttaattcc tgctgacggc taaggcagtc attgagtgat tggaaagaag 299400
acggaagata gacaagatca gttaattggg ttggagggaa gactgaagat aggcaaggtg 299460
acaaattagg aactgttgca atgatctagg caagaaggaa cctatgaact aggagggagg 299520
cttaaagaca gcaaggaggg aactataggc agggacatgt gaggaaatgc ttagtagtta 299580
aggtgagttt gtaggtatga aaggagagaa ggaaagaaca ttaagtagca ttaagtgaac 299640
cagataattt atagctcctt gacctgaaac atttagaggc tgtgataaca ctaataataa 299700
taatctataa ttacataaat tacgtagtgt aatgatatat catgatataa tcatcttacc 299760
aatgctttac agtcaatgac attgtggtac agagactttg gaggcagata gacctcgatt 299820
gtaacctctg tgctgcccgt ggtatgacct tgagcatggt agttaatctg aacttctttc 299880
ttttctgtta aattggggac aatgacagta cttaacctta tagtacttga agggagagtg 299940
ttagaattga tactggggag tctctccaca gaaagttgta ttagttattg tctttatttc 300000
attcttaatg aattagcact cccgttttct ttaacatgtt gaatttaaaa cctcttagtg 300060
tatttctttg tcttgccttt taatacccca tgaattattg agaaacaaaa gaaagtgatt 300120
atgcaaatgt ttgaaatatc taataataca tgaacgtagt catgggaaac tggagaaata 300180
actttactga tattatacta gttttttttc tggaagcata gcatattaag aaaactcatt 300240
tcaatgaaag aaaatttaaa aattagagtg cattagaagc ataatccaat gaattctatt 300300
cctaatgaat actcaggcag tatgttaact ttttctgaga tacaatagcc aagccaaaga 300360
atttaaagaa tgaaaaaaac agatgattaa acaaactgtg aagtaattag aggtagtctt 300.420
tgaaaatgcc tcattaggca tttgactcat taggacagat ccttttattt tagggccagg 300480
acataattat ttaagcagtt gatgtgtctt tagctccttt caccttgcca caagttgtcg 300540
cctgtactgc ctttccacct agcttccaag tccaggccga ctttgaagag attccttagg 300600
gCtCdCCtCC CCtggagagt gccctctgta CCatCt CtCt CCCtttCCtC CtCattCCta 300660
ttgcctgagt ttattgtttt aataaattcc cataagttaa cacctcctag ggtggattag 300720
aatcattcaa atccacattg attgttacta agtagaaatt ttatactgag cctttctaaa 300780
tccttacaac aacgtgacga ggatattata gttgctttaa cccaaggaga tgaaattcaa 300840
actggtggca ttgcacactt acagtgggct tgcaggatga aagagagctt ggtatctcga 300900
tcccttatac aaaacaggtg ggtcttgtta gaaaaattct tcaataattg ttaaggttaa 300960
aattttgaaa agtggttcaa agaaatttgc tttgatgcaa atattgtcta gtcagttaca 301020
taacttgagc tataatgaca gtgtacacta gctatccagg gcacgacatc tctattgtgc 301080
tgttgaatat actgctcaac cattctggaa aatggcatgt tcatgtatga atgacaatgt 301140
atcttgtgtg tatggcattc caagccaaca tgttggtccc tgcaagtaaa cttcttgact 301200
gtcaagaggc tgcctgttta atatttgcat gatctaaact aattgtttcc tttgtttttt 301260
tcctctgctt tatgagctgg tagtttgacc ttttggcttt tcccctgaga gttaacaaaa 301320
gttagacagt tggggggtga acttaagtaa aatccatatc actctatgtt gctgctctac 301380
taacaattca agaaaatgtc ttggtagaaa gcaaggaatg agttttaaat tttctctttg 301440
aatttcaatt atccatgcca ctcctgtggt ccaccattct atataattaa gaataagctg 301500
tatgttccat agtgacacag gctgttattt ctgatttgca gttttcactt aacctagggt 301560
aaaattgaaa tagaagtcgc atcctttttt ttttaccttc ttccactcaa ttctagttag 301620
atatttttga acttctataa aatgtctatg caatattatc accaataatg tgcaaaatta 301680
ctactcccat gtagaagagg atccattctt cattgaacca tacccttggg atcctatcac 301740
atgcagttgg ccatataata ttttatatta ttgttttttt gttttgtttg ttaagtttgt 301800
acctacataa tggattaaat tcaaaatctc tgtttaactg aaacaaaatc tgtttaactg 301860
~3
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
aagcaaaaaa acaaaatctc tgttttttgt ttgtacaaaa caaaaaacaa taatattttt 301920
gttttgtttg tatacttcat agggactttg gaatttggaa aatatcgttc atttagggta 301980
tatatattag tccattttca tactgctata aagaaatact tgagactggg taatttataa 302040
agaaaaatag gcttaatgaa ctcacagttc cacatggctg gggaggcctc acagtcatgg 302100
cagaaggtga aggggaagca aaggcatgtc ttatatggca gcaggcaaga gagtatatgc 302160
aagggaactg ccctgtatga aaccatcaga tctcatgaga cttatttact atcatgagaa 302220
cagcacagga aaaacctgcc cccatgattc agttacctcc cactgagtcc ctcccacatg 302280
tggggattat gggaactaca attcaagatg agatttggat ggggacacag ccaaaccata 302340
tcagtacatt aaagaaaata tttgttagcg ctaagtgaat ctactttcac ctacttgatt 302400
atttgatgat tttataaata gtcatctctt tcctcatctt tccagtcgta ttttgttgtt 302460
ccaaagccaa aacctgtgtg tcttgtattc aacaacctga atcatacagt tgtgagacgt 302520
aaatgggtgt ggtggttcca cttacttctt tacatagtac tacaactaag ccatctaagt 302580
agtctgctcc taaattcctc caagaaggga aatatcatga tttgatttaa atgtgacatc 302640
ctttcttaga gaagttttct ttgtctcctt cttccccagt cacttcctcc catccactgt 302700
gctttcggca gttcattcgt tcattaattc attcaacgaa tattgaataa cttttgatca 302760
atgtcttcct ccctccaagc tgaaaacttg atggagggta acatgatctg tctttgttta 302820
ccactgcatc ttccgtgaat atacattgta agtattgaac ggatttttac taaatgaaca 302880
aatactttga taaaatattt ttgattactg ccaatatcag tttctgaatt gattctaaaa 302940
ttcttctgct ggaaagtaga ttagcgttag tatgactgct gaagcctttt aaagtgggtg 303000
gtaatactac gtttcgtttt gtttcattaa cctaagtgct gttctttgga atctttttaa 303060
agtaagataa attacattca tgaaagaagc atattatttt taaagtactt tattttggaa 303120
aggtaaaatg cttgtgtagt tataatttgg ttactcttga tttcacctta ggaaaaacaa 303180
tatcaccttc taaccatttc ttttttagtc aaatctcttg cttctatttc tctctgtaga 303240
tccgctatta aagactgtaa tcactgctgc atctttcctg taaggcttga tcgcattgtt 303300
aatttctttc taaacttgta gagtaggtgt ataaatcgta tttgggtaat acactgacta 303360
atactgaaga accaggcatt ttcttacccc agtcctcaca cgaagtaggg aaatacaagt 303420
cagaactta,t cttctcaaaa ctctgacctc agaatttcct gagaaatctg aacctaaaaa 303480
gattctttgc ttttgacatt ttttctctgg tgtccaccgc aaggctcttg ctcttacatt 303540
tttttttttt ttctaatgtt tcaaatagaa gatggtagag tcatatagta caagctcagc 303600
atcggagggg ctactggagg tcaactagtg caaatgcttt ctgaataatg gaatcctttg 303660
ggaatacccc cttgaaagtc ttcatctagc ctcttcttgg aaaccctcag tgatacccct 303720
catcgtctcc tatgatggca gcttctatct ttgtcgtcag ctctgactat tacaaactgc 303780
ttccttacat tgagctgtaa ctaactaaaa agtttccaca ccctgcttct attttagcct 303840
ttgggctcat aaagaacaag ttgaacccgt cttatgcaga acaacccatc tacgggagat 303900
gctcaggttt cctccatgtt ttcctttctc taggctaacc cttcgttgtt cctcacttac 303960
tcactatata acctgatttc atgtctcctt acccttcttg ttactctaac ttgagtaggc 304020
tagtttcagg atccagcaat aagtgtgata catcaggtat gctctgatga gttgagagta 304080
gagtggacat agcatctccc ttaattcaga tattgtgatc taattggcaa atctggcaat 304140
aaaagttgaa atgcctgatc caggacaatg gctggtcagg tgccattgtt ctcatctttt 304200
acttttaggt gtccctcaat ttgttaagtt agtacctacg taatgtcctg aaacttgtta 304260
agtttgtacc tacataatgg attaaattca aaatctctgt ttaactgaaa acaaaagcaa 304320
acttcttttc agagccagaa tctggaatca tacgtaacag agaatgatat tgtacaagtt 304380
gcttcatctc tttaagtaac ggtttctcaa acttacaaga ttattgtgag aactaaatta 304440
gttctaaagt gcttccatgt aaagtgtatg taaatgctta aaatatatag taagtgctga 304500
atgcatatta gaaataataa taatctttat tataattttt actatttcat gagaagtact 304560
tattttaata ctgagcaaat aggaagagtt catggcttct ctatgttttt gaagtgtcat 304620
ttaatatatt atatatataa aacatatata tatttcagtc acacatttgt ccaaatacct 304680
tgacaaatta aaacaaaata agacaaaatt ctcacgctag ttatttgtta taaagtaata 304740
gaacaagtga tatgttataa agagcattta tttctcatgt ctttgatatt aaaaatagtt 304800
gtattaactt tttatcaaaa cgattgcttc cttcatataa atctaagaat tatgctgtct 304860
gataaatatt ggagagatta acttctttga aaatatagaa gctttttgtc tttttaaaat 304920
agttgttttt ttgcagatgt taatacattt cagcagtaca gtatggcctt tttcaggtta 304980
aggtgctgag cccaaacctc aaagaatcac tgcaaaaaga ttggatcccc cctcttcacc 305040
ccatttcgta atttagttag tgagaaccac aactggctaa acctttgtgg ggggccgggc 305100
actgtggctc atgcctataa tcccagcact ttgggaggcc gaggcaggca gatcacaagg 305160
tcaggaaatc gagaccatcc tggctaacac ggcgaaaccc cgtctctact aaaaatacaa 305220
aaaattagcc gggcatggtg gcaggtgcct gtagtcccag ctactcagga ggctgaggca 305280
ggagaatggc gtgaacctgg gaggcggggc ttgcagtggg ccgagatccc gccactgcac 305340
tccagcctgg gtgacacagc gagactccat cttaaaaaaa aaacaaacaa aaacaaaaac 305400
aaaaaaaaaa ccacctttgg ggggaaatta tcaaataaaa caaactcttt ttagaatttt 305460
acaactttta tgttaggaaa aaacaaatac atttgtgaaa agcttaaaat ccagtaaatg 305520
~4
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
acttgaggga cttggggcaa tcctagggtg atgaggagca ggttagtaac agtgaaggac 305580
ttagcacccc agggggccag aggctgtaat ataccttatg agcaagtcat-tcttatttag 305640
tcttgcccat taagaagtct acttggacta aatgctttta aaaatgccct tttaatttac 305700
tattaaaaga atattcctag cagaagtagt cttggatgct aaattctatt ttaagaataa 305760
ctaaaattag aattctgttc tttttataac acctgttaca cacacacccc tacctagtgt 305820
gtcggaatca gtttgtatgg gctcaccaaa gcctactgtt caattttcag gagttttgta 305880
agccatttga tgtcagacaa gtggcctgaa gtttgttatg gtggtggtat ttacaccatg 305940
aaaattggca tgttatggtg gtagtattta caccatgaaa actgctacaa atagaaatct 306000
ttttcttctt ctcttggaga gccacttgtt gaacacttac cagctcacct gtgcttgaaa 306060
gtatttcttc aaataaaatg aaagctggtt agctttgaaa attttttgta taaaagttta 306120
cacgggaaaa aaataaacta attttttttt tccacctgtg ttttcaggga tacgaaaaga 306180
ccgaagagga gggagaatgt tgaaacacaa gcgccagaga gatgatgggg agggcagggg 306240
tgaagtgggg tctgctggag acatgagagc tgccaacctt tggccaagcc cgctcatgat 306300
caaacgctct aagaagaaca gcctggcctt gtccctgacg gccgaccaga tggtcagtgc 306360
cttgttggat gctgagcccc ccatactcta ttccgagtat gatcctacca gacccttcag 306420
tgaagcttcg atgatgggct tactgaccaa cctggcagac agggagctgg ttcacatgat 306480
caactgggcg aagagggtgc.caggtaagaa tgcgaagcgc agcttttaag agtcaatagc 306540
ttttcaagaa cttgttgtga tgtcatggga gaaatagtgg gggaaaaaga agcaataaca 30600
tgttatgtaa ttggtttcaa ggttacagga gatgtgttca ttttcagtat caatacactg 306660
taattttcca ggagattagg aaataatatt tttaaatcag aatctagaag actgaaattc 306720
ttaaattgac ataatttatt tttaacccat ctcatttacc aaaaagattt agggtggaca 306780
ctacatggta aaactattta atagtgtatg ttcacagtag cagaaacttt taacactaaa 306840
tgaactacaa aagtttgtaa tattaatgac ctttgttgaa aacatctcaa ttattaatca 306900
aacgatttta tcttaaaaag atttttaaga ttcggtgtgg tggctcgtgc ctgtaatcct 306960
agcacttttt ggggctgagg tgggaggatt gcttgagccc aggagcttga ggccatccgg 307020
ggcaacgtgg cgaaaccctg tctctacaac aaatttttaa aaattagctg gatgcagtgg 307080
cacacacctg tggtcccagt tatgggggag gccgaggtga gaggatggct tgagtccagg 307140
aggtcaaagc tacagtgaac catgtttgtg tggagtgcca ctgcactcca gcccaggtga 307200
cagagcaaga ccgtgtcata aaaaataaac cacacacaaa aagagaaaga tctttatgga 307260
ttaaaaagat aataataagt gtatttactg aatgccaatt atttatccaa cctggtgtat 307320
gcttagtatt ttaggagaaa gagaaaggca atggaaaaat aaattaaggt atcatccctg 307380
aaagaaactt ttagaaagac acagtggctg aagtgatacc ttgttccttc agttgattct 307440
ctcagaactg gtgttctggt aaaattggac tgttactcct gttattcagg gagaagaact 307500
caagtttgta tggcaacaag actagaaaat gactttctcc ctgccccagt gtattcgttc 307560
aggagctaat gtagataaac cgaggcaaga agaagctaaa ttttttttct gggcttatag 307620
gttaaatgag tgatagattt agttggaggt tttctcattt ggtttctttt aatagatgaa 307680
attaattgtt tcctatgaag catgaaatgt tttatatgaa actaaaaaaa tgtggagttt 307740
gtacttgcat ttcaagggtc actgctctgt tataggccaa gtgaacttat gtctggcctt 307800
agagaatctt acatgtattt gcatctatca gtatataaac atgtgggccg tagaataagg 307860
agccagcagt accagaaccc agccttgtta gaggccacca ttttggtggt tgagtggtta 307920
ttagtttaca tggaagcatg gagaataata ggcaaatgta ggttttcagt gtcagtcgaa 307980
ctggcaaaca aaaatttctg gtcatcttca gaatgaaaag ttttcttgag tacctacata 308040
ttttagcatt ttcatatgaa gcagatacat tataagttaa ttgttggaat ctaattgtaa 308100
tatggctgta agttttttct ttatatttgt tattgccttg ttcttatatt atagggaaag 308160
agaaacaaac aaacaagcaa agaaactaat ggtcatatat ttgagagcca actcttggtt 308220
gctgttcagt tttattttcc tgtaaacata tattttccct tatgaaatct tgggaatatt 308280
agctctggag cactgctgaa ctcaagtaca gacattttca tgtgtatcag tagattccca 308340
tcatgacatt tttataataa tgttgaagag cattttaaac aactggaatt aagctcaaat 308400
acattaccag tggttgaaga attcacatca ataatcttct gaatttagga ataaaatgga 308460
gaagtcaagg aaagccaaat attatacaca ggctagcaat agttaaaata caattattaa 308520
agccagagct agacaaaatt atggcaatga gatgtgtaac aaaaccactc tgtaacttca 308580
tcatgttcgt ttaaaagacc tgaatgattc caaaatcctt agaccaataa actatgtctt 308640
cttacttgat aattaaaaaa aagaattata aaggcaaaaa tgaaattata tgtatgtgtg 308700
tttgtgtgtg ttccatggga atacagctgt tgtaaatcaa aggcctactt gcctgaccaa 308760
gcagaataaa aatagtcatt gattttaaag agactaaaag tgagggaaga aaaaagtctt 308820
ctgcaaaagc tctacagatg gttgtcaaac ttttcagaaa aatagacaaa gcaacatttt 308880
gaaaaggatt tatatctttt atatattcaa ataccatctg ttatttaaaa aacatagccc 308940
acactgaata tctgatatag acaatataac gtttatgaga taatagtttg agaatgacaa 309000
taataatagt aagttttaaa agaggaaata agccgggcac agtggctcat gcctgtaatc 309060
ccagcacttt gggaggccga ggcgggtgga tcacctgagg tcaggagttc aagaccagcc 309120
tggccaacat gacaaaaccc tgtctctaca aaacagtaca aaaattagcc aggcttggtg 309180
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gcacacatcc atagtcccag gtacttggga tgttgaggtg ggagaattgc ttgaacctgg 309240
gaggcagaga ctgcagtgag ccgagacccc acaactgcac tccggcctgg gcaacaatga 309300
gactctgtct ctaaataaat aaataaagaa ggaaatagta aacgtcatta gtaagaagaa 309360
tagcaaaatt tcagttctag aaatacccag aattagctat atgatacaaa aaccctcatg 309420
aaacatttgg ataatcctca gaatacctat caatataaca aaaactatga attgacttca 309480
ttttgaatga tgaattttta acaaaaatag tcaatacttt gggcttagta gctctagaag 309540
tgcttctttc ttctttcttt taattaacag aatattgtca gaattttcaa atgttgatga 309600
ttataagttg aattttcctt ttcattaacc cctggggctt attttttgac ttgatatgtt 309660
tctctactca gaattaagat gtgaagagct ttgggataga atgcatcata caagtgtgag 309720
agtcaagttc caatccataa agtacttctg gtagacctgg ataaagatga ccttaagaaa 309780
tgattttttt tctctttgca gtttaaaaac aacagtagca acaagaatga taaaacctat 309840
gaagccagct ctgacaaaag atgttttttt ataacacata ctatgtatct actttttgat 309900
atttatctat cgagaagact tttctcctta ttgtttgctc tgaaatttgt ttatatttaa 309960
taggaatttt atagccttat ccctgggtag aaattcagtt tttttaaaag tagataatta 310020
aatcttaatt tactattatt ttacacatgg tgaaactagt caataaatgt aatatcattg 310080
agctgaaggt taaaaaggaa aaaatatgac tgcaagagtg gttgtatttt tgatttcagc 310140
atcacactca attgcatcat tgagtggttc attcttagtt tcagtgttaa tgaaatacat 310200
ctgagttttt ttccccagaa gcttgaattg tgtcaccaaa gtgtcatttt gatttattga 310260
aagttaagcc ctttccaaaa ttcaccataa ttttacatgt ctcgaaagca attttatact 310320
tcaagtctgt gctatagttc tatatatttt atgaagattt ggatagatat ctagccctga 310380
gttttttatt gcctgttaaa tacttataac ccaaagtgta gcagcctcat gaactgctgc 310440
tgggcacaga tctgggagag tgcactcaga gtgttggccc aggaagagga aaagaggaaa 310500
aggggcagtt cagtggcagc ttggcttcct gtgaaacatg tcaccttaac cacttcctca 310560
ttcttttagt ggcaaactag acgaccttct ccttcccctt tcctgccgag tccccctcta 310620
atcaacactc tagaaggccc ctcttcctcc tcagtcctga ctccctgtca tttacttcag 310680
gttgcctcct tgctcagttt tggccccagg ggtaggcaat ctcctctttc tggacatgtc 310740
tcccaccagc cccaagttca gatttcttgg aagtttctgt gttgtctcga ggatgcatgg 310800
ttgtgtgagt tattccaggg ctcaaggcct cttctgtgtc tgtattcccc aggaatccag 310860
gaattcactt ctctgcctct catcctcatc ctcatcatta aaatgagcag atttgagctc 310920
aggaagtgct tgaataaatg aataaatgaa caaatgaaag gtgatttttg aaagtcttaa 310980
ttttaagaag tctctgagcc ctgttacagc tcaattttcc cataaactag aactgctctc 311040
taaggctgtg acatttctcc tttttcctct cctcaaaatc tacctgctgt tctgatatct 311100
ccctgacagc caccatagtg agattctatt tccatttcca atctctcttt tgtaagggac 311160
agagaaacag ctagagaaat atggagccat gcgctctgag gactttagca ggcttcaact 311220
ctatctgcaa gtgagtttca cttagcgaat gaaattggaa acttaaagtg ggtagggatg 311280
agggttcccg gagaaggtgt aatacctcag tctgggaatt gggagcatct acaaggaaca 311340
cactcaattc tgggaggttc ctgtagattt cagagattta gcagggcttc ccagcactct 311400
gcttcccaac ctgtcattgg accagtaaac cctgctctca aactgttgtg gtgtccagca 311460
tgctttggca aggtaatgaa agataacatg acatggacat atgggtgaca tcctggagag 311520
atgacagaag tctctgttta aggacaagat ttgccattta gattttgcac ccactgtata 311580
ataagagcct taggattggg ctggaatcgc cctagcaggc atgatggcag cccctctgga 311640
ctggcaatat gcagcttttt tgcaagtgtt ccatgtccaa gtcaccccac ccagctttct 311700
actgctcccg tggaagctct ggtgaaacgc aaggaaagca gctgctgttg actggatttt 311760
tctttcacat gaaactttga agcctcatag atgcttattg gcctggatgc tattaaacct 311820
ttaaaaatcc ctttctcatc ttgagagtat ttgagaaaca tgtctggggc attttgccca 311880
ccctcctcca ggttctgtgt cagtgagtga tatggtttgc ctgtgtcccc acccaaattt 311940
catcttgaat tcccatctgt tgtaggagag acccatggca ggtagttgaa tcatgggagc 312000
aggtctttcc catgttcctg tgatagtgag taagtctcaa gagatctgat ggtgttaaaa 312060
aggggagttt ttctgcacaa gctcttcttc tcttgtctgc caccatgtga gatgtgcctt 312120
ccaccttctg ccatgattgt gaggcctccc cagccacaat ggaactgtaa gtccattaag 312180
cctctttctt ttgtaaattg cctactctgg gatgtgtctt tatgagcagt gtgaaaacag 312240
actaatacag tgagtctggg tcagtgtgtg tttatgttga acgtagtgga cttgtggtgt 312300
ccccagggca ccctgtgggg aatgttggcc tgtggctttg ctacttccag ggggatttgg 312360
catggagaat gtgtgtttta agtaatagat agattatgat tgaagtgtgt tatgggctga 312420
gttgtctctc ctcaaaaaga catgttaaag tcctaacccc cagtatctca gaatctgacc 312480
ttctttggaa atagtgcctt tatataggta atcaacttca agtgaagtca ttagcacaag 312540
ccctaatcca ataaggactg gcattctaat gaaaggggaa atttagacat agaaacagac 312600
atgcacagaa gaagatgata tgaagagaca caggaagagg acggtcatgt gactggagtg 312660
ctgggtctgc aagctgagaa atgccaaggt ttactggcca acatcggaaa ctagaagggg 312720
caagagtgga ctctccccct cagagagagt atggccttga tttcagactt ctagcctcca 312780
gaactgtgag gcgtacattt ctgttgtttt tgaagccacc tagtttttga tactttgtat 312840
86
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gggagcccta ggaattaata caaagtgtat taaaaataga attttcttct attgtatttt 312900
tgaggcaaaa gaaataagga gctattgatt taaggaggaa ggtttggctc atctagtata 312960
gacttggcta atcatttact cttgtatatt tctcttctgc ctgcccaagt agttcactga 313020
acaggcttag aagttgattt ataattgtaa gagtttacac atcagaagtt aatttataat 313080
tgttaacagt ttcatgcatc tacctcataa ataccttgta aaagatttta cccttcagaa 313140
taatgttttc ctctggtact ttagtagttt atcctttttt tgcatctttg atgcatttga 313200
attcatcctg gtatgctgtg tgagctgggg ctccaatgtc gttttcctac agatgactcc 313260
acagttgttt cggtttcatt cgaacagcct cctacagaag tatttttcag acttctttta 313320
tacttgactt ccaagtttac tactggttaa gagcttttaa agtaggggga aagatatgac 313380
ccattggcct actcgtttga ttattttttc caattctgaa atcaaaaatt aaaaaattta 313440
ttcaaagtta tagtttcact taatttatat taactgcata gatagtgtga ttcatctgtc 313500
ctgcttggac atatttagta acttttaatt aatcttagag ataaaagata gaaatctatg 313560
agacttgaga cattcaaata agaccagtac tgataagagg taatcaggtg aagtgccatt 313620
tggttgtaat aggacatcaa aattgttccc caagagtgaa ggatgttcca ttctcacttt 313680
tcccatctgt cctcccaaat tctttcactc ttcctgatgc tttgaaccaa cttgaaaagt 313740
tagtccactc agaacctcag ctgttaaact tttagcctct gcaaacaaac tagccgtttt 313800
cctctttgtc cctttaccat caagctcagt tgcttctcct actcctctcc cttctgccag 313860
gggctccacc cttgttcctc attcaacagt ggaatcatct gtgtgcctgt ctcctcttta 313920
ctgtgtacca ttgggtcctc ttcttcacca tctctaaatt tatgcttctt ccctgttcca 313980
ctgtcaccag cttggtctac atcctacttt gatcatttgg atttaggtcc caccctaatc 314040
gagtatgact tcatcttaac ttgattgcat ctgcaaagac ctgatttcca aatacgacca 314100
caagtaaagg ttcaggtgga catgaatatt aggagagaca gcacttcaat taacagtttg 314160
gcattaggac tttattatct agcttagtaa ttgttttaac agataaataa tagtatcccc 314220
taaagtttaa aatgcagaac cagattatgc ctcagggtgc ctaacctgag aggaagagtc 314280
tttcttcaac agactctggg aaagaccttt gtaaaaaggc tggtgaccat tctatttgat 314340
ttctactttc caatattaac tgcttaagtc agacaatctc cttggcccac gctttcccct 314400
gccattctcc ccttcacata atgtcttcat tttatttttc ccttgtttta ttccctgaac 314460
tcccttctct ctattcagat tccctgccca ttttttctcc taatgagacg cctgacttcc 314520
tacctccttt.ttgaaacttc aaactgctta gcaaatacaa ttttgaattg agtttgctgt 314580
cacagaacaa aaactagtcc ttggtccaga gtatcttgca ggactgaatc aactgtggtc 314640
taagacacaa taataactct taattatttt cttgtttcct tcatggtata tttgttgctg 314700
gatgatgagt ttatattatg gttgaatttc ctttttgaaa tgaaaagatg aatagtcttt 314760
attggctggg tatctatttt tatccagaag actttgcaaa tgagaaatat ttctacaatc 314820
tgagtttaat ttgcttaagc aatgaacttg ttctttaaaa gtcgtatatg tgcaaaataa 314880
atttaaatta aataaatcat attttaatgt agtcagggta gctttcattt aaataaaacc 314940
tatgacaaat atccacgtga aggtatcact cctttaacaa aacaagtgtt ctcctttttt 315000
attgaaatac tagttttcac aaattgagat tccttaatgt gatgaccgct tggactgact~ 315060
atagtatagc tgcgttctta gaatggccct gaaaccacaa ggcctctcca agatgcatgt 315120
ggctgacttt ctgaggtgac tgcattgaat ctttctggct tagcttattc tgcatccaga 315180
tccctggaag ctatttatcc ccaaacagtg gtatatttag acccattgtg tgctaacctc 315240
tctgtgccct aagtaccaac atagccaagc caaagttcga actttgctgc cttacaatgg 315300
aggttacatc gtagtgatga aagaggttaa ttttctttag gagttgaaga ccagagaact 315360
gcaaaaaggg gagaaaatca gtgtggcctc taatgagagc taagtgagtg aggcaataga 315420
aaacagtgag gaccggccag tgcggtggct catgcctgta atcccaatac tttggaaggc 315480
tgaggtgggc ggatcacgag gtcaagagat caagatcatc ctggccaaca tggtgaaacc 315540
ctgtctctac taaaaataca aaaattagct gggtgtggtg gtgggtacct gtagtcccag 315600
ctactcggga ggctgagcgg ggagaatcgc ttgaacccgg gaggcagagg ttgcagtgag 315660
tcgagattgc gccactgcac tccagccgga gtgagactcc gtctaaaaaa aaaaaagaat 315720
acagtgagga ccttggaggg aatcttacag tggagcagaa ttaaaagaga agaattcacc 315780
tatttcctat ataactccct ctgtaaccga taactttcta gagaaagctc actgaatata 315840
tttgaaattt gtttcatacc acttttatgt tattgccttc tttcacagga accagagagc 315900
tctaacctgt agatttgctt tgttgtcttt actttagact acagcctaaa ctgactgttg 315960
atttttggca caattattac atctctcctt tcaccccgcc tctagccctt tcttaattac 316020
ccccattagg catttttctt gctagcgtga actaaatccc ctgtctcaag cacgcgcctg 316080
tacattgaaa tagaatgtta attcattgac gaaattaact gttcttgatt gggaacccct 316140
agttccaggg aatcttaagg tttcaattct gttgccttgg ttactaaact gttccatgca 316200
gtttgctcaa ctttgaatgg atacttctct taggaacatt ctcccttgta agtaaattgc 316260
ttgacgtgtt aaaatctaag ttctgtttta caattcttga gacaaattca ccatgattta 316320
gttttaaaaa caagtggcct tgtcctttta gtctaggatt tatcacttag ctgtatctag 316380
caaagcccct cacacaatag taggaaaaag cagaagtgtg attgctaaat gaaggggaaa 316440
tgtaataaaa tgatggaagt gccctttttt agggggaatt aaagtttctc tttgtagtgt 316500
87
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tacatgtatt cattatgtga ctttcataaa tacaaacccc aataaaacgg tgggcagttc 316560
cgtctctgga gatgttaagt gtctcttcat agaataacat ggcacatcat aacatttgat 316620
tccttttacc tggtcaagat gtttgcttat ggcatttgaa atgcatattt tcaaactagg 316680
tagatgaatg gtttaaatat aaaaattcat tcaaggccct gagctataga agaatatctt 316740
ccaaaacatg cattcaagtt ctatctgtca gtgtttttct ttttgcatca ataaggcagc 316800
aatggaatac aatcagattt attttttctt tattgctgtc tacaattcag agatataacc 316860
tgaaaaatat gttgtctctt cccaagtaga tcttgtaatt ctctgaactg tgatccagac 316920
caatgccgcc tttacattgg gtctgtggaa gtgggagggt ccactgaacc tggttatgag 316980
aggtttcaaa ttgaaaagat ttacaagtat gtaaataaaa tcaaatagtc aattagtatc 317040
taacatatac atgtcaaaac acatagcccc aatctcataa aatcaaagag atctacctaa 317100
atagatttgt ttgcctaaca aatagcaaga ccactttgac agaatcttta gcatgacagt 317160
gattgtcaaa atgggtaaat ggttattatt gcccagttaa gtaatttctg atttgctttg 317220
ccttgattac tcttaataaa ctaaacttaa cataccatag aagcaatatt ttttaaaaag 317280
agggtatatt ctagagctag atagggtgtt gtgcagcaat gtgaatgtac ttactaccat 317340
taaactgcat acataaaaag ggttgaaatg gtaaatttta tgttatatac attttaccaa 317400
aataaagaaa agttataata ctttccgtag catatataaa aaagaaacag acatttcata 317460
gcaaaaatag gataaaaatg atattaaatt cataggggat ttctcttatc taaaacttta 317520
gatttgattc ttagataaga atataaacac attgcaagaa gataaatcaa taagccaatg 317580
aagtaaggtg gaataaataa atagaaatag gtgatacttg cggctctgac agcatctgat 317640
aataatagta caaacagttt catttcattt aacagttatt tgatgaactc ctgtgtgcta 317700
ggaactgtta tttaaaaaaa gtaactttta ttttaggttc aggggtacat gtgcaagttt 317760
gttatatagg taaactcatg actcggggct tggtacacag attattttgt cacccaggta 317820
ctaagcatag tacccaacag tatttttttt tccgaacctc tcctcctctc accctccctc 317880
acgtaggccc agtgtctgtt gctcccctct ttttgtccat gtgttctcat tatttagctc 317940
ctacttataa gtgagaatat gcattatcag gttttctgct tctgtgtcag tttgctaagg 318000
ataatggtct ccaattccat ccatgttcct gaaaaggaca tgatctcttt ctttgttttt 318060
atggctgcag tgtattccat ggtgtatatg taccacattt tcttcatcca gtctaccatt 318120
ggtggacatt taggttgatt ccatgtcttt actattgtga atagtgctgt aatgaacata 318180
cgcgttcatg tgtctttatg gtagaacgat atataatcct ttgagtatat acccagtagt 318240
gggattcctt ggttgaatgg tagttctgtt tttagttctt ttagttctgt gtgtgaaaac 318300
acaccagaga acaaaattga ccagatctct gccttcacag aacgttcatt ctactgtacc 318360
agttatttca tgaggaatat gaatactgtt attactctct gcccatttca cacatgaagg 318420
°agcagaaatg gagcagagtt tactaattta tctgttgcag atagtagcta attgtgtgcc
318480
aggtgctgtt ccaagcattt tacccctgtt aactcagctg agtgctttta ttttccccat 318540
tgtatgccca acttatggat gacagcactg aggtagagaa aggttaataa catagaatag 318600
tttagtatta gggaaacaat ttgaattcta ggacactttt actgaaactt agcataggct 318660
aaagaagtga tcgtgcatgt ttaaagagtt gtatcatttt atcattattt gactttcttt 318720
tccaaaaaaa acaacccttc tcctttctct ctcttccatg tgacaaatac atgtctgtat 318780
acatacatat atatataaat ataaatatat atataaatat atataaacat aaatatatat 318840
atataaatat atatatatat aatttttttt tttgagatgg agtctcactc tgttgcccag 318900
gctggagtgc agtggcatga tctcggctca ctgtaagctc cgcctcctgg gttcatgcca 318960
ttcttctgcc tcagcctccc gagtagctgg gactacaggt gcccgccacc acgcctggct 319020
aatttttttg tattttttag tagagatggg ctttcactgt gttagccagg atggtctcga 319080
tctcctgacc tcgtgatccg cccacctcgg cctcccaaag tgctgggatt acaggtgtga 319140
accaccacgt gcgacccaca tgcctgtata ttacagccgt tgaaggacac aacttttgcc 319200
attgggcgac ccagtcccct agtaagtgtt caaaaatatt cgctattatc attgttggtg 319260
atttcgagga tttggatata attaatttga gcctaatttt ttaagactat tacataacta 319320
tacaaaaaaa tcatgagaga gcctggaatt ttgcaaaact aggatagaaa ccagtttcta 319380
aaaagcattt taaacattca gcttgtgtat ttcttttcac ttgtattttg tgatctgcct 319440
ccatgctttc atgcctttct cttcaaacaa tcttattacc actaaccaaa aacaattaaa 319500
atttgattgt tttgttttgt ttttacatgt tgttacagtt aagaaaaaaa aattctaggt 319560
attgacccct gccagttttc ggagttaata ttaactagtg atttggggct acatttaagt 319620
gctttaagct atcctacaag cttaaagtag tatacatgca aatacttaaa tgaattaggt 319680
acaagaatac agaggtaaga aatagaatct attgtagaat aaatcctatt tcaaatgtga 319740
ctgttttagg atttgaatca accacatatt acagaaaacc ccaagataaa gccttggcat 319800
aaccaagaca aagtttattt ttttctctca cataaaatta gtccagactt attttaccag 319860
tggtatggca actccacagt caaagggacc caagctcatc tgaccttcga ttcccttatc 319920
ctgggacagg cttacattct caaggtcgac tcctggccta atggggctac tggagcttca 319980
gccatcacac tctgtgcttc ctgttatatc tactggtcag aacttcagat acatctgtct 320040
aaaaggaacg ctgaaaatac aatctttaag ctgtgcaatt gtacctggaa taaatgagtt 320100
cttttaataa aaagagttga atggatattt ggtgggcaaa tagcagtcca tgctacaata 320160
$g
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ataaacttca caattttaga attagatatc ttgtaatgaa tattctgacg tggtgtcaac 320220
ttataccata gatagattat aactttgaaa aggaattaga acacaataat aataaattca 320280
cactaaggct cttttgggga aaaaaaatct ctaccattta ttgagtgttt attatcttca 320340
caacatccct atgagttagg gactattttt gtggacattt tacagataaa gaaacagagg 320400
cattgagatg ataactagct tgactaagga gtggcggagc tctgggcagt gtggttcctg 320460
tgtgcccata aggccattgc acaatgctgc ttcatcatgt aattcagaaa gtattccagg 320520
atgtggcagt tggtcatcat gaatgttcat tgttatcttg tggctttgtg aaaaattctg 320580
gtcattcaaa cgatttgact gttgagattc tgtgcacatg agattgtact gtgtacatgt 320640
ttctaaaaat gtatgttata gatcaaaatg cacacactca tttacctcta agaacagttc 320700
ttatattgaa gggaaattat ctgtacatga gagaacaacg tggttttgag tacaagtggt 320760
gaacagacat tgaatagttg ttttcagaaa gcatcactcc cctgtacctc agaacccagc 320820
ctcagtgctg gttgcgagcc aacagctttg atgtcctgaa gtttttgcat cacttctctt 320880
ttgcccctct ttgggattca aagatgataa gtttgaagtg gagttctacc gcttccattg 320940
gaagagaaaa agtttccgtg tgtgtgtgtg tgtgtgtgcg tgtgtgtgtt tacggagagg 321000
agttctatgc atctgcagag ggtgctgcca tcaacaagga gaacagagtg ggatgaaggg 321060
tttgggaagc caggatgggc atctctgacg agctccagaa ctctccacct aagtgtgcaa 321120
gtgtaaacac~tccctgatgt gtgaactggc catctcaaga ctaagtattt agcaggaaat 321180
gccccctatt caacccttgc cttctcaggt gtagaggttg ggttgtctct tccatctttg 321240
tttgaattat gtcattaatc aaccttagtg aaagatcact tagtcatttg tgacagcata 321300
agttcttaat tgttaggaat cactggtgcg gcacacatct ttttctatcc atgaacaacg 321360
tcaaatgctt attttctcat gagcttttat tttttccttt taaaaaaagt ttcttaggat 321420
aaacacagcc tttttccttg tctctccctt gccctctcat ctttttctca atctttatat 321480
tcctatatgt cactgaagag tccccgtgcc aacgctgtgc agtgggaggc tcctacctcc 321540
accagctttt gaggaggttg tagtcctgca accttagagg ttccacagcc aagctggggg 321600
tctttctgga gcatgggtgg tgaatctgag atctatgcac ccaggaagcc tgacacatta 321660
ttgtggtgtc tcaattcttt tttttttaat tagaaaaatt gtatcaaatt gcattgggtg 321720
agagcaaaaa taaactgaag ttggttgagc tttggaagac tacaagccac tgtaatattt 321780
aagatttctt gacctccaga actaacattt gtcctgtcag agaaaataat tactcctgtt 321840
gagaatacat gcattaaagt aagatgttca ctactctata tgatcaccaa acattaaata 321900
atatgtttta cacatgtatg tactatgtgt tcaagtgttt ataaatccat ggagccaata 321960
gaatgtaagt tctatgaggg cagaaatttt aatccatttt gttcctagaa cagttcctga 322020
cacatactgg tgttaggggt aggtcttcag attttatgga tcaaatggaa tctccacact 322080
taaaaaaact tagagaaaaa ctgccttaat gtgcccatag tctggttgga aatggcagct 322140
ccaggttcat tgattgcttt gttcattcgg cacttttcac tggacatgct atgagcccag 322200
cagtgttctg ggtttttggg atacaccaag ccctgcctcc ccggtgctta acattctagt 322260
gggggagaca gaaagaaagc aaacatggtg gacaacttaa ttatctattt ttgaaagttg 322320
acaggaactg tggacaaaag aaaacaagag ctggagacag cagtgccagg gcagggtgag 322380
ggtcaagtta gagtaagcct cattgagaga tcttttgagc aacacctgaa gggggaggtg 322440
agaaagttag ccatgtggag ggaacagcat tccaggcaag tggcccacca agtgcagagt 322500
cctgacagca agagcagttc tggaatattc tagaaacagg aagaagacca atgtgactag 322560
agcagagtga ggcaggagtg agagaaaatg tgatcaggaa agtaaggtcc tgtggccact 322620
aagattttgg cttttattct gaaggaaatg aggactcatt gcaggacttt gagagcatga 322680
tctgacttgt cacaagtgtt ctctttgtct actgggttga gaagacatcc aaagggggcc 322740
aaagattgag gcagggagag cagctaggac aggctctagc aatctaggtg ataaatgagg 322800
accgatggtg gctctgacaa gggtggtaat ggagacatgg tgaggagtga ccacatttca 322860
aatatatctt gaggtagagc tgacaggatt ttcccgatgg gctgggcgta gtatgtgaga 322920
gaaagaattc agttatggat gattattttg tcctgaacaa tgataaaagt tgagtcaaca 322980
actgatatgg ggaagtctac aggtggaaca agtttttgag gaggaaatca gttcagtgtt 323040
ggctatgttg aatttgagat gtttttagac catctgagtg gagaaatctg gagtttagga 323100
gagaggctgg acttgatatg atgttatggg tcctcagcat agagatgatg aatgggatta 323160
gcaaagtagt gagcgtaaaa aggaaaggga aggagaccaa agattgagcc ttgggacagt 323220
cagaaagaag agagggaacc cgcaaaggag attgaaatgg aatccatctc actgtggcat 323280
cgtgaaagac aaatgaagat ggtataagat gaaaaagtga tcagctgtat caaatgctgc 323340
tattgggtca agtagggtga gaattgataa ttttccatct tgtcaagagc agccatgata 323400
gagggagggg gtggagatat acttggaatg agttcatgaa aaaatgggag ggaagggatt 323460
agaagcagca agtataagca gctctttcaa aggagggaga tggggaatgg ctactgggat 323520
gccatcacat agataggaag gtggaaccct gtgcactgga ggagggagtg tcctcacaga 323580
ggaggacagg caggaaggta gagtgggctg ctttgggcac atgtggttct gtggatgttc 323640
tcttttgaca gcttcagttc ttcagggaat tgggagcaag ttcatcagct gagagtgaac 323700
atggggcaga cagtgtgaga ggtcaaagcg gcaagagtag ttgtgccaca gtcttttagg 323760
agagagggaa agtaaatgga atggggaagg aaagtaaata gcatggctgc tgagctgcgt 323820
89
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tacaagccca cccggtgttg ggttgtgagg tgtagttgtg ggctcttctt cagtcggatt 323880
gtcagcatgg gcagctggca gagagttgaa tctgacaggg cagcagttct ggaaaatgag 323940
tatgatgagt caagaaaggg accaggaagt ggaaactgtg tgtgaggcag tgatgctgat 324000
gaatgactgt ggaaaacaat ggaggtgagg agggagtgga tgttgagtgg ctaggggaca 324060
gtgaaaaggg agtaggatcc actagcttgc tgcttgtctc ttataattag gatcaagagc 324120
ttctgccatc ttctaggcat tctgctgctt caagggagtc tctgagattg ggttctgcat 324180
ggatgtattg aaacatgcac ctaggtgtgt ttggagtcct gccagagacc tgctttctct 324240
ttattcttat cctgaggccc tttaggaggc tcagatggaa taatttttat ggtttcttaa 324300
aacccaagtg ggttacctaa gccatcctag ttctgccccc tgttccctga gaggaccacg 324360
ggagcaccct gaaatgggtt ttccactctg ccatccccca cttgcctgct tgggtgttga 324420
cctcagccat ctacacatat cccggatgta gtgttgggcc cctggttgat gtcattcctt 324480
ttcaaatggg atcttttact acagcaatcc agcaacaaac taaatagcga tagagttttc 324540
tttcccttac aaaccacaac cacaaccaag ggaaaaacca aaccaaacca accaaacaaa 324600
caaaacaaaa gtatgtggct tcttaccaca gccccctatc tcgcccaagc cttgtggctc 324660
tttgatctct ggtgttctga aattgcgtaa tcatgtgctt gctctttttc attcattgtg 324720
ctgggcacac acttaatgga ccctttcaag ttggttttct tttatggggt aagggtaggc 324780
aggactattt tttaagattt cttccacttt gtcttccaat tgttctaatg agttttttaa 324840
aattgtgcct gtcctgtttt taaattccaa gagatattct ttgtcctcta aatgtttctt 324900
ataaatatat ataaaatgaa taatataagc atatagtttt gcatagattt gagttcgctg 324960
ttacagtgtc cttttatttc tctgaggata ttcattatag gttttttaaa aaacactttt 325020
tctggtcccc aaattatctc ttctctctag acttcctcca ttcatgcctt ccttcccccc 325080
tccctccctt cctttgctct tgctcttgat tttggaggct tgtcataaat atttgaccat 325140
ccattcattt tttaaccata acgaactaaa aatgttaatt ggagccctgt gtgttccttg 325200
agcagaatgt ttggattaat gagcttccgt gcaatgtttt ctctggaatg gattaatttc 325260
tccagatcta taatttttca atctctttcc agggggtaaa agcctgattg tctgtttcat 325320
gaaagtaaaa atgtgggtaa gagtgatccc agcattcaga atgcagactt agtagctgct 325380
tgttttcagt cctgggactt cacccaccct caccacagtt ggtatcccaa agtgtgaaac 325440
tccttagatt atctttctca agaaaatgaa actcagatat tcgtgtcctt tggccatttt 325500
tgattagctt atttgttttc ttccttttga attgtttgaa ttccttatgt attttgaata 325560
ttaacccctt attagattta tggtttgcaa atattttccc ccactctgtg ggttatcttt 325620
tcactttgtc aattgtttac tttgctgtgc ggaaagcttt ttagtttcat gctatcaaac 325680
taattttgct tttgttgcct gtgcattcaa ggttgtatcc aaagaactca ttgcccagat 325740
caatgtcatg gagcatttct cctatgtttt cttctgatat ttatatagtt tcagtgcttt 325800
tctttaaatt ttaatccatt ttgaatggat ttttaatagg gcataagtgt cacttccatt 325860
tttttatatg tggatatcca gttttcccaa caccatttat taaagaggct gtccgttccc 325920
tattgtgtat tcttggcact tttgttgtaa ataagatgat cttacttgtg tgggtttatt 325980
tctgggcctt ctaatctgtt tcattaattc atgtgtctgt ttttatgcca gtatcacact 326040
gctttgatta caatagcttt ataatatatc ttgaaatcag agagtttgat gcctctagct 326100
ttgttctttt tgctcaagat tgttttggtt aattggggtc ttttgtggtt ccatacagat 326160
ttaaagatta ttttttctat ttctgtgaaa aatggcattg gaaatttgat aggaagtgca 326220
ttgaatctgc agatcacttt ggatagcata gatttttttt aacaataata atttttccac 326280
tccatgaaga ggtatacttt tttcatttat ttttgttttc ttctatttct tttatctgta 326340
ttctgtagtt tttagtattc aggtgtttca cctccttggt tgaatttacc ccaagtattt 326400
tgctgttgtt gctattgtaa atggaattgt tttcttaatt tcctctttgg ataattcttt 326460
attattatat agaaaagcta cagatttttg catgtttatt ttgtatgctt caactttact 326520
gcatttgttt atcagttttt aacagttttt tgataaaagt tttggtgttt tctgtatata 326580
tgatgatgtc atcagcaaac agagacaatt tcatttccct attttccttc tttttttttt 326640
ttgagatgga gtctcactct gtcacccagg ttggagtgca gtggtgcgat ctccgctcac 326700
tgcaagctct gcctcctggg ttcacaccat tctcctacct cagcctcccg tgtagctggg 326760
actacaggtg cccgccacca cgcccagcta atttttttgt attttta~ta cagacggaat 326820
ttcactgtgt tagccaggat ggtctcgatc tcctgacctc gtgatccacc cgcctcagcc 326880
ttccaaagtg ctgggattac aggcatgagc caccgcgccc ggcccctatt ttcttaatca 326940
cgcgatatat acaggcttgt tgaaaaacat gaaaatggta aagaagttta tgtattaaga 327000
ggcaaaagct atgatgttca actcctctaa aaccacttct tagtaggtga acattgttaa 327060
acagttttgt gaatctgctt ccagattttt tctaggcatg ttcatacaca tatacacaca 327120
taatttattt ttacccagtt gcgatcatgt atcatctgat ccaaaactcg ctatttttca 327180
gttaatatgc agtgactgtc tttccaaacc atagtatata tatatatctc taagaatttt 327240
tcaaatctgc tatagttttt aaacatattt attgttacat acatatgtgt ataagttact 327300
tatttgctta tttctttgaa tatctttgtc tagctttgga atcacataaa taatgagtac 327360
aaatggtaaa caaatttcat gtggaaggat atatagaaaa agtacaagtc tctcttctca 327420
tccactctat ctcattacct aaaaggttat ccttagagct ttatataata cacccctgaa 327480
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gtttagatca ttttattgcc tcccaattgt tgagagtaag gaatttagta catatacctt 327540
tcctttcact ttcctaccct ctacctactt aatgagttcg attatagttt ttcagttcac 327600
ccactgttaa ataatatacc tatatttata atatacctat ataatatacc tataataaac 327660
ctatattttt gacttatcaa ctttggacat atctattggt gacttgtgat gagagatgaa 327720
ataatttgta catttaccct tcttttccat tcttttcccc tacccattct cccctttttg 327780
gctaaatgat tgcttttagg ttgataaggt ttataatagc tactgttctg tggttaataa 327840
aatttgtttc atattttatg tgaaatttga ttatacaact agcattcaaa acattattat 327900
gtaaatatta gttactgtaa tcacacagtg acgctcaagg aggtatttac taagcataca 327960
gatcattcct tctggatcca actcagcagt cctttgctgt gccttacctc atctttcgtg 328020
gattcctttt cttttgattg caatatatcc ttgagtaatt tttcagaatc gatatgtact 328080
gtctgaactc tcttataccc aaaaaatttg ctttcacatt tgctaatagt ttgacagagt 328140
ataaaattct gctttcaaat tctttcccct tcatggcttt gaagatactg ccccactata 328200
tattctaaaa tccactgctg ctaatgagaa attctggtgt cagtctgact cttatttctt 328260
tcatatcact tggcattttc ttccgagaaa atattactta tcttcagaat gatgaacctt 328320
ctctatcatg tctctaggtg ttagggcttc tttcatttaa tcctgtaggt cctcaatagg 328380
ctttttaatt aaagtctcat tttattcggg ctctgtgaaa ttttttgtta tgttttggct 328440
tctttttctc ttttgttgtc tctcttttct ccttgaatgt ctttctgata gatatagcat 328500
tcccattatc tatcatgtct ttcagattat cctacatttt tctctttgtt ttctttttct 328560
accatgttta gaattctctt acacgtaaga catcacttac tagatcttca gtcatatcct 328620
ttttattatt cagtctgtgc atttttaatt ttcaattttg gcaaccacat ttttaatttc 328680
taagaatcta ttttgctaat agtacttttg tcctgaaact ttttatatcc tgcaatattt 328740
agaaagagca cacccttatc cacagctgat taggagtaca ctctgaatgc agggcacgat 328800
gggcgaacat tttgttactg gcctcctcaa gcctcaatgc ccagaagtta ttgcctccat 328860
cagaaaccct tcttttgttc tatctctcac ttccaaatga agttccagct taatttttgc 328920
tgtcactgta gtgggacaag caaatcccta tttcacgtga tcattgctca aacctctatt 328980
gacaatcctg ctttgcattc ccttatttag agtgggatgg aaaataaagg ctatgaaggg 329040
ggaagaatct gatcccacca ttctcctttt tcattgcagt tttctcctgt tttatggatg 329100
caataagctg ttgcaatctc tcaggatgga aaagaacatt ttaaaactac tctactgcca 329160
gaatgatctc ttttttttaa ttatactgta agttctggga tacatgtgca gaacatgcag 329220
gtttgttaca taggtatata cgtgccatgg tggtttgctg cacccaccaa cccatcattt 329280
acattaggta tttctcctaa atgctatcct tcgcctagcc cctcacccct tgacaggtcc 329340
cagtgtgtga tgtttccctc cctgtgtcca tgtgttctca ttattcaact cccccttatg 329400
agtgagaaca tgtggtgttt ggttttctct tcctgagtta gtttgctgag aatgatggtt 329460
tccaacttca tccatgtccc tgcaaaggac atgagctcat ccttttttat agctgcatag 329520
tattccattg tgtatatgtg ccacattttc tttatccagt ctgtcattga tgggcatttg 329580
ggttggttcc aagtctttgc tattgtgaat agtgccacaa taaacatacg tgttcatgtg 329640
tctttatagt agaatgattt ataatccttt gggtatatac ccagtaatgg gattgctggg 329700
tcaaatggta tttctggttc tagatccttg aagaatcacc acgctgtctt ccacaatggt 329760
tgactaattt acactcccac caacagtgta aaggcattcc tatttctcca catcctctcc 329820
agcatctgtt gtttcctgac tttttaatga ttgccattct aactggcata agatggtatg 329880
tcgttctggt tttgatttgc atttctctaa tgatcaggga tgatcagctt tttttcatat 329940
gtttgttggc ctcacaaatg tcttcttttg agaagtgtct gttcatatcc ttcgcccact 330000
ttttgatggg gttgtttttt tttcttgtaa atttgtttaa gtaccaaaaa cagatacata 330060
gactgatgga acagaacaga ggcctcagaa ataacaccac acacctacaa ccatctgatc 330120
tttgacaaac cggacaaaaa caagaaatgg ggaaaggatt ccctatttaa taaatggtgt 330180
tgggaaaact gactagccat atgcagaaaa ctgaaactgg accccttcct tacaccttac 330240
acaaaaatta actcaagatg gattaaagac ttaaatgtaa gacctaaaac cataaaaacc 330300
ctagaagaaa acctaggcag tacaattcag gacacaggca tgggcaaata cttcatgact 330360
aaaataccaa aaagcaatgg caacaaaagt caaaattgac aaatgggatc taattaaact 330420
aaagagcttt tgcacagcaa aagaaaccat catcagggtg aacaggcaac ctacagaatg 330480
ggagaaaatt tttgcaatct atccgtctga caaatggcta atatccagaa tgatctctat 330540
tttatttttt atgacatatt aatcatgttt gttctcttgt gtcctctctt tctttctctc 330600
gattttccag tggtccacgg tggtctattt gtagggttca tatttacaaa tgggagtcaa 330660
ggtgactcca ctacagttat gtgaaaaagt ttccctgcca tgcctctccc tacactgggc 330720
gagctgatct ggttccgggt cagtggatgg agcatttcct ctcgcaggca caccttcagg 330780
ctggtgggag caacttgggc catggactgg aaccatgtca atggagaaga cttcctctgt 330840
gccaggtcct ggtcagagct gccgtcttga tttatttgta tccctctttc cgtctgtggt 330900
aaagatctgg aggttcttaa gctctctctg gcctcaaaac ccacagcagg aaatttcctc 330960
actcagatca cccacatttt tagcaagcag agcttcagtt ttgagtggag ggcaggagta 331020
ttgggcagta gggaaggaca cagttctcta cgccgttctg aatgcagtgc attaataaac 331080
tctcttcaca gttgctccag ggtgctttgc attggtgaac ttctggcttc caggaagaac 331140
91
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ctggttacct ctgatgtgtt gggttgttgt tccatctact ctaaattctg tgccaatcca 331200
tcccatctgt ttcctaccat tggtttattt ttaaaaaata ttttatattt atgtagattt 331260
atgaacttga ttattatacc atcattagag tttgggtcca gagtcaaact tctataaacc 331320
tgtaatcaaa aattggcctt tattttcatg tagaaggaag tagcagacca aaatggagtt 331380
ctatattcca tttttctaaa tgagccattg agatgtagag caagcaagtg cccttttgag 331440
ggaatgtgtg tgtgtgtgtg cacacatgca agggcatttt cccatgtctc ccatccttta 331500
attattccag tagacagtgg gccagcagca ggtggtggca taacttctcc atttgcagtg 331560
ctgtggctgt ggtgggatct gaacaggagg caaccttggc aacagtagga atagaatgtg 331620
gagtcagcag gaagcgcttt tccctcccac ttacctgtct tcttgtagca gacagcagtg 331680
cgggcagctt cggctgactt gcttagcctg tttccattgt gagcataaac accttagacg 331740
ttttttcatt tcaggacact ggagcttgat gaaattaaac tacactcatt gtctcaggca 331800
aatctcctaa tcctattctg tgcttttgtt gttgttgttg ttgttgttag tggtgtgttt 331860
ctctctccac ttcgctttcc ttttaaaaca caacaaattt ttttttttaa ttttaaatga 331920
acttattcat tgcctcccta tgtgtcccct cctttctagt gatattgccg ctgttcattc 331980
ccagctgttc ttgattcttg tacaagactc tttgctgggc ttctgccttc tagacgcttc 332040
accttcccgt tatttcttcc ctctgccccc ggaaaggccc ttaccatggc tctgatgatg 332100
atgacagctg acccttttcc aaggtggaat ccacgtttga ttctctgatc ttgtactggc 332160
ttagcacagt gctcggcatt cagtaaataa ggttaaggaa ggccagtgat atacagtagt 332220
agaaaacagc agttaatgaa ggcttgcttt ctgtcacagg ttcctctcct ccaggactgc 332280
agcatctctg tctttctgtc gtagcataca agatagcatc tctgtctttc tattgcaact 332340
tccaggtgag aagccctccc acaagcatat acaaatttta tggaaacaga caaaaatttg 332400
tagggaagca aataccttca aggttgagtc tttctggtct tctagaaggt aagcttggtg 332460
atggggcagt cacagcccta gtgcttatgg aacttggccc tttggggaca gatctcagtt 332520
aactaaagaa atgctatggc acagagtacc ttgaatctcc tctaatttat gctgtacagg 332580
gaattattca cactttattg ttaataacac attacatggg ggaacaccag acagctgacc 332640
aggactcctg tgcttgaaag cttctgctct tcagcagggc agccagcctc ttctcggttt 332700
agcacagagc ttttattctc ctcgctctct ctaaactcct gttcaagaca gtttccaatt 332760
ctgttgaatt cactcattta cctcatctgt gcctttcccc acctcattct ctccccttca 332820
gagtgcccat ttctgtgttt caaatcccac aaggccaagc ttagatgcta ttatgtctat 332880
gacattctcc acctctatcc caataaaaac ctttgatttc atcttgctgt ttgtatcttt 332940
actctggtat atttcaccca taccagagtt gtttgtggac atgcctgatt tccttcaggc 333000
tgtaggcata tttgattcat ttttgtactc catgagtgcc taacatagca tcttatacac 333060
catagataat taatagatgc ctcttggctg catttgtatt aaatttttac catgtacttg 333120
tcctagctag cagagacttg gggggaaata atgatgactg atttttactt atttatttat 333180
tttttattcc cataggtttt tgaggaacag gtggtgtttg gttacatgaa taagttcttt 333240
agtggtgatt tctgagattt tggtgcatcc atcacacgag cggtgtacac tgtatctagt 333300
ttgtaatttt tttatccctc actcctttcc ctccctttct cccgagtccc caaagtccat 333360
tgtatcattc ttatgccttt acatacccat agcttagctc ccacttatga gtgagaatat 333420
atgatgtatg gtttttcatt cccaagttac ttcactttga atagtggtct ccaattccat 333480
ccagaaccct caaaaccatg caaaaccatg gaaacaaaac agcctgctcc tgaatgatca 333540
ttaagtcaac aatgaaatca agagagaaat ttaaaaattc tttgagctga atgataatag 333600
cgatacaact taccaaaacc tctgc~gatac agcaaaagca gtgtcaagag gaaagttcat 333660
agcattaaat acctacatca aaaagtctga aagagcacaa atagacaatc taaggtcaca 333720
cctcagagaa ctagggaaac aagaacaaat caaacccaaa cccagcagaa ggaaagaaat 333780
aacgaagatc agagcagaac taaatgaaat tgaaacaaac aacaacaata aaaaagataa 333840
atgaaacaaa aggctgtttt tttgaaaaga taaataaaat ggatataaca ctagtgagat 333900
taaccaggaa gagagaggat ccaaataagc tcaattagaa acgaaacaga agctattata 333960
atcaatacca cagaaataca aaagatatta gaagctacta tgaacatctt tacacacata 334020
aactagaaaa cttaaaggag atggataaat tcctggaaat atacaaccct cctaggttaa 334080
gccagaaaga attagaaact ctaaacagac caatagcaag cagcgagatt gaaatgataa 334140
taaaaaaaat tgccaacaaa aaaagtccag gaccacacag attcacagct aaattgtatc 334200
agacattcaa agaaaaattg ataccaatcc tactgaaact attccacaag acagagaaag 334260
agggaatcct ccctaaatca ttttatgaag ccagtatcac cctaatacca aaaccaggaa 334320
aggacataac aaaaaagaaa actacagccc aatatccctg ataaatatag atgcaaaaat 334380
ccttaacaaa atactagcta agtgaatcca acagcatatc aaaaagataa tcaactatga 334440
tcaggtgggt ttcataccag ggatgcaggg atggtttaac attcacaagt caataaatgt 334500
gatacaccac atgaatagaa ttaaaaacaa aaatcacatg agcatctcaa tagatgcaga 334560
aaaagcattt gacaaaacct agcatccaat tatgacaatt tttaaatatg gggaatggtc 334620
ttcatggaaa agtagatgtt aatggcacct gtattagggt tctctagagg gacagaacta 334680
ataggataga tgtatatata aaggggagtt tattaagaag tattgactca cacgatcaca 334740
aggttgggtt ccacaatagg ccgtctgcaa gctgaagagc aaggaagcca gtccaagtcc 334800
92
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
caaaacctca aaagcaggga agccaaaagt gcagccttca gtctgtggtt gaaggtataa 334860
gagtcccaaa gctgaagaac ttcacgtcag aaattcgagg gcaggaagca tccagcatgg 334920
gagaaagatg taggccagaa gactaaacca gtctagtctt tccatgttct tctgcctgct 334980
tttattctgg ccatgctggc agctgattag atggtgccca cccagattga gggcgggtct 335040
gcctttccca gctcactgac tcaaatgtta atctcctttg gcaacatcct cacagataca 335100
cccaggagca atactttgca tccttcaatc caatcaagtt gacattacat attaatcatc 335160
acagcaacca aaagattatc tcatttaatc cttacaatag ctctgtgtag tgggtatata 335220
ttttcctttt gctgaagagg aagtaggctt agaggggttg agtaatttgc ccagaatacc 335280
taggtagtag aagatagtag agccattata ttctgtctgc attcaaaaga gtgtgctgct 335340
ttatttgttc ctgaattgca cacaagctaa agaatacaac tggatgttca gtctactcct 335400
attttgataa cttggctaac tttactgcag agtctgcaga ggtgaccaat tttactctgg 335460
gagataccag ggaatccgcc atgtaattcc tcaggctgag tgttttggaa acacaaagct 335520
gtcactgcta ttaagtgatg ttttttcctg agagtctact atgctcccag taccagcctc 335580
cgcaggccct ctgtctaccc cttttctgtc ctgatgtgtt ctagcaggca ctgagaaagt 335640
cattgtagaa gttaccatga ctttccaaat gcttccagaa gcagaacaca atttcacagg 335700
agggccaata agtatgaatg ccaccttgat agaaagtgaa gttttgcgtc ctgttgaaca 335760
ctcagtaaat gcttcctgaa tagatgcagg attggcaaaa catagctccc cagctttcat 335820
aattcagact cagaggccct tcgtgctcct gttattcttg ttacttcatg tcaggtacct 335880
aaaagggttg tttttcagtt ttcgtcattg atttaaagca gaggttagta aactttttct 335940
gtaaaggcca ggtagttagt attttagcct ttgtgagtat ttggtctcac aaaagcagcc 336000
atagatgata tgtaaatgaa tgtgcatggc tgtgatctga taaaacttta tttaaaaatg 336060
aggggtcatc tgggctgtgg tttttcaacc cctgatttaa aacaaaaaca aaatgtgcta 336120
tgcctgttag atgctactac atttgattct gtgttttcca tatttttcta aaatgtactg 336180
aacaggaaat gaacaaactg atgacacaat gatctaattt aatcattgag ataagagtgg 336240
cgccaactct tattgagtat ttgttatgtg tcaggcactt ggctaagcac tttacatgtt 336300
ttctatgatt tataaagcaa atattgttat tatcttcatt tttttgctga gggaaggaat 336360
aaagtcacag ccagcttaca gaggctgccg gaggtcacac atcaccagta cactgaaaca 336420
cgtggtctga ttacaggatc catgatctcc tgtacagatc atagtgatat tgacctgaga 336480
ggaaagagcc taggacttac aatcagaaat ctgggttcac atttcaactc cgttccatgc 336540
caaattacat taaaactggg cctcaccttt cccacctgtg aaagaggaat aatactagga 336600
cttgccctcc caaccttaga gattgctgtg aggataaaag cctatatgaa tgtgctttat 336660
aaactataaa caccatacaa atgtttgtta taagtctgcc atttgaatac atcttagtct 336720
ttttttccta tgtgaaataa aacattttaa gacaagcaat gaaattcttg aaactataac 336780
aggtttttaa gggtgttgat ccccaaagcc gtcttcacta ttttgctccc tctctgactc 336840
gctctgtctc tgcctagcag cgctagtctt ttctacgtgt ttgatctgtt gttcctgtgt 336900
ttaggcccat ccctactaca cagcggaagt cagctatttt ttctctttcc tttgctctgc 336960
tgagcaagat taaactcttt tcacctggac ttttcctaga ttactcaggc tgggtggaaa 337020
tggggtagct gtgaggctgg gatgttactg tacaattcaa atttatgatc tgaacttaac 337080
tagatcttgc tgaagattga cctggctagc acagttttga ggcacctatc tttcagtccc 337140
ttctgtcctc ttggcctggc cactggccac atgttagtag cttacttcta aggatggaat 337200
gccatgcatc tcctacaagg ttgtctctat gcttcacaca aagtaaaaga atggaggcaa 337260
ctttgaatgc tgctcatttt cactcaggca atccctttac aatattgtgc ttagtaaact 337320
ccccccactc tttttttccc ttagcttgtt ttttttttct aataaaagtc tatatcaatt 337380
tgatgtatta gttagggttc tctggagaaa cagaaccagt aggatcaatt gattggtcaa 337440
tcaatcaatc aagacaaaaa gagattcatc tggaaggagt tgattcatgc cattgcggtc 337500
attggctagt ctgaaatctg taaggcaggc tggctgactg gaagctcagg cgggatttct 337560
ctgctgcagt ctcaaggcag aattccgtcc tcttggggaa acctcagtct ttgctcttaa 337620
agctttcaat tgattggatg aggcctacac acattatgga gaataatctg ttttacttaa 337680
agtctactga ttgtaaacat taattatatt taaaaagtac tttcacagca acatttagac 337740
tagtgtttga ccaacaactg ggcaccacgg tcaagccaag ttggcatata gaattagcca 337800
gcaaacttgg tattcacaat ctgtcattat agtcttgtct ataaacctaa ggtttagaga 337860
aacgctggtc attctgaaca attccctgtg aatgcagaga tcaaggagcc tccccttaac 337920
tgggtaggca gtgtgaaata cctgcagtgt gcttgacctt actgttcacc cactggcagc 337980
tgttcctaca gcttggcttc agatatataa tattacattg gctaacttca aagagcattg 338040
ttttccaagg atagagatgg tgatggtgta tattactttt accagcccca gacctgtaag 338100
aggttctcat ctcttttgtt,taagattttg ttgttttttt ttaatgctca ataaaagaag 338160
ctttattctt tcattaaaaa acaaatctca gaagaacagg gaagaagagg gtagcctatg 338220
aaagtgtgat tgttatttga taccatcgtg acttagcttg ttttcaccta agactctgag 338280
attctattct gtttatgtga gatttgggct gagttcaact actatccata ttaactgaat 338340
cataaaacaa ttaatccatc atctggttac attttggtgg ggagggagca tttaacacaa 338400
cactaagcca catatttcac tatttttttt ttttgcagca aattgactta actgcttgct 338460
93
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ttcacaccat gcctataaaa cctttttggt tttagaggtt ctatgtgtct ggaaagtaca 338520
gtgaagtatc tcatcagaat agtattaata tttcttatga catttcatat gtcctgatat 338580
gggttaatgg agaaatatca taagagtagt aattctcttg ctgttattat ttgtcctatt 338640
tagacaaaca gaacatagaa ttaataagaa ttcaaaaact ttaatcactg atagagatta 338700
aatgatgttt atattagtca tcatcaccta atatcttaaa tatttaacct tttatgcagt 338760
gtttgcctct ctacttgggt atgcccttaa cagtaaaaag tgttgataat gctctccctt 338820
ttggcactca cagaattgct atacatatat atgtataaaa tatatgtaaa tataaaaata 338880
catagttaaa aaaataaatc taccactaaa tatagtaagg gagttttaaa ctgaggtttt 338940
tgaagtcttt aagaatttat ttagagactt cttttgttgg aagtatggtg gctagatgcc 339000
atgaaaaacc cactgaaaac aagtgtaagt gctaggtaat atgtt.gaaac atatcttttg 339060
aaatgtatta ctgagctggc aagaaagtat gccattgtag agagtgaaaa taagtgaagg 339120
cagaatcctg ggaggtaagc cagcctgaag atattgatga cactggatgg ccttaagttt 339180
ccattttgac tggcatgtaa tccagccaaa gattcccaca gaaatccgag gttccaaatg 339240
gtaaatccgt ggtgacattg gggtgaccga gaaatgaact ctgtgtagaa aggaatggta 339300
acaacacttg tctcgtacaa ctttggctct gggtagggga aaggaaaaca gcttcctaga 339360
gaaatgttaa ccacaagcta gccctcatga gagatttcag ctaggatgga tgctatctgt 339420
gtagtgcaaa aaaaaaaaaa aaaaaatcca tagccagatt ttgtgcttta atgtggacct 339480
aggtcaatag tgactgcaaa gccagaagca gtggctcacc cctgtaatcc cagcactttg 339540
ggaggccgaa ggaggtggat cgcttgaggt caggagttcg agaccagcct ggccaacatg 339600
gtgaaaccct atatctacta aaaatacaaa aatgagccta gagtggtggt gggtgcctgt 339660
attcccagct acttgggagg ctgaggcaca agaattgctt gaacccagga ggcggaggtt 339720
gcagtgagcc aaaatcgcac cactgcattc tagcctgggc aacagagtga gacaccatct 339780
caaaaataat aataataaaa aaaagtgact gcaggggact gggaagagga aacacaaatc 339840
tttactgggg aatggaattt caagtgtatg caccaaccct tagaaatcac aaaacatctg 339900
acccttctga aaataaccac catgagtgag acagcaggaa aaaaaaaaag aaaaaaaaaa 339960
aaaaacaagg aaagagaggg acaatagaat cagactcata cctacaaaac ttaaaaatta 340020
aataaaatga atcagactca gaggcttcag agtttgattt aaatacatta tacaaaagtt 340080
ctgtgtgaaa tatgtttaag atgtagaagg gtgcttgaaa tgcacaaagt caacagctga 340140
aaaattgacc aagcagatat gaaaataaaa tccaatagag ggcatctgga aataaaaaag 340200
tataataatt atagtgaaaa aagttattag atgggttaat tagtagaatg gatatagcag 340260
aagaaagatt tagtcaactg aaaaatatat ccaaagaata ggtccagaat taagcttagg 340320
gagataaaga gatggtcaat acgaacatta ggagacatgg agaacagtgt acgaaggtgt 340380
aataaattct aactggagtt aaagaggaga tagtaaagag gaagaaaaaa cacaaaactc 340440
aaaaaatgta gtggctgaga atcttccaga agtattgaaa gacaccaatc cacagattca 340500
gaaacctaca atttgcaaga aaaagtaaaa agaatttcac accaagatcc atcttcatgg 340560
actggcagag cataagagat gaagagctta tcttgaaaat gcagccagag agaaaaggtc 340620
tatcgcagtt aaaggaagag gcaagcagat gactgagttc tcaatgccaa ctgaaaatga 340680
gaagccagtg gcacaccttc aatatgttgg gagaatataa ttttcaactt aaaatagtgt 340740
acattgtaaa attacatttc aaaaaaagag ggtagtataa tgacattatc aaataaaaac 340800
cattccttat aacaaatatc actaaagaaa ctgttggagg atgtagttta ggtttctaga 340860
aaggatgtct gatatgcaag aaagaatggt aagtcaaata ttgagaaata tgtgaggaaa 340920
tagaaacaag aataactaat gaatcaatga tactgtctaa tttgaaggtt aaatgattag 340980
gtagaactaa aatatgaaac aataatagta tgtaagtcgg gaggaggagg atgaagcttg 341040
aagtgctcta tgcatcttgc atctctggtg tctttcttgt gtccaaactt tttcttcttt 341100
caaggacacc agttagacta gattagggtc cacctaatga cctcatttta acttatttgc 341160
ctctttaaag gttctatctc caaatacggt cccattttga ggcactaggg gttagggttt 341220
caacgtataa attttggggg gacacattcc agccgatagc aattataaat acaactttta 341280
tagtaaaagc ccatcttcta gaacaggtag agaacaaggt tacttatttt ttttaagaac 341340
aaaattggtt taaattatcc taaaatgatt ttaggagaaa atggacatta aatatacaac 341400
atttcctcct ttattatttt attgatgact tgatatgttt tttaaaactc agtaaaataa 341460
atgattagtc tcataatcat aagagagtta tgcccttatt ttaatgccat aaaactgtga 341520
cttctgaaga aatacaatca tataaaatca tattttaatt tacttttgag aatgtacagt 341580
aactcaggaa ggcagagtgt ggaacctgct ttaatgaata gataagaatg actagcaatt 341640
aaaaattaat tatctataat tcttctgaag ttcttgaaaa taatctcttc taacctgggt 341700
aaatattcct ccttttcaga aatgtttgca atgttgcttt tttttaaatt aatctctttt 341760
tcttagataa tggaacataa atcttaggca catttgcttt gtaaatacca aattgcacac 341820
agattaaaat ttaatgagct tttactgctg taatctcaac aagcagagtc tttgctgttg 341880
gtttttcaat aagaaatact ttattttgtt atacagtggt cattaagaac cttaaagata 341940
atcaggacag attttccaaa ttgcataatg ctattgccta gctatttgca tgtatttttt 342000
ttaaatgaca agacatttcg ttaaatattt acttgcctga cgttgaaaga tttagacaaa 342060
caatgtactt ctagttgtca ctttttcaaa aagattctta gggaaaagtt agccgttttg 342120
94
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ttggttggta agtgatgggt tttcttggaa cgtgttgctt gctaatttta ccagagaaga 342180
aaataaattc aaatggtaag ctacattcca atttgtattc ttcttctaaa gtcctccctg 342240
tttgcattct cggattttga cactcctaca caccagttaa agcacttgtt agagtgtcca 342300
aaaaattgtt gcaattaatt tcccagtctc ttctctcttt gatgtgtcac tataatgctt 342360
tgagtaattt tcagtgtctg gcatctgttc aaggacaatt tctggatttt aggaggggga 342420
gaagcaataa aggaaacaac atatgttttt tcctaaatag gaggcatttt ttgtttgttt 342480
gtttgaacaa aaatcgaaaa ctttcttttc tatataggtg acaaaaagat acacgactca 342540
ttggttgtta actaccattg cattcttttc tctttggagt agcccttaag gaccagatta 342600
gaccagccat ctgcatcatg tagcatgtct gggttacctt tcccaaaaga agttcagata 342660
gatgaacttt gcaaaccaga gccatctgaa gtttgttttt tctttttgag acagagtctc 342720
attctgttgc ccaggctgga gtgctgtggt gcaatctcag ctcaatgcaa cctccgcctc 342780
ccgggttcaa gcgattctcc tgcctcaacc tcccaagcag ctgggactac aggcacgtgc 342840
caccacgtcc agctaatttt tgtattttta gtagagacag ggtttcagca tattggccag 342900
gctggtctca aactcctgac cttgtggtcc acccgttttg gcctctcaaa gtgctgggat 342960
tataggcata agccaccacg cccagtccat ctgaagtttt aaaatggctg caggtatctt 343020
agtaggagac taattttatt ttccaatgat tagaaaaaaa tgaccagacc aagaactcta 343080
gggttatgtt tcatctcata tcctgtgcag gatgttctga gaagtttcta tttgtatctg 343140
tggagtggtt ctagtcttgt tcatcttgca ttttaaggtt tggaggtatt ttatcttgcc 343200
ttgcttcttt accaccttgc tttaatttcc ccctatattg ccatttctaa agtaatgact 343260
cattttcaag ggtgggtctg aaaggaaaga aataataaaa ccagagatct ggagcagttt 343320
ctcgttcatg gtcttattca ctttttaata agagcatcta gaacagtgag tggtgcccca 343380
gcagatatct ggaaattttt gtggaattga attgaatttg ttcttagaat aaatgacaat 343440
aaagaaaata gtattatgga aactttcgac ccaagggaaa tatcaaggct aaagttgcta 343500
tattcttttt cttctgatgg atgctgagtt tttctcctta aaaaacaaat ccacatttaa 343560
acataaggca ttgtttgatg gcctatcaca ttcagtagaa tggatttgag aaatacgtgt 343620
aggatgccta ttaaaaactc tgttttgaaa ttaaacctaa gactataaga ttgtctgttt 343680
aaaaaaatta ttgctgctgt aatttgagca aatctgaact atattgaact ttagaaattc 343740
aaatgtatgc aatcttgtaa tataacttac tccatcggta gacatagttc tttgtcccac 343800
ctggcttcca gcagtttgtc tgtctgtcat taggctaaac tcttcatgtt cctaaacata 343860
ttttcctcaa aaggggacat atttcttggg tcagatgtaa acatcaagct aaggagttct 343920
gctgtgcgtc tagacaaata aggttcattt tcatcctcta catagtgtta aacttgaatt 343980
taagatcaca cagattcctt tacacgttac caatgtaatg atatagacaa tctcacttta 344040
ttcattcact ctgtttaatt cattcaataa aaacgtatac attggctgcc tactgtgtgc 344100
cagttggtga agatataaag atgattaagg caagggtctg tgctgacatg cctaatgggc 344160
aggctgacac acctaaacgc cagggaaaaa gagggatgag acctgggcct ctgaagccct 344220
ggccacctgg ctcgaagctc actttaatgt gcttctgggt gtattccatg actttttaaa 344280
ggcgcttatg tttcctttct ggtaaagcat gtttaacatg caaaatgctt atttcattga 344340
gtagctttta aaaagtgttc atagaatgtc tagaacagtg cttgtctaat agaagtataa 344400
ttcaggtcac gtaggtaata ttaaattttc tagtagccac attaaaaagt aaaaagcaac 344460
aggcaaagtt aatatttttt tttttcctga gatggagtct tgctttgtca cccaggctgg 344520
aatgcagtgg tgtgatctcg gctcactgca agctccgcct cccgggttca agccagtctc 344580
ctgcctcagc ctcctgagta gctgggacta taggcgcccg ccaccacacc tggctaattt 344640
tttgtatttt tagtagagac ggggtttcac cgtgttatcc aggatggtcg ttaattttaa 344700
taatatattc attaatttta ataatatatt catttagtcc tatataaaaa aattagcatt 344760
tcaacatgta atcaatagaa tatattatta gtcaactatt ttgcattctt tgttttgtac 344820
catctttgaa tttcaatttg tattttatac ttacagtgca tctcaatttt aatgctaaat 344880
gtcatcggag atattcgatc tctgtttagc tttaatatat ttttgggttg aaaaagtaaa 344940
ttcacataac caagttcttc caaatatact tgaaagtgtt tctgataact gagttatcaa 345000
cttaaaaatg taagttaatg acaataaatg aaagaaaaat tctgttcctt agctgcactg 345060
accacatttt agtgttcaat agtcgcaggt ggccagtggc tatcatattg gatagtacag 345120
ctttagaatg acagttcagt gcaacaagtg ctataataga ctcatgaact ggaagctccg 345180
ggaagttaag aatgggatca atgaagtggg tcttgaaaaa ccaataaaaa ttcaccacgt 345240
agagaggagg agggcgacta ctccaattca atcttttgaa agcatgtgaa ggagcaacag 345300
tagacttctt taattattta atagtaattt attgaacatg aattatggga ggtgcatggt 345360
gtgggtgctg gtgagacata gttcctgagc tcaagtagct tggtgtctaa atattcatgg 345420
gcccattttt cagaaaggat ggatatgtgt gtgatcctgg gtgtgccaaa tgctgtggct 345480
tcctgaagct tagatttcca gcttgtcacc ttcaaggtta ccttgtgaat aggacttttt 345540
tgagctgtaa gtaaatttac tttgcctatt tatttccaat ggaaaaaaag cttttttaaa 345600
aaataaatct catcttattg cctatgattg gccaagacaa catggcccat acagaaggtt 345660
tttgatggct tctgaggtct gttatcattt gcttattggc atttcagctg tcaaccaggg 345720
ttctgtcaaa ttccattcct gcctttagct cttttacttg aatacctggg gcaatggcag 345780
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
aagtggttgc tatttgtcac ctttccagga tgttagtcgt gtccttgaga caaatagaaa 345840
atttaaagtc agatgacttg attcctctgc cagttaagac ccttagagag tcctcagcat 345900
gttgcttatt tttaaatttc aagtccctgg taaggatcaa gtaaactccc caatttgcag 345960
atttctatcc agttgactat ggattttgcc tgttgctttg tttccaccaa ctctccctga 346020
agatgaggcg cacagacaga caactcacag gcaagaacag cctggtccat cttgaaagat 346080
tctcaagact attctccaca agataattgt ctacttttaa aaatattcag taaagggaat 346140
ttttgctgtt atccttggtt gtgtttttag tatctcatca tccttctagt tgtaggaggc 346200
ttttcctaac atctaaccca tatgtctgtt gtctcatcag gtgtttctat taaggctact 346260
tccccatcaa tcttaatttt ttttttaatc ttctgagatg tataggttaa gttgaaatca 346320
gagactttca taaaatggta agatggccat ttaaatgcaa ctatgaggaa ataatgtaag 346380
caggattcca ttggagaacc aaacactagc aacaactaac ttggtaatca atgttgggac 346440
ttgaagttag gctaaaatca atagtaatgg cactcgtatg tacaaatgca gaacttttta 346500
cacacaatga tttttccctc tgttattata cactagctgt gtctgagtag acagtccagc 346560
tccactacct gcagtccacc ctgggctgtg taatctgagc actgatgggc tgttatttgt 346620
acgtattact tctatgacac tgttttttca tctgtgttag aaatgtcttt ctttcttgaa 346680
taagctgctt caatttctta tagacagatt ctgcttttat gacccttgtt tctacaaagt 346740
aatctctact catgctgaaa tctcagacaa ttttaacaaa tatttagagt acttaatttt 346800
tctttgaatt ctaaatatta tccttcttta gttcaccata gttggatatt ttgagataac 346860
tgtggaggaa acagcactga tcctggggcc atgaaacctg atttcaagat ctagtccctt 346920
ctttaatttt gcacaactaa tttaatcaca ttcatcctta atttcatcat cattaaaata 346980
gcagagaata attcccgttt catggagttg atatgcaatg aaatagcata tcaatgtatg 347040
tatgaatgtc cccccacata gagtactaca caaatgaaac gtgtcactca gcataacgtt 347100
atgtgctcct tcctgcaact ggattgcact ccagtgggat ttcatgctgg tgagatggct 347160
gtgctgctgg acttcatggg acaccaatct ttgaaaataa gcctgatctg gctgggcgtg 347220
gtggcttatg cctgtaatcc cagcactgtg ggaggctgag acgggcggat cacctgaagt 347280
caggagtttg agaccagcct ggccaacatg gtgaaatcct atctctacta aaaatacaaa 347340
aaaattagct gggcatggtg gcatgtgcct gtaatcccag ctacttggga ggctgaggca 347400
ggagaatcac ttgaacccag gagatgaaga ctgtagtgag ccgagattgc gccactgcac 347460
tctagctggg gcaacagagt gagactctgt ctcaaaaaaa aaaaaaaaaa aaatagcctc 347520
taacaaaaaa aaaaaagaaa aagaaaataa acctgatcta tagatgaggc cagtggatct 347580
tgtgaagagt tgaaaggtca ggtatcagtc ttataccatg tcggatgggg caatcgtcat 347640
aactttttaa aaaattattt atttattttg agacagtgtc tcacgctgtc ccccaggctg 347700
gagtgcagtg gcatgttttc ggctcactgc aacctccgcc tcctgcgttc aagcgattct 347760
catgcctcgg cctccctagt aactggatta caggtgtgtg ccaccatccc tggctaattt 347820
tttgtatttt tagtatagac agggtttcac catgttggcc caggctggtc tcgaactcct 347880
gacctcaggt gatccacctg cctcagcctc ccaaagtgct gggattacag gtgtgagcca 347940
ccgtgcctgc cccaattgtt acagcttttt aagtggatta tatgcctgct tcaggcatta 348000
gacataataa gttaatctgt tgataagttt cttcatttct taattttcag ttgtgttttg 348060
atgtgtgtgg tctgggtgag cggctcagtg ctgctgctgt ggagaaggca tgatatggaa 348120
gggatgtgac tgtccttctt catcttcata acggggccag gactggggtg aggtgtgtga 348180
gatgaatgaa gcactggttt tgatacaaaa tttaagaaaa atcaaattca agaggtaata 348240
ttttaatacg atatttgtaa aaaatcaaaa ttagtgcaaa aatttgtgat gagcaaaatg 348300
ttagataaag gcattgttgc ttttcttttt ctgtgtattg taacacacca tcacttagtg 348360
gagaaacagc tctcactttc ctcctcccca gatacaacca tttatgttga attaaacttc 348420
tagttctcct atacctgtga gcatccccca ggccccttgg tatggagaaa gcagtttatt 348480
tgtcttagta agattataaa agtggcaata aaatgtgaat gtaatgaaca aaatgcacat 348540
tttgtggacc aactcgttgt tttagatcta tttttgaaaa ctcattaggt atgtgcatga 348600
ggcaaaataa ttcaagtgca gttggatatt aaatgaaaaa gtgtcaggtc cccttttctg 348660
ccatattctc ttctgtgtct tcattagtgg aaaccatttt gaccagttct tataattcta 348720
atgatttgct gatggctcta attcttggtt tatcaacttc aagcagaatg tcttgacatc 348780
ttggtatgaa agttaaagaa tatgaatcat ttgttctctc ccttctcctt tcctctttct 348840
ctgcctctca gtttttgttg tatgctcacg gagtatgtgt gtgagcatgt gtgtgtgtgt 348900
gtgtgcacgc gagcacgtgt gtgtgtgtgc gcgcccatgg gtccattttt gcatggcagg 348960
ctttgtttta gaaagattgg ttacaacagc tgccccacca atctcctcta cagggaagga 349020
ttcctactct gagaccttgg tcttttccag gcagatcact tacatttcct cacagattat 349080
ttctcatcct gcagcctggg tccaaatggg ctttgctgtg aacagtgact ctcaggcttc 349140
tggtctctgc tgtgcttgag tgtcgttgag atgctccatc tcctcctact gcacccaccc 349200
agcaatcatc tctctttcag gaattcacca aagtcttttt taaaattatt cttttgtttt 349260
gagacagagt cttgctctgt tgcccaggct ggagtacagt ggcgcaatct ccgctcgctg 349320
caacctctgc ctcctgggtt caagtgattc tcctgcctca gcctcctgac tggcagggac 349380
tacaggcatg tgtcaccaca cccagctaat ttttgtattt ttagtagaga tggtgtttca 349440
96
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ccatattggc caggctggtc tcaaactcct gacctcaggt gatctgccgg ggtccatttt 349500
acgtggcaga ctttatttta gaaagatagg ttacgacagt tgctccaccc atcccccctg 349560
cagggaagga gtcctactct gagaccttgg tcttttccag gcagatcact tacctttcct 349620
cacagattat ttctcatcct gcagcctggg tccaaagtgc tgggattaca agcgtaagcc 349680
accacatccg gctcaccaaa gtctttgggt ggttgatgtc atatgcctcc agttgatagc 349740
acttttaaga atttttcctt tttgtatgct gttattattt ttagaaggct tttggattat 349800
tattgttaaa gagtatgcca tgtctatctt ttaactttta agcatctatt gctttgttac 349860
ttgtacttta tatatatgta tatccttccc ccaataagac aaagagtgca aataatcacc 349920
tcccttgcct gttgtttggg tttaattcag gagtcagtgg aattaaaagc ctaaactcag 349980
tatagtttta aagcagcagt ccccaaccct tttggcacca gggactggct ttgtggaaga 350040
cagtttttcc atggaccagt gtgggggctg gaaggtgatt ccaggatgat tcaggtacat 350100
tacattaatt gtgcacttta tttctattat tattacattg caatacataa ggaagtaatt 350160
atacaactta ccataacata gaatcaatgg gagccttgag cttcttttcc tgcaactaga 350220
cggtcccatc tgggggtgat gggagacagt gacagattat caggcattag attatcataa 350280
ggagtgcaca acctagatcc cttgtgtgca cagttcacag taggattcgt gctcctatga 350340
gaatctaatg ctgccactga tctgacagga ggtggagctc aggcagtaat gcgagcaatg 350400
ggagtggctg taaatacaga tgaagcttca cttgcacgtt cactgctcac ctcctgttgg 350460
gcggcccagt tcctaaccag ggttggggac ccctgcttta aagaatatgt ttgtggattc 350520
atagagggaa acaacacaca ctggggcctt tcggagggtg gagggtggga ggaggcagat 350580
gatcagaaaa aatattaata actaatgtgt actaggctta atatctgggt gttgaaataa 350640
tctatacaac aaacccccat gacacaagtt tacctatgtg agaaacctgc acgtgtactc 350700
cagagcttaa aataaatgtt aaaaaattcc ctccaaaaag gatatatttg catcggagtt 350760
atatttgtat atgagtatat atttgtatat ataaatatac ttgtatatga aaaaaatatc 350820
ttttttcttt cattttattt tccaaacatt aaagtcgggc acattggtta ggaatttcac 350880
caatactttt tacaaaactg aggacttgga tgataaaggc actttttaaa agattacaca 350940
ctggcatggg gaataatacc tttataaaga tgatctatgt gttcctgaat atcccgatgc 351000
atctcctagc tggatcttcc gctccacaaa aattcataag atgagattct tgaattagaa 351060
tgcatgcctt aatgtattaa gtctatgtag agagagttat ttagtccatg taaattaagt 351120
gggaatattt ttatttgatt actgttttat ctggatcttg cccacttaag gccttcaaaa 351180
atgaaattta aggcctgtta agcagaccca acatcaacag catattctct ctctcttgta 351240
agtattgtct agttgataaa aaatttcaaa aacatgtctt aatcaaaaac aagatgatcc 351300
agcacaggtt taataaatgt tttgtgaata tggcacattc gtgtctcatt actacagttt 351360
tcctatgctg tctttctcaa taattccccc caaaattgta gtgtttacat tatggcattt 351420
atagttacct ctgaacctaa aaaattaact tcaaaagtat ttaaaaaaat cattatattt 351480
aaaaccattt catgtttaaa tggtttgtac agggcaatga aaggaaatgt agtaataaac 351540
acagaatcag atttggtcac taatattttt ctgcagttga aatatatgta gactggctta 351600
gggtctaaat agcattgaa't cctgttacct tccatctata atcaattaat gtattatgac 351660
attgttgtcc tcagatcact gggatctcat ggtaagtaag taaagggatt attctgtgca 351720
ttttcccaat atctatatta gttttaatat acctttatgt taatgtatga cactgacact 351780
tagtaattgg attaacttcc tatcagaatt tgtttttcac tcatactttg tatacatgtc 351840
ttaagggtag ggtagatgta catttttttc tgtgttagcc tatctgtttc tgtgacacta 351900
catgctttct gtcctccaat ttgtgtttct ttccgtgtac aaatatgcat catctaccat 351960
ctacatctac aaaacatgta ggcttccaat gttttcatgt aaatacattt catgagtcct 352020
cagtagagtg ttagatgagt ggttaattag taatgttaat aaatgtaaat tacaataaaa 352080
acatttataa tgttaataaa tataagttta ttgaacttaa ataatttaaa catcttctga 352140
aatgtagtag aaattatgat tagccataac tagtacagta ttttttgctt gtttaatttt 352200
tttggtgata ttccatttgt ggaatgagtg tgtgtgtgtg tgtgcagtac agacagaaag 352260
gagagaaaca tatctgcatg ttatgttaga aagagtagtg ttagctaccc taccaaattt 352320
acatactggc tgaacacagt atgtaaaaaa ttattttttt agtccattgc tggtgttcct 352380
tgttgttggg tgactctatt ccacatggtg atgcagggaa ccaatctcct tccttctgtg 352440
gctgtgtaat cccttgcaac cttgaagtcc tctgcatcta actttaggat gaggaaagtg 352500
aaggtggagg atatagccct cttgactgcc ttgacctgga cctggaacat ctcttttgct 352560
cccattccat ggggaagaac tagtgacatg gtggcccata gctgcagagg ggaggctgag 352620
aaatgcagcc tctggataag aagcctactc ccagtggtta ctgtacattg tgggagggaa 352680
gcttgaattc tgatggacag tgagaaccat tctccacaca ataacgaaat gacgtcttct 352740
caaccttggc aatgtagcat cctgtgactt aagtatgtaa ataattatca gtacaggtca 352800
gtgaaaaatt aggtcacctt tcccttccac ttttaattct atagtttaat ttgcctatct 352860
gctacatatt atatatatgg gaatagataa gattatctat aaacatgtat aaatttgttt 352920
cctacactaa aaagaaaaat gacaaagaag aattaagtta gttgcccaaa tccacacaat 352980
accaccagga gaaagtctag gaaccatacc ttctaaatcc aggtctacac ttctttagtg 353040
cactaaattt tttcctaata tagctctgag gagactggtg tttaagagga gaatgttaag 353100
97
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
ccaaaagccc atttcacttg gctctgtaca gacagtaagt taatttccag gatgtataac 353160
tcctgatttt ctgtgatgac agagaaaata ctgacctgat ttgggtaact ctgaggtttg 353220
gagatcttga atagcctcat gttcctgaac ttctttacca tacatgaatt acttcttagg 353280
aagaaacatt tattctgtag aatttggttt cgcattttat ttttattttc ttagacactg 353340
gtagttggaa attcaggaag aatttgacta caaaaaacat ttattaaaaa gagtttctaa 353400
tctcacctgc taagtgctac aaggaaaaaa aaaaatacat tttgagccct caaggggctc 353460
caaatacggt tgaaggaaaa ttagacccag aatagtatat gattaggaac aaaacgatgg 353520
cagagaaatg agagtttaga gaaaggagag ataatcctga gttaccttag gaagagaaaa 353580
tttcacagag aaaacggccc ccacactgat ttggggaaga tgattcagac ttgtctcaat 353640
ggcatgagga gcaggggcca gatgggaaag gacatcgtgg tggaaatgac acgatgagca 353700
gaagcttaga agtacttctg cttcacgtct gtgattctgc ctctcccctt gtttctgcag 353760
tgctaagttg agtgtagttc cccacacaaa ccctgagctt tcttcccctc caggctgctc 353820
catcagtcag acaggagtgc cttctcaggg gatcctcttc ctcatcttat cgggccactc 353880
atctcgtcgc agacattccc atactcctgg ttgacttgct cttccctctt tttaactgac 353940
atgagcaggc atcacctctt ccaggaaact tccctgacac caggctgagt ctctctggtg 354000
tcggggaagg cttctgtatt actgcatctg ccattttgat ttaaggtttt ctgctcattc 354060
caactcaaca gtgagctctt tgagggcaga aattgtgtct tattcatttt tcttgttatg 354120
ccctaaaaat gtattgtgat aatatataag taacgtacaa tttaccattt tcacctcttg 354180
aagtgtatag ctcagtggcg ttaagtgcat tcacactgtt gtgcaaccat tatcaccatt 354240
catctccaga actttctcat catcccaggc aaactctgta tccattacac aatagctctc 354300
catttcctcc tgccctcagc ctcaggaaac ctcccatcta ctttctcttt ctacgcgttt 354360
aactactcat atagatggaa tcatccaaca tttttccttt tgtgcctggc ttatttcact 354420
tgacataatg ttttcaaggt tcttttatgt tttcttatgc gtttttatat ctctctatct 354480
ttgatagcac ccaatacata gaagacaatg aatgtttttg tgagtgaaaa cataagacca 354540
gaaagaaata ggatgtcata ttctagggac actcaagaca ctttcttgag gacagaggca 354600
ctgtagcttg gaatttggaa gatgaggttg gcaaggtggg tggggaaagg atggaaaagt 354660
gatacgtttc ttgaagcatg tggatttgct tccataagca gtggtggacc agtgggcacc 354720
cttatctatt aaaagaatga ttttttttgt gactcgtgta gagcactgtc ttagttacct 354780
accccagtgg tagataagag aagcggatta aaaagagatc tgaacctgag gaaatggaga 354840
ctaccaagtt ttttgtaaat atgtctgtta taacatatat tatctagtac ttgcgatgcc 354900
tgtgccaaag catgcttttt ggtttagtta agcctactta gctcgctaat ttcagtaatt 354960
ttggcttgaa ttgcaaaaag ttgatggggg agatggggga gtctctgaca tccttccccc 355020
actcacaggt ttgaaaaata aaattatgaa gagcaaaagg atctttttct gtggtaaatt 355080
gtacttcatg acaataaacg agttgtggtt ttagtggtta atttataaat taggccatct 355140
ggttcttctg taatctaaag atttttatat atatgtaaaa tacaaagttg tcctgggcaa 355200
ctgccaatct ataaaggaga aaacatcttg aactctgtgg agataataaa accatattca 355260
gctgccaaag tgctgctgac atactgtcca atgagacacc caacgccttt gcattacagc 355320
cagcaaggtg tggagctaga tgtattgatc tatttaataa tattagcttc tcttctctgg 355380
gtcggacttg gcccagagca agtgaacagg acctatctat ctccttctca aaagtcacag 355440
ctttcttacc aaattgtaca actcaagcca caaagaaaac aagtcaagga aaggaccaga 355500
ggagcacgag ggcacatgcc ttgttcccag accctgggac cagctccagc tctggctcct 355560
tgcagatccc gctcttctca agttctctgg ctttgatcct agttttctgc cctactattc 355620
ctgacatgta cagcacttag caattcataa cttgctttat taaccaatat ctcaacagaa 355680
cttttaaaca acctgggagg aagcagagtg ggtgttactg tcctcattgc acagataatg 355740
aaactgaggt tcagaaaggt tgagtgtctt gcccaaggcc acacggcttc ttagtggaga 355800
agccaggatc tgcaccaatg tcttccattg gacacactgc cacttaatat ggtacttagt 355860
ttttctttct agatgaagca gtatgaggaa ttctaccatg gatatctctc tctatttttt 355920
taaactgcaa aataatgata atgataataa tgaatacttc tagaatacag tctctatgcc 355980
aggcactata tgctttatat gtactaactt gcttaattct cctaacaacc ctagaaggta 356040
gttactaata ttatcactat ttttaaatgg ggaaactgag ttacagagat ggtaaataag 356100
ttgcccaagg tcacagaggc agccagatta gtgacaaaag tttgagagta ctcagtttga 356160
attttacatg ttccgtggat atggtttatg ccaaatacct tctcctttct agacctcagt 356220
ttcctcatgt atcaaacaag tggactgcac tatacaactc tgaggtccct tctagcctga 356280
agattagagt cttttatgcc cacatgatat ggaaaacatt aatgctggct ctttaagact 356340
ggaaccttgt catttaaaaa aataagctct actaaatttg cagtaaactg tccaaatacg 356400
atctctggtc tctgatttgt atctctcaca gagcatgata caatgctaga cacatatata 356460
ctcattaaaa acttgctgaa ttaaattgta aaacattcct ccagatagac cgtaagggtg 356520
agctgatgcc ctaatatgct cctcagctgc tgacttagga cccgtgggtg acaaaccctg 356580
tccttgttgt tccatctgtg acagtgggca gtgtccaaaa tgagtctctt catcaaaagt 356640
gagtccagga aactggatca gagtaagtaa ggagtcttcc ttgcttcttt ttctctaaaa 356700
tacaatacag tgcattctag caaactacca gcatgcctat aaatctcatt ttaaaaatat 356760
98
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
caggaaatag atgctcattg ataaagaggg taagaatgag caagggagag agtcaagcct 356820
gtacatttgt gcttagggta ttttcatttg agaaattatc attggaaaga tcaatttcca 356880
aggcaggcgt tttgtcttga cttaataaac taatctttat caataataat taaataatgt 356940
cattttccca gatacaaagg ggaaaccata atgcctttca tatgccttct catatcttca 357000
gtgtttctca aacccagctg tggggtcttt ttagggaaga tacaaggagg gtgagaccat 357060
gtggagcaca cactcagcag ccactgtgaa gtcatgggtc ccttgctacc tttggaagct 357120
gacaatctgc atgaaaagca gcccctagga acatgggtag tggcccggga tccaaaactc 357180
ctgaatccat aaaagggctt ttgacttctt gttccaggac aagtgacatc tgacatgctt 357240
gcctgcttgt ttgcctttct tccttctcct atccgtcttt ccatccatct gtccatcagt 357300
ctatctgtcc atccagtcat ccatccatcc ttccatccat tcgtctattc atccatccgt 357360
ccttccatcc atccatccaa gatttattga gcacttacat gacaggaagt atgagacaca 357420
aaagaaaatt ctacacaatt ctcctaggga catgaactaa tggttagcaa aaatatatgg 357480
gaagtcctgc ttcaagtaaa attatgactt aagatataca tcagatattt gaaaaagata 357540
tttttaagtt caacattgaa attctaacta cattgtgtcc ttaatttcta ttttctagtt 357600
agactttttt gaagatacaa atcatttgaa ttatcattat tattgttact tgattttatt 357660
tattccacat gaatggtaag aattttaaag gaaggtgggt gccctaaaaa tacatttatg 357720
ccaactggat tgaatcacct tgaatcacaa tgagtacaac aactgctaat gagctaacac 357780
ttaatgagta atgaccaggc accagacact gttctagcac tttatactta ctgatttctt 357840
tactcttcat gataacccta tgaggaaagt gcttttttgt taagctccat tttcagctga 357900
agaagctgag gcctggagaa gttacatagc tttctcatgg tgtctccact atgaagtagc 357960
tgagctgaga tctcacccaa ggccctgctg ggttcaggcc acactcttaa gtactcacag 358020
ctgcatcaca ctgaatatca tctccctgca ctgccatttc atttgagcag ggctttgcct 358080
gtcaagaaca ttcatatctt ttgataaaca gtgcattttt tccctgatag tctgtatggg 358140
acagcctcct tgtttgcatc tgaaggacag ggacttcagg acctcctgct gtggtcacca 358200
aggaatcaca ttcaaacttc tcagcaaggt gttatggtcc ttctcagttt gcctacgatc 358260
cattgaggca aaggtttcct tctctcaata caccctctgc tttagccagg gggacctccc 358320
actgtcctct ctatgtgttc tatttgttcc tgactgttag tacccgcttg tgtggtttcc 358380
atgatccttc ttctgcctgg aatgaggctc ctcttgagtc ctgagagctt catttctgtc 358440
tgtcttttgg gctgtgccaa agcccctctg ccttcgtgga ctccccactg attcattacc 358500
aattttcctc tcctctgggc tcttcttaga ttgcaaatgg tgcctctgga ttgggtacca 358560
agacttgcag tgccttattt tgataccact aatatgagac catgttatat gcctcttgag 358620
atatcattcc ctttctagca atagacagtg ataagcatgc gtatagaggg taaacgtagg 358680
actttgaggt tcatccatct caatagacaa aagtaaaagt atgctaattt caatccttca 358740
cacagtaaat tgaatgtaat aggtcttcag taactatttg aggaatgaaa ttgttattga 358800
tatattgatt taactgagca aatccataag tgccacgctt ggagtaaagt acagggaatc 358860
tcattttttg ggtaatttca aacaagtagg agaccatcca ctatctatta aggacaaagg 358920
agatttgagt gacaaacatg ttccagacca tccaatggtg ttattctact acttcatccc 358980
agctagtaaa atggggcaat aagaaccaaa aagcaggtac tgtccctatg taagtagact 359040
tcctagtcct ggccaaaaca aaaacaaaaa aaaaacaaag caacacaaaa caaaaacaat 359100
gtgtgaagag catcttaccg ttcattgctt tggatgattt gtgcaaatct agttaatggg 359160
ggtggatctg atcagtcttt gtaggaagtc agtattggca tatgtctggc ttctgaattt 359220
tctaaaaata taattattta tttttaaatc cattcaatca acactgaatt tactaatcaa 359280
ctactaaata agtaaaagat cctatagtag atccttcaag aaatggaaat tgagacatta 359340
ggtcactata aaccccaacc cttgtaatct ttttgtggca accttaggaa acttggaatg 359400
ctttttacac tctgataaag gtttaattgt aatcatagcc ccagtgttgc aaaatgagtc 359460
agaagataca aagtatctca taggataata ttatagctgt aggtacttca aatggacaag 359520
tataacacat tatgactgct aatatggatg cattgggagg aaaataagcc ctaagaagca 359580
atatgcagaa aagctatgat tgctggagac agatagatcc aagaacctag gtaatttttc 359640
agcaaactgt ggttccactt tcgcctcttt cttgacattg actgtgtttt taacagggaa 359700
aaagttatct gaaatttttg atagagttca aactttaaat cgtgttcact ttgctaaaac 359760
tccactggat ggagtggcag aagagaaaaa acacagaaat aaaagaaaag cagtaatgga 359820
gaatggaaaa tctttaaaga tgctaccatc ctgaaaagat tcgaaagcaa gcccaggaaa 359880
gccacgggga gggaaagagc gcttagaggt gtccccaaag ctttcagaag tgatgaggga 359940
aaccccagct cttcttgtta cttcttggca ttttgttcct ctatacgtta gcttttggtt 360000
aatctttcat gttacttatt atctctgttt taaaatttca cattaactca ttggtttcat 360060
atcccactta acaaattaga tattttcctt gggcttatta agaaaattat ttgctctcat 360120
atgttatggc tttagatttt ctgtgtagct aggactgttc ttaaattttt atctttacct 360180
ttgttatttc tctgaagcat ccccattggg gtggcagtgg ggggtattaa atggttatgt 360240
aaaatttaca tgtaattgtg caatttacac atagcctcaa atataatgag gcctagtcta 360300
gctgcccata ccaagaggat attatagttg ccaataaaat cagtattatt tctttttttt 360360
ttctgttctt ttttagcttc ttgcaaacat tcactcagaa tcctttttga atatcagttt 360420
99
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
tgtgaaaagc accgtgctgg gttctttggg aaaagccaag atgagggcaa atgcatcctc 360480
cttcctagtg agtctagcac acagatgact caggaagtca tgcactggag gaggagtatc 360540
ttctagaact ggggaaaggt taaggaaggg atcagaaacc tttttcactc aaccaattac 360600
attttcctga aagcatgtta ttaatcgtac atgatcttgc agaccccaga tagagactat 360660
atcactatat caattgtttt cttgaacaac tggagttaat tctcatatgt ttggttaccc 360720
ttcaagtatt tatgtttagg atctgttttc ttcctcttaa cttacattcc aaagtttagg 360780
tatccttccc ctccatttgc tgtccaaaac agcatccttt catgtagcta catgccattg 360840
gaatgatttg gtttttgcca tggattccta gtcctaaatt tggactttta ttggtatcta 360900
agatgtcatg gacagaaccc acagatgttg tacaaaaagg gctgagtgga cagtccaaca 360960
gagttacatc atctgttcca aacacccttg taatggttgt atcagcgtca atgtctgagt 361020
tgctgtcctg gttctcctgg ccagtcctca gctggccatg cctgttcagg caccagagaa 361080
agcttcatac ctcaggcaaa tctttacaag ggatttgaaa ggcaagaaac atgtattttg 361140
gaggttttac ctgtttattt catgtatagc ttcatatt~aa cagattttgc tatcacttaa 361200
aagtaaataa aatgattttg atttctcaaa atcatcttat aatttattaa tctattttaa 361260
ggcttgcatt tacatttaat cttcaaatct tgatgcattt tcacagagtt tctttagtta 361320
gttaaggata ttaatgactt cctttaatag ttgatgaagt gagtcatcat cgacagtgag 361380
tcactaaggc caactcttgt acctgctctt aaatagcagt tgttttacta gatttgtact 361440
gaaacctttt taaaaatctg tttgtcttat atataacaag catttccagt agttaataat 361500
actttcttag ctcttcaatc attttatgag agcattacaa gaaaagcagg agatggggaa 361560
agagatatct tgtttgccat gtaggatgca tgaaattctt acttagtctg ttgtgttttg 361620
gattcgagag aaaatatgta atgaatcaaa atgtttccta cagtcctctg aaaagatgta 361680
atgagacagt cttccagcag cctttgatca tctgggaagt cattgacttt gatccttatc 361740
ctatcagggg ctcttaccct ggggtccata aatacccagg catttttaag aagtggattt 361800
cagtataact tgtttcattt tgtgattttt aaaaatattt tgttttatgc acttaaaacc 361860
ttaatctgag aagtcatctg tagactatac cagatttcca aatggaataa aaatatttaa 361920
gaactctctt atgtgtgtgt ttcaacctat aaattttata tgtgtagctc atggttaggt 361980
ggtaagtaga gaatttgcta tctgtgtaat atttggtact ttttataatg aaaaaggaag 362040
taatacaatg ataggtacca tttatttgtt gaccacccat attttccagg gaatgtgata 362100
gatacttttt atatattctt tctagttttc accataacat gctgcaggga tagtgttacc 362160
attctcattt tgcagatgaa gaaattgaaa cccagaacaa ttcgttcatt cattcaaaaa 362220
atatccatag agcatacact aagagaaggc actctgctag gcaccagaaa ttgaataatt 362280
gaccccaaat cacctaactc ataagtggca aagctggacc taacaaagcc cattatccct 362340
tctatcacac attccatcct cataatatca tattctacat agaaaaactt aacagtcctg 362400
ttgagacact tggaactcta agaaggtagt caacagatac ttttctcttt atataaatat 362460
gatatctaat tagcttttcc tggaaaggag tgattctgcc tttttttaat tctagcattc 362520
cctgagcaaa ttagagccca ggtaatgatt tcctgagata agtcaattct cttctaggac 362580
aatctctagt cttgtcatca tgagatggaa taacaacggt ctatgtcatt tcagtgacgg 362640
cacctgcatg tccttgtatc taagaaaaga cacctccttc tctgccttgc taaatatttg 362700
taaactttgc tttaattggt atatgtgcca ctgttttgta tgtgggaggg gtttatggtt 362760
ttgttttgtt ttttggtctt ttttagtaac cccaatccaa actattctca tttgtaacct 362820
aaaatactta gaacaagagg ctttgcaatc ttgaagaccg aatacatttt tactactaaa 362880
tgtaaggcag atttgagcca cccattttgt agtgcttgat tatggcaacc cgaggaaact 362940
aatacggtta ctctttatct ttattaggaa atactgctgt agttcctgtt gtaatcctta 363000
gggagccaac attgttgatg agacctagta ccaagccaga ggccatgttg aactagcaag 363060
atatgggata gtttttactt tcaaagtaat tagcatctag agtctagaga gtttctctta 363120
cagggtggcc tggtgtctta gtctattttc tgttcctata atagaatacc tgagactggg 363180
taatgtacaa attataaaga tttgtttgac tcacaatcct agaggctggg aggttcaaga 363240
tcagacagcc acatctggcc atcctttaat gagggcctca tgctgtgtca taacacagca 363300
gagaattgga aggagaaatg ggcacatgca aagagaaaga aaggggacga aaggggctaa 363360
ctcactttgt aactatgaga ctaatccatt ccctggagaa ctaatttatt ctcatgagaa 363420
agacatgaat acatcttaac atcctaatca cttcttaaag gcctcaactc tgtacactgc 363480
tacattgtaa caggcaatta aatttcagca tgagttttgg tggggacaaa ctacatccca 363540
actgtagtac ctagctaccc actttatttt tagagtggct atttaatgac ctggcaagat 363600
ctactgtgct tgtaaaagaa tccaccatgg gttaaagaaa aatagtttct ggcttccagt 363660
ctccttttgg cctctctcta gaatggcata tacaagttca gtggttactg acttcaaagg 363720
tggggtggaa gacactgaaa tgaatttttc tcctttcttt ggttggttgc tctctctctt 363780
tgttgctgaa atttgtgtag gataatggaa tgaatatggg agatagggaa ctatagaaag 363840
actggaggga agggagaagt cttttctgaa ttaacccccc atgtgcttgt gagacccttg 363900
gaccccaaag ggctcctgac tggctgggcc cactccttct gtatatggag ccatagggct 363960
tttctctggc ttcccagttg aagcattgtc atatgctttg atgctcagca tttctggcaa 364020
ttttaccttg taaaactccc gtttcgacat tctgaactta agtagaaaat gggaatataa 364080
100
CA 02426405 2003-04-17
WO 02/34945 PCT/USO1/25990
gcctcttgtt ttttgctctt aatccattcc agaactataa gtccctgggt tcttggcaac 364140
aacaggtgtt cctctagatt ttaaatcaag tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg 364200
tgtgtggaat atctcactaa aacgacagtg ttgtcatcaa ttttggcttc atggagggtc 364260
ttgagctggg tggagatggg aggaagctat ccttgtccat gcggtttgga gacttgctct 364320
aaaaaagaga ccgtctactt ccctcgtagt ttttgttttg aagacatttg tagtgtttac 364380
caggagcata cagttatctg gaaaatgcag actgatgaca atagtatttg aaatgctcgt 364440
agatctgctt ctaggttgat ggaaagaatg tatgttccaa ggtacaagtg cttgttgact 364500
tttcggatgc agccagtctg tgctctttgt caggtaactc ggaatcactc cacagtagct 364560
gtccttcctg tccatttgac aagcacttaa aagggcagtc ttaagtactt tacttcatag 364620
tttattaatt ttttcccttc tttagtttgc aatctactct cagaaactga aaaataattt 364680
cttttacctt tttccccttt ctcatttaag ctgaaattga tttctttctg agcgtgtaag 364740
gaaaaaaata aaaagaagct gtggttaata caattgcctt tgctgaacaa aaataaaaga 364800
ctagtttacc ttcaagctgt gctgtatcag agtaaggatc tgttctgtca ctcccaggag 364860
attttgataa gagagagtac aaaatttcat aatatctaca tagcataatt gtagcaaata 364920
taagaagtat tataattgtt tatttgggga tgagggtggg gatgggtttt tttgtgtgtg 364980
tttggaaaat tgggaagcta gaagatactc ttaaatccat cagcttcttc agaactcttc 365040
tcaaatgctt attgtcatga caaccatctc ttcataaacc aaggctctga gtgtaataca 365100
gatggggctg gtaacaaggt aggattgcca tctgctttgt tttctctaag ggacattatt 365160
tttttgtgat ccccaagtct catcctcaaa tctgaaagtc ttgacttatt tttctttctg 365220
gagtcagata gagctgtgag attaattctt ttctcctgac aaactacttc ctcacctgtc 365280
atcaaacaac ttacttgtta aatggaggga aaaaagggta attatgtgtg tgtgtgtgtg 365340
tgtgtgtgtg tgtgtgaaaa caaatataca tattttaatg atttatttat ctgtctactt 365400
tgcaaagtct cctatgaggt acctagtaat tcaataatac agtcaagtgt gagatccaga 365460
aacaagtagg agtgaggcaa tcattttccc atgaaacaag taaaattatt actgcttttg 365520
aacattttaa cacctgtgct tcctgatggt ggggctgcat gaagtttgta agtagtgtca 365580
tcattctctt attaggtaac aaataggagc ataattattt aggagaggaa aaccttttct 365640
tgttaccaaa tttggtgaga aatttgccaa agaaatgaat gcttacagga gggatacagc 365700
ttaatatctt catactcccc tttgtcaaag atacaaatga cattttctca tatcaacttc 365760
ctacaaaaag tgaggccata catttttaaa aagaatatac ccagtatttt aaaagtttgt 365820
atatatcgtg atcagaatta agatatatcc agcttttgaa aaaatataca tatttagcca 365880
ttaaaaggta tgtggtaaac taaactgatg aataaaggtt atgggaaata tttcataaaa 365940
tttatattta aagtaaagaa caatttctct ctttgtatta tagttatttt acataagcta 366000
caatctataa ttctaaacct taatttcttg aagggcttta taagcctcat ttttctttct 366060
aaatagagaa gttcatacac tgcttttatg tcctatatgt tgatgtgtaa aaataatcaa 366120
atactagtgg gtgagtagaa tgtaactaca atatggtaca cacacagaca cacaggatga 366180
ctaaactgtg cacatgagct gatgtccaga gcagggaaaa gctgctaaag aatgtttgaa 366240
gtagagtcag aatgcagttt tgtggttaag accaataatt tttcaaagga gcattataag 366300
gagtgtggtt acttgggttg gagttgaaaa ccaagcaaca gttgggcaga cttgaaacca 366360
gttttgtctt taggtttctt ttcttaatga ttggtctaca atgagttagc cactcatcgt 366420
atttaaggtc ttggtaaagg agagactttc tttgccatgt agtttatacc tcatgtatgc 366480
attacagtag agagctccag gaaatactgc aggccttcta ctggttttta tcctctattt 366540
agataaaaat gaggaagaag tagaattatc ataaacaatc ctgttggctt ttagttgaga 366600
tatactacag aaacatcacc tttgaatctg tatatgtaaa aaaaaaaaat ctcagagtaa 366660
gatataagtt ctgttgcatt gttctgaagg aatgggtaat gtcagaaatg tcttcattac 366720
attacataaa gtaatacaca gtgctgttat cagattgcat agtcaaagtt ggcaagtttg 366780
catatttaca tagatatcat gaccttcatc attcatactt ctttcaagaa atggtcatct 366840
taatatgggg tatttatttg aggcatacac catttatttt aagaagcagt acctttgttt 366900
attgtaaaac ttctggacta aattcttcaa ttttttctca aatgaattca gttttttgtt 366960
ttttttctta ccactggttt ttactgcata gcgtttgcct gaagaacacc actttgtttc 367020
ccaaggcaag tagtcactac aaggcgagtt ttgttctgtc tatcccaagg caaatagaca 367080
gcagcaaaca tagtgtggag ggctgctggg ttcagtagaa aaccatcaac tatttctaat 367140
tgggggtgta tgaagacagc tgcattctgg acatgctaaa catcttgaaa tgcttggagt 367200
gtaataaaac cccaaacgtg ctttcttttc tcatttcttt gcacatgtat tttaggcaaa 367260
atataatcca catgctgttg ttccctctcc ttttaaatca tgaaaaatgt tgtttttata 367320
gggctatttg aggtccagga tgccttttta tcctttttat taggttattt ttatatataa 367380
atgaaaagaa aaacataaac agaaaataca acatgacatc atgaatgagg gcaagcacaa 367440
actgcccaat ttaagtttga agttataaac ctaaaatatt ttaaaacaaa acatttctct 367500
tggtgttttg caaaagtaat gctttcttct attgggcaga aattgcagcc tgttgggatg 367560
aaggagagaa tagaactaat atttattgag tagctaccat ggctttctgg gacatctgct 367620
aa~ccccttaa tttttacagt aaccctaagt ggtaggccag tccatctgca ttttacagac 367680
aggaaatgct ttcagagata ttaattagat ggctgtagac cacagaagaa ttgaaagtca 367740
101
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