Note: Descriptions are shown in the official language in which they were submitted.
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 7
~~ TTENANT LES PAGES 1 A 239
NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des
brevets
JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME
THIS IS VOLUME 1 OF 7
CONTAINING PAGES 1 TO 239
NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
Human Secreted Proteins
Field of the Invention
The present invention relates to human secreted proteins/polypeptides, and
isolated nucleic
acid molecules encoding said proteins/polypeptides, useful for detecting,
preventing, diagnosing,
prognosticating, treating, and/or ameliorating diabetes mellitus and
conditions related thereto.
Antibodies that bind these polypeptides are also encompassed by the present
invention. Also
encompassed by the invention are vectors, host cells, and recombinant and
synthetic methods for
producing said polynucleotides, polypeptides, and/or antibodies. The invention
further
encompasses screening methods for identifying agonists and antagonists of
polynucleotides and
polypeptides of the invention. The present invention further encompasses
methods and
compositions for inhibiting or enhancing the production and function of the
polypeptides of the
present invention.
Background of the Invention
Over the past few decades, an increasing percentage of the population has
become
diabetic. Diabetes mellitus is categorized into two types: Type I, known as
Insulin-Dependent
Diabetes Mellitus (117DM), or Type II, known as Non-Insulin-Dependent Diabetes
Mellitus
(N117DM). )DDM is an autoimmune disorder in which the insulin-secreting
pancreatic beta cells
of the islets of Langerhans are destroyed. In these individuals, recombinant
insulin therapy is
employed to maintain glucose homeostasis and normal energy metabolism. NIDDM,
on the other
hand, is a polygenic disorder with no one gene responsible for the progression
of the disease.
In N)DDM, insulin resistance eventually leads to the abolishment of insulin
secretion
resulting in insulin deficiency. Insulin resistance, at least in part, ensues
from a block at the level
of glucose uptake and phosphorylation in humans. Diabetics demonstrate a
decrease in expression
in adipose tissue of insulin-receptor substrate 1 ("IRS1") (Carvalho et al.,
FASEB J 13(15):2173-8
(1999)), glucose transporter 4 ("GLUT4") (Garvey et al., Diabetes 41(4):465-75
(1992)), and the
novel abundant protein M gene transcript 1 ("apMl") (Statnick et al., Int J
Exp Diabetes 1(2): 81-8
(2000)), as well as other as of yet unidentified factors. Insulin deficiency
in Nll~DM leads to
failure of normal pancreatic beta-cell function and eventually to pancreatic-
beta cell death.
Insulin affects fat, muscle, and liver. Insulin is the major regulator of
energy
metabolism. Malfunctioning of any steps) in insulin secretion and/or action
can lead to many
disorders, including for example the dysregulation of oxygen utilization,
adipogenesis,
1
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
glycogenesis, lipogenesis, glucose uptake, protein synthesis, thermogenesis,
and maintenance of
the basal metabolic rate. This malfunctioning results in diseases and/or
disorders that include, but
are not limited to, hyperinsulinemia, insulin resistance, insulin deficiency,
hyperglycemia,
hyperlipidemia, hyperketonemia, and diabetes.
Numerous debilitating diabetes-related secondary effects include, but are not
limited to,
obesity, forms of blindness (cataracts and diabetic retinopathy), limb
amputations, kidney failure,
fatty liver, coronary artery disease, and neuropathy.
Some of the current drugs used to treat insulin resistance and/or diabetes
(e.g., insulin
secratogogues - sulfonylurea, insulin sensitizers - thiazolidenediones and
metformin, and alpha-
glucosidase and lipase inhibitors) are inadequate due to the dosage amounts
and frequency with
which they have to be administered as a result of poor pharmacokinetic
properties, the lack of
effective control over blood sugar levels, and potential side effects, among
other reasons. Diabetes
Therapeutic proteins in their native state or when recombinantly produced
exhibit a rapid in vivo
clearance. Typically, significant amounts of therapeutics are required to be
effective during
therapy. In addition, small molecules smaller than the 20 kDa range can be
readily filtered
through the renal tubules (glomerulus) leading to dose-dependent
nephrotoxicity. Therefore, there
is a need for improvement in treatment (e.g., a need for prolonging the
effects of therapeutics of
diabetes and/or diabetes related conditions).
Summary of the Invention
The present invention encompasses human secreted proteins/polypeptides, and
isolated
nucleic acid molecules encoding said proteins/polypeptides, useful for
detecting, preventing,
diagnosing, prognosticating, treating, and/or ameliorating diabetes mellitus
and conditions related
thereto. Antibodies that bind these polypeptides are also encompassed by the
present invention; as
are vectors, host cells, and recombinant and synthetic methods for producing
said polynucleotides,
polypeptides, and/or antibodies. The invention further encompasses screening
methods for
identifying agonists and antagonists of polynucleotides and polypeptides of
the invention. The
present invention also encompasses methods and compositions for inhibiting or
enhancing the
production and function of the polypeptides of the present invention.
2
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
Detailed Description
Polynucleotides and Polyneptides of the Invention
Description of Table 1A
Table 1A summarizes information concerning certain polypnucleotides and
polypeptides of the invention. The first column provides the gene number in
the application for
each clone identifier. The second column provides a unique clone identifier,
"Clone )D:", for a
cDNA clone related to each contig sequence disclosed in Table 1A. Third
column, the cDNA
Clones identified in the second column were deposited as indicated in the
third column (i.e. by
ATCC Deposit No:Z and deposit date). Some of the deposits contain multiple
different clones
corresponding to the same gene. In the fourth. column, "Vector" refers to the
type of vector
contained in the corresponding cDNA Clone identified in the second column. In
the fifth column,
the nucleotide sequence identified as "NT SEQ ID NO:X" was assembled from
partially
homologous ("overlapping") sequences obtained from the corresponding cDNA
clone identified in
the second column and, in some cases, from additional related cDNA clones. The
overlapping
sequences were assembled into a single contiguous sequence of high redundancy
(usually three to
five overlapping sequences at each nucleotide position), resulting in a final
sequence identified as
SEQ )D NO:X. In the sixth column, "Total NT Seq." refers to the total number
of nucleotides in
the contig sequence identified as SEQ >I7 NO:X." The deposited clone may
contain all or most of
these sequences, reflected by the nucleotide position indicated as "5' NT of
Clone Seq." (seventh
column) and the "3' NT of Clone Seq." (eighth column) of SEQ ID NO:X. In the
ninth column,
the nucleotide position of SEQ >D NO:X of the putative start codon
(methionine) is identified as
"5' NT of Start Codon." Similarly , in column ten, the nucleotide position of
SEQ )D NO:X of the
predicted signal sequence is identified as "5' NT of First AA of Signal Pep."
In the eleventh
column, the translated amino acid sequence, beginning with the methionine, is
identified as "AA
SEQ >D NO:Y," although other reading frames can also be routinely translated
using known
molecular biology techniques. The polypeptides produced by these alternative
open reading
frames are specifically contemplated by the present invention.
In the twelfth and thirteenth columns of Table 1A, the first and last amino
acid position
of SEQ >D NO:Y of the predicted signal peptide is identified as "First AA of
Sig Pep" and "Last
AA of Sig Pep." In the fourteenth column, the predicted first amino acid
position of SEQ )D
NO:Y of the secreted portion is identified as "Predicted First AA of Secreted
Portion". The amino
acid position of SEQ ID NO:Y of the last amino acid encoded by the open
reading frame is
identified in the fifteenth column as "Last AA of ORF".
SEQ >D NO:X (where X may be any of the polynucleotide sequences disclosed in
the
sequence listing) and the translated SEQ >D NO:Y (where Y may be any of the
polypeptide
sequences disclosed in the sequence listing) are sufficiently accurate and
otherwise suitable for a
3
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
variety of uses well known in the art and described further below. For
instance, SEQ ID NO:X is
useful for designing nucleic acid hybridization probes that will detect
nucleic acid sequences
contained in SEQ ID NO:X or the cDNA contained in the deposited clone. These
probes will also
hybridize to nucleic acid molecules in biological samples, thereby enabling a
variety of forensic
and diagnostic methods of the invention. Similarly, polypeptides identified
from SEQ ID NO:Y
may be used, for example, to generate antibodies which bind specifically to
proteins containing the
polypeptides and the secreted proteins encoded by the cDNA clones identified
in Table 1A and/or
elsewhere herein
Nevertheless, DNA sequences generated by sequencing reactions can contain
sequencing errors. The errors exist as misidentified nucleotides, or as
insertions or deletions of
nucleotides in the generated DNA sequence. The erroneously inserted or deleted
nucleotides
cause frame shifts in the reading frames of the predicted amino acid sequence.
In these cases, the
predicted amino acid sequence diverges from the actual amino acid sequence,
even though the
generated DNA sequence may be greater than 99.9% identical to the actual DNA
sequence (for
example, one base insertion or deletion in an open reading frame of over 1000
bases).
Accordingly, for those applications requiring precision in the nucleotide
sequence or
the amino acid sequence, the present invention provides not only the generated
nucleotide
sequence identified as SEQ ID NO:X, and the predicted translated amino acid
sequence identified
as SEQ ID NO:Y, but also a sample of plasmid DNA containing a human cDNA of
the invention
deposited with the ATCC, as set forth in Table 1A. The nucleotide sequence of
each deposited
plasmid can readily be determined by sequencing the deposited plasmid in
accordance with known
methods
The predicted amino acid sequence can then be verified from such deposits.
Moreover,
the amino acid sequence of the protein encoded by a particular plasmid can
also be directly
determined by peptide sequencing or by expressing the protein in a suitable
host cell containing
the deposited human cDNA, collecting the protein, and determining its
sequence.
Also provided in Table 1A is the name of the vector which contains the cDNA
plasmid. Each vector is routinely used in the art. The following additional
information is
provided for convenience.
Vectors Lambda Zap (U.S. Patent Nos. 5,128,256 and 5,286,636), Uni-Zap XR
(U.S.
Patent Nos. 5,128, 256 and 5,286,636), Zap Express (U.S. Patent Nos. 5,128,256
and 5,286,636),
pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600
(1988); Alting-Mees, M.
A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Aping-Mees,
M. A. et al.,
Strategies 5: 58-61 ( 1992)) are commercially available from Stratagene
Cloning Systems, Inc.,
11011 N. Torrey Pines Road, La Jolla, CA, 92037. pBS contains an ampicillin
resistance gene and
pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the
Lambda Zap
4
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express
vector. Both
phagemids may be transformed into E. coli strain XL-1 Blue, also available
from Stratagene
Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained
from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All
Sport vectors contain
an ampicillin resistance gene and may be transformed into E. coli strain
DH10B, also available
from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59
(1993). Vector
lafmid BA (Bento Soares, Columbia University, New York, NY) contains an
ampicillin resistance
gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR~2.1,
which is available
from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an
ampicillin resistance
gene and may be transformed into E. coli strain DH10B, available from Life
Technologies. See,
for instance, Clark, J. M., Nuc. Acids Res. 16: 9677-9686 ( 1988) and Mead, D.
et al.,
BiolTechnology 9: (1991).
The present invention also relates to the genes corresponding to SEQ >D NO:X,
SEQ
)D NO:Y, and/or a deposited cDNA (cDNA Clone )D). The corresponding gene can
be isolated in
accordance with known methods using the sequence information disclosed herein.
Such methods
include, but are not limited to, preparing probes or primers from the
disclosed sequence and
identifying or amplifying the corresponding gene from appropriate sources of
genomic material.
Also provided in the present invention are allelic variants, orthologs, and/or
species
homologs. Procedures known in the art can be used to obtain full-length genes,
allelic variants,
splice variants, full-length coding portions, orthologs, and/or species
homologs of genes
corresponding to SEQ m NO:X and SEQ >D NO:Y using information from the
sequences
disclosed herein or the clones deposited with the ATCC. For example, allelic
variants and/or
species homologs may be isolated and identified by making suitable probes or
primers from the
sequences provided herein and screening a suitable nucleic acid source for
allelic variants and/or
the desired homologue.
The present invention provides a polynucleotide comprising, or alternatively
consisting
of, the nucleic acid sequence of SEQ ID NO:X and/or a cDNA contained in ATCC
Deposit No.Z.
The present invention also provides a polypeptide comprising, or
alternatively, consisting of, the
polypeptide sequence of SEQ )D NO:Y, a polypeptide encoded by SEQ )D NO:X,
and/or a
polypeptide encoded by a cDNA contained in ATCC deposit No.Z. Polynucleotides
encoding a
polypeptide comprising, or alternatively consisting of the polypeptide
sequence of SEQ 1D NO:Y,
a polypeptide encoded by SEQ )D NO:X and/or a polypeptide encoded by the cDNA
contained in
ATCC Deposit No.Z, are also encompassed by the invention. The present
invention further
encompasses a polynucleotide comprising, or alternatively consisting of the
complement of the
nucleic acid sequence of SEQ )D NO:X, and/or the complement of the coding
strand of the cDNA
contained in ATCC Deposit No.Z.
5
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
Description of Table 1B (Comprised of Tables 1B.1 and 1B.2)
Table 1B.1 and Table 1B.2 summarize some of the polynucleotides encompassed by
the invention (including cDNA clones related to the sequences (Clone )D:),
contig sequences
(contig identifier (Contig )D:) and contig nucleotide sequence identifiers
(SEQ ID NO:X)) and
further summarizes certain characteristics of these polynucleotides and the
polypeptides encoded
thereby. The first column of Tables 1B.1 and 1B.2 provide the gene numbers in
the application for
each clone identifier. The second column of Tables 1B.1 and 1B.2 provide
unique clone
identifiers, "Clone )D:", for cDNA clones related to each contig sequence
disclosed in Table 1A
and/or Table 1B. The third column of Tables 1B.1 and 1B.2 provide unique
contig identifiers,
"Contig D7:" for each of the contig sequences disclosed in these tables. The
fourth column of
Tables 1B.1 and 1B.2 provide the sequence identifiers, "SEQ >D NO:X", for each
of the contig
sequences disclosed in Table 1A and/or 1B.
Table 1B.1
The fifth column of Table 1B.1, "ORF (From-To)", provides the location (i.e.,
nucleotide position numbers) within the polynucleotide sequence of SEQ >D NO:X
that delineates
the preferred open reading frame (ORF) that encodes the amino acid sequence
shown in the
sequence listing and referenced in Table 1B.1 as SEQ ID NO:Y (column 6).
Column 7 of Table
1B.1 lists residues comprising predicted epitopes contained in the
polypeptides encoded by each of
the preferred ORFs (SEQ >D NO:Y). Identification of potential immunogenic
regions was
performed according to the method of Jameson and Wolf (CABIOS, 4; 181-186
(1988));
specifically, the Genetics Computer Group (GCG) implementation of this
algorithm, embodied in
the program PEPT)DESTRUCTURE (Wisconsin Package v10.0, Genetics Computer Group
(GCG), Madison, Wisc.). This method returns a measure of the probability that
a given residue is
found on the surface of the protein. Regions where the antigenic index score
is greater than 0.9
over at least 6 amino acids are indicated in Table 1B.1 as "Predicted
Epitopes". In particular
embodiments, polypeptides of the invention comprise, or alternatively consist
of, one, two, three,
four, five or more of the predicted epitopes described in Table 1B.1. It will
be appreciated that
depending on the analytical criteria used to predict antigenic determinants,
the exact address of the
determinant may vary slightly. Column 8 of Table 1B.1 ("Cytologic Band")
provides the
chromosomal location of polynucleotides corresponding to SEQ ID NO:X.
Chromosomal location
was determined by finding exact matches to EST and cDNA sequences contained in
the NCBI
(National Center for Biotechnology Information) UniGene database. Given a
presumptive
chromosomal location, disease locus association was determined by comparison
with the Morbid
Map, derived from Online Mendelian Inheritance in Man (Online Mendelian
Inheritance in Man,
OMIMTM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins
University
(Baltimore, MD) and National Center for Biotechnology Information, National
Library of
6
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
Medicine (Bethesda, MD) 2000. World Wide Web URL:
http://www.ncbi.nlm.nih.gov/omim/). If
the putative chromosomal location of the Query overlaps with the chromosomal
location of a
Morbid Map entry, an OMIM identification number is disclosed in Table 1B.1,
column 9 labeled
"OMIM Disease References)". A key to the OM1M reference identification numbers
is provided
in Table 5
Table 1B.2
Column 5 of Table 1B.2, "Tissue Distribution" shows the expression profile of
tissue,
cells, and/or cell line libraries which express the polynucleotides of the
invention. The first code
number shown in Table 1B.2 column 5 (preceding the colon), represents the
tissue/cell source
identifier code corresponding to the key provided in Table 4. Expression of
these polynucleotides
was not observed in the other tissues and/or cell libraries tested. The second
number in column 5
(following the colon), represents the number of times a sequence corresponding
to the reference
polynucleotide sequence (e.g., SEQ )D NO:X) was identified in the
corresponding tissue/cell
source. Those tissue/cell source identifier codes in which the first two
letters are "AR" designate
information generated using DNA array technology. Utilizing this technology,
cDNAs were
amplified by PCR and then transferred, in duplicate, onto the array. Gene
expression was assayed
through hybridization of first strand cDNA probes to the DNA array. cDNA
probes were generated
from total RNA extracted from a variety of different tissues and cell lines.
Probe synthesis was
performed in the presence of 33P dCTP, using oligo(dT) to prime reverse
transcription. After
hybridization, high stringency washing conditions were employed to remove non-
specific hybrids
from the array. The remaining signal, emanating from each gene target, was
measured using a
Phosphorimager. Gene expression was reported as Phosphor Stimulating
Luminescence (PSL)
which reflects the level of phosphor signal generated from the probe
hybridized to each of the gene
targets represented on the array. A local background signal subtraction was
performed before the
total signal generated from each array was used to normalize gene expression
between the
different hybridizations. The value presented after "[array code]:" represents
the mean of the
duplicate values, following background subtraction and probe normalization.
One of skill in the
art could routinely use this information to identify normal and/or diseased
tissues) which show a
predominant expression pattern of the corresponding polynucleotide of the
invention or to identify
polynucleotides which show predominant and/or specific tissue and/or cell
expression.
Description of Table 1C
Table 1C summarizes additional polynucleotides encompassed by the invention
(including cDNA clones related to the sequences (Clone )D:), contig sequences
(contig identifier
(Contig 1D:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and
genomic sequences
(SEQ )D NO:B). The first column provides a unique clone identifier, "Clone
1D:", for a cDNA
clone related to each contig sequence. The second column provides the sequence
identifier, "SEQ
7
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
ID NO:X", for each contig sequence. The third column provides a unique contig
identifier,
"Contig >D:" for each contig sequence. The fourth column, provides a BAC
identifier "BAC ID
NO:A" for the BAC clone referenced in the corresponding row of the table. The
fifth column
provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of
the BAC clone
identified in column four of the corresponding row of the table. The sixth
column, "Exon From-
To", provides the location (i.e., nucleotide position numbers) within the
polynucleotide sequence
of SEQ 1D NO:B which delineate certain polynucleotides of the invention that
are also exemplary
members of polynucleotide sequences that encode polypeptides of the invention
(e.g., polypeptides
containing amino acid sequences encoded by the polynucleotide sequences
delineated in column
six, and fragments and variants thereof).
Description of Table 1D
Table 1D: In preferred embodiments, the present invention encompasses a method
of
detecting, preventing, diagnosing, prognosticating, treating, and/or
ameliorating diabetes mellitus;
comprising administering to a patient in which such treatment, prevention, or
amelioration is
desired a protein, nucleic acid, or antibody of the invention (or fragment or
variant thereof)
represented by Table 1A, Table 1B, and Table 1C, in an amount effective to
detect, prevent,
diagnose, prognosticate, treat, and/or ameliorate the disease or disorder.
As indicated in Table 1D, the polynucleotides, polypeptides, agonists, or
antagonists of
the present invention (including antibodies) can be used in assays to test for
one or more biological
activities. If these polynucleotides and polypeptides do exhibit activity in a
particular assay, it is
likely that these molecules may be involved in the diseases associated with
the biological activity.
Thus, the polynucleotides or polypeptides, or agonists or antagonists thereof
(including antibodies)
could be used to treat the associated disease.
Table 1D provides information related to biological activities for
polynucleotides and
polypeptides of the invention (including antibodies, agonists, and/or
antagonists thereof). Table
1D also provides information related to assays which may be used to test
polynucleotides and
polypeptides of the invention (including antibodies, agonists, and/or
antagonists thereof) for the
corresponding biological activities. The first column ("Gene No.") provides
the gene number in
the application for each clone identifier. The second column ("cDNA Clone
ID:") provides the
unique clone identifier for each clone as previously described and indicated
in Tables IA, 1B, and
1C. The third column ("AA SEQ >D NO:Y") indicates the Sequence Listing SEQ >D
Number for
polypeptide sequences encoded by the corresponding cDNA clones (also as
indicated in Tables
1A, 1B, and 2). The fourth column ("Biological Activity") indicates a
biological activity
corresponding to the indicated polypeptides (or polynucleotides encoding said
polypeptides). The
fifth column ("Exemplary Activity Assay") further describes the corresponding
biological activity
and provides information pertaining, to the various types of assays which may
be performed to test,
8
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
demonstrate, or quantify the corresponding biological activity. Table 1D
describes the use of
FMAT technology, inter alia, for testing or demonstrating various biological
activities.
Fluorometric microvolume assay technology (FMAT) is a fluorescence-based
system which
provides a means to perform nonradioactive cell- and bead-based assays to
detect activation of cell
signal transduction pathways. This technology was designed specifically for
ligand binding and
immunological assays. Using this technology, fluorescent cells or beads at the
bottom of the well
are detected as localized areas of concentrated fluorescence using a data
processing system.
Unbound flurophore comprising the background signal is ignored, allowing for a
wide variety of
homogeneous assays. FMAT technology may be used for peptide ligand binding
assays,
immunofluorescence, apoptosis, cytotoxicity, and bead-based immunocapture
assays. See,
Miraglia S et. al., "Homogeneous cell and bead based assays for highthroughput
screening using
flourometric microvolume assay technology," Journal of Biomolecular Screening;
4:193-204
( 1999). In particular, FMAT technology may be used to test, confirm, and/or
identify the ability of
polypeptides (including polypeptide fragments and variants) to activate signal
transduction
pathways. For example, FMAT technology may be used to test, confirm, and/or
identify the
ability of polypeptides to upregulate production of immunomodulatory proteins
(such as, for
example, interleukins, GM-CSF, Rantes, and Tumor Necrosis factors, as well as
other cellular
regulators (e.g. insulin)).
Table 1D also describes the use of kinase assays for testing, demonstrating,
or
quantifying biological activity. In this regard, the phosphorylation and de-
phosphorylation of
specific amino acid residues (e.g. Tyrosine, Serine, Threonine) on cell-signal
transduction proteins
provides a fast, reversible means for activation and de-activation of cellular
signal transduction
pathways. Moreover, cell signal transduction via phosphorylation/de-
phosphorylation is crucial to
the regulation of a wide variety of cellular processes (e.g. proliferation,
differentiation, migration,
apoptosis, etc.). Accordingly, kinase assays provide a powerful tool useful
for testing, confirming,
and/or identifying polypeptides (including polypeptide fragments and variants)
that mediate cell
signal transduction events via protein phosphorylation. See e.g., Forrer, P.,
Tamaskovic R., and
Jaussi, R. "Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and
p38 Kinase
Activities" Biol. Chem. 379(8-9): 1101-1110 (1998).
Description of Table 1E
Polynucleotides encoding polypeptides of the present invention can be used in
assays to test for one or more biological activities. One such biological
activity which
may be tested includes the ability of polynucleotides and polypeptides of the
invention to
stimulate up-regulation or down-regulation of expression of particular genes
and proteins.
9
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
Hence, if polynucleotides and polypeptides of the present invention exhibit
activity in
altering particular gene and protein expression patterns, it is likely that
these
polynucleotides and polypeptides of the present invention may be involved in,
or capable
of effecting changes in, diseases associated with the altered gene and protein
expression
profiles. Hence, polynucleotides, polypeptides, or antibodies of the present
invention
could be used to treat said associated diseases.
TaqMan~ assays may be performed to assess the ability of polynucleotides (and
polypeptides they encode) to alter the expression pattern of particular
"target" genes.
TaqMan~ reactions are performed to evaluate the ability of a test agent to
induce or
repress expression of specific genes in different cell types. TaqMan~ gene
expression
quantification assays ("TaqMan~ assays") are well known to, and routinely
performed by,
those of ordinary skill in the art. TaqMan~ assays are performed in a two step
reverse
transcription / polymerase chain reaction (RT-PCR). In the first (RT) step,
cDNA is
reverse transcribed from total RNA samples using random hexamer primers. In
the
second (PCR) step, PCR products are synthesized from the cDNA using gene
specific
primers.
To quantify gene expression the Taqman~ PCR reaction exploits the 5' nuclease
activity of AmpliTaq Gold~ DNA Polymerase to cleave a Taqman~ probe (distinct
from
the primers) during PCR. The Taqman~ probe contains a reporter dye at the 5'-
end of the
probe and a quencher dye at the 3' end of the probe. When the probe is intact,
the
proximity of the reporter dye to the quencher dye results in suppression of
the reporter
fluorescence. During PCR, if the target of interest is present, the probe
specifically
anneals between the forward and reverse primer sites. AmpliTaq Fold DNA
Polymerase
then cleaves the probe between the reporter and quencher when the probe
hybridizes to the
target, resulting in increased fluorescence of the reporter (see Figure 2).
Accumulation of
PCR products is detected directly by monitoring the increase in fluorescence
of the
reporter dye.
After the probe fragments are displaced from the target, polymerization of the
strand continues. The 3'-end of the probe is blocked to prevent extension of
the probe
during PCR. This process occurs in every cycle and does not interfere with the
exponential accumulation of product. The increase in fluorescence signal is
detected only
if the target sequence is complementary to the probe and is amplified during
PCR.
Because of these requirements, any nonspecific amplification is not detected.
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
For test sample preparation, vector controls or constructs containing the
coding
sequence for the gene of interest are transfected into cells, such as for
example 293T cells,
and supernatants collected after 48 hours. For cell treatment and RNA
isolation, multiple
primary human cells or human cell lines are used; such cells may include but
are not
limited to, Normal Human Dermal Fibroblasts, Aortic Smooth Muscle, Human
Umbilical
Vein Endothelial Cells, HepG2, Daudi, Jurkat, U937, Caco, and THP-1 cell
lines. Cells
are plated in growth media and growth is arrested by culturing without media
change for 3
days, or by switching cells to low serum media and incubating overnight. Cells
are treated
for l, 6, or 24 hours with either vector control supernatant or sample
supernatant (or
purified/partially purified protein preparations in buffer). Total RNA is
isolated; for
example, by using Trizol extraction or by using the Ambion RNAqueous(TM)-4PCR
RNA isolation system. Expression levels of multiple genes are analyzed using
TAQMAN, and expression in the test sample is compared to control vector
samples to
identify genes induced or repressed. Each of the above described techniques
are well
known to, and routinely performed by, those of ordinary skill in the art.
Table 1E indicates particular disease classes and preferred indications for
which
polynucleotides, polypeptides, or antibodies of the present invention may be
used in
detecting, diagnosing, preventing, treating and/or ameliorating said diseases
and disorders
based on "target" gene expression patterns which may be up- or down-regulated
by
polynucleotides (and the encoded polypeptides) corresponding to each indicated
cDNA
Clone >l7 (shown in Table 1E, Column 2).
Thus, in preferred embodiments, the present invention encompasses a method
of detecting, diagnosing, preventing, treating, andlor ameliorating a disease
or disorder
listed in the "Disease Class" and/or "Preferred Indication" columns of Table
1E;
comprising administering to a patient in which such detection, diagnosis,
prevention, or
treatment is desired a protein, nucleic acid, or antibody of the invention (or
fragment or
variant thereof) in an amount effective to detect, diagnose, prevent, treat,
or ameliorate the
disease or disorder. The first and second columns of Table 1D show the "Gene
No." and
"cDNA Clone 1D No.", respectively, indicating certain nucleic acids and
proteins (or
antibodies against the same) of the invention (including polynucleotide,
polypeptide, and
antibody fragments or variants thereof) that may be used in detecting,
diagnosing,
preventing, treating, or ameliorating the diseases) or disorders) indicated in
the
corresponding row in the "Disease Class" or "Preferred Indication" Columns of
Table 1E.
11
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
In another embodiment, the present invention also encompasses methods of
detecting, diagnosing, preventing, treating, or ameliorating a disease or
disorder listed in
the "Disease Class" or "Preferred Indication" Columns of Table 1E; comprising
administering to a patient combinations of the proteins, nucleic acids, or
antibodies of the
invention (or fragments or variants thereof), sharing similar indications as
shown in the
corresponding rows in the "Disease Class" or "Preferred Indication" Columns of
Table 1E.
The "Disease Class" Column of Table 1E provides a categorized descriptive
heading for diseases, disorders, and/or conditions (more fully described
below) that may
be detected, diagnosed, prevented, treated, or ameliorated by a protein,
nucleic acid, or
antibody of the invention (or fragment or variant thereof).
The "Preferred Indication" Column of Table lE~describes diseases, disorders,
and/or conditions that may be detected, diagnosed, prevented, treated, or
ameliorated by a
protein, nucleic acid, or antibody of the invention (or fragment or variant
thereof).
The "Cell Line" and "Exemplary Targets" Columns of Table 1E indicate
particular cell lines and target genes, respectively, which may show altered
gene
expression patterns (i.e., up- or down-regulation of the indicated target
gene) in Taqman
assays, performed as described above, utilizing polynucleotides of the cDNA
Clone >D
shown in the corresponding row. Alteration of expression patterns of the
indicated
"Exemplary Target" genes is correlated with a particular "Disease Class"
and/or "Preferred
Indication" as shown in the corresponding row under the respective column
headings.
The "Exemplary Accessions" Column indicates GenBank Accessions (available
online through the National Center for Biotechnology Information (NCBI) at
http://www.ncbi.nlm.nih.govl) which correspond to the "Exemplary Targets"
shown in the
adjacent row.
The recitation of "Cancer" in the "Disease Class" Column indicates that the
corresponding nucleic acid and protein, or antibody against the same, of the
invention (or
fragment or variant thereof) may be used for example, to detect, diagnose,
prevent, treat,
and/or ameliorate neoplastic diseases and/or disorders (e.g., leukemias,
cancers, etc., as
described below under "Hyperproliferative Disorders").
The recitation of "Immune" in the "Disease Class" column indicates that the
corresponding nucleic acid and protein, or antibody against the same, of the
invention (or
fragment or variant thereof), may be used for example, to detect, diagnose,
prevent, treat,
and/or ameliorate diseases and/or disorders relating to neoplastic diseases
(e.g., as
described below under "Hyperproliferative Disorders"), blood disorders (e.g.,
as described
12
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
below under "Immune Activity" "Cardiovascular Disorders" and/or "Blood-Related
Disorders"), and infections (e.g., as described below under "Infectious
Disease").
The recitation of "Angiogenesis" in the "Disease Class" column indicates that
the corresponding nucleic acid and protein, or antibody against the same, of
the invention
(or fragment or variant thereof), may be used for example, to detect,
diagnose, treat,
prevent, and/or ameliorate diseases and/or disorders relating to neoplastic
diseases (e.g., as
described below under "Hyperproliferative Disorders"), diseases and/or
disorders of the
cardiovascular system (e.g., as described below under "Cardiovascular
Disorders"),
diseases and/or disorders involving cellular and genetic abnormalities (e.g.,
as described
below under "Diseases at the Cellular Level"), diseases and/or disorders
involving
angiogenesis (e.g., as described below under "Anti-Angiogenesis Activity"), to
promote or
inhibit cell or tissue regeneration (e.g., as described below under
"Regeneration"), or to
promote wound healing (e.g., as described below under "Wound Healing and
Epithelial
Cell Proliferation").
The recitation of "Diabetes" in the "Disease Class" column indicates that the
corresponding nucleic acid and protein, or antibody against the same, of the
invention (or
fragment or variant thereof), may be used for example, to detect, diagnose,
treat, prevent,
and/or ameliorate diabetes (including diabetes mellitus types I and II), as
well as diseases
and/or disorders associated with, or consequential to, diabetes (e.g. as
described below
under "Endocrine Disorders," "Renal Disorders," and "Gastrointestinal
Disorders").
Description of Table 2
Table 2 summarizes homology and features of some of the polypeptides of the
invention. The first column provides a unique clone identifier, "Clone >D:",
corresponding to a
cDNA clone disclosed in Table 1A or Table 1B. The second column provides the
unique contig
identifier, "Contig ID:" corresponding to contigs in Table 1B and allowing for
correlation with the
information in Table 1B. The third column provides the sequence identifier,
"SEQ 1D NO:X", for
the contig polynucleotide sequence. The fourth column provides the analysis
method by which the
homology/identity disclosed in the Table was determined. Comparisons were made
between
polypeptides encoded by the polynucleotides of the invention and either a non-
redundant protein
database (herein referred to as "NR"), or a database of protein families
(herein referred to as
"PFAM") as further described below. The fifth column provides a description of
the PFAM/NR
hit having a significant match to a polypeptide of the invention. Column six
provides the
accession number of the PFAM/NR hit disclosed in the fifth column. Column
seven,
"Score/Percent Identity", provides a quality score or the percent identity, of
the hit disclosed in
13
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
columns five and six. Columns 8 and 9, "NT From" and "NT To" respectively,
delineate the
polynucleotides in "SEQ 1D NO:X" that encode a polypeptide having a
significant match to the
PFAM/NR database as disclosed in the fifth and sixth columns. In specific
embodiments
polypeptides of the invention comprise, or alternatively consist of, an amino
acid sequence
encoded by a polynucleotide in SEQ ID NO:X as delineated in columns 8 and 9,
or fragments or
variants thereof.
Description of Table 3
Table 3 provides polynucleotide sequences that may be disclaimed according to
certain
embodiments of the invention. The first column provides a unique clone
identifier, "Clone >D",
for a cDNA clone related to contig sequences disclosed in Table 1B. The second
column provides
the sequence identifier, "SEQ ID NO:X", for contig sequences disclosed in
Table 1A and/or Table
1B. The third column provides the unique contig identifier, "Contig ID:", for
contigs disclosed in
Table 1B. The fourth column provides a unique integer 'a' where 'a' is any
integer between 1 and
the final nucleotide minus 15 of SEQ 1D NO:X, and the fifth column provides a
unique integer 'b'
where 'b' is any integer between 15 and the final nucleotide of SEQ >D NO:X,
where both a and b
correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and
where b is greater
than or equal to a + 14. For each of the polynucleotides shown as SEQ 1D NO:X,
the uniquely
defined integers can be substituted into the general formula of a-b, and used
to describe
polynucleotides which may be preferably excluded from the invention. In
certain embodiments,
preferably excluded from the invention are at least one, two, three, four,
five, ten, or more of the
polynucleotide sequences) having the accession numbers) disclosed in the sixth
column of this
Table (including for example, published sequence in connection with a
particular BAC clone). In
further embodiments, preferably excluded from the invention are the specific
polynucleotide
sequences) contained in the clones corresponding to at least one, two, three,
four, five, ten, or
more of the available material having the accession numbers identified in the
sixth column of this
Table (including for example, the actual sequence contained in an identified
BAC clone).
Description of Table 4
Table 4 provides a key to the tissue/cell source identifier code disclosed in
Table 1B.2,
column 5. Column 1 provides the tissue/cell source identifier code disclosed
in Table 1B.2,
Column 5. Columns 2-5 provide a description of the tissue or cell source. Note
that "Description"
and "Tissue" sources (i.e. columns 2 and 3) having the prefix "a_" indicates
organs, tissues, or
cells derived from "adult" sources. Codes corresponding to diseased tissues
are indicated in
column 6 with the word "disease." The use of the word "disease" in column 6 is
non-limiting.
The tissue or cell source may be specific (e.g. a neoplasm), or may be disease-
associated (e.g., a
tissue sample from a normal portion of a diseased organ). Furthermore, tissues
and/or cells
14
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
lacking the "disease" designation may still be derived from sources directly
or indirectly involved
in a disease state or disorder, and therefore may have a further utility in
that disease state or
disorder. In numerous cases where the tissue/cell source is a library, column
7 identifies the vector
used to generate the library.
Description of Table 5
Table 5 provides a key to the OMIM reference identification numbers disclosed
in
Table 1B.1, column 9. OMIM reference identification numbers (Column 1) were
derived from
Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man,
OMIM. McKusick-
Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore,
MD) and National
Center for Biotechnology Information, National Library of Medicine, (Bethesda,
MD) 2000.
World Wide Web U1RL.: http://www.ncbi.nlm.nih.gov/omim/). Column 2 provides
diseases
associated with the cytologic band disclosed in Table 1B.1, column 8, as
determined using the
Morbid Map database.
Description of Table 6
Table 6 summarizes some of the ATCC Deposits, Deposit dates, and ATCC
designation numbers of deposits made with the ATCC in connection with the
present application.
These deposits were made in addition to those described in the Table 1A.
Description of Table 7
Table 7 shows the cDNA libraries sequenced, and ATCC designation numbers and
vector information relating to these cDNA libraries.
The first column shows the first four letters indicating the Library from
which each
library clone was derived. The second column indicates the catalogued tissue
description for the
corresponding libraries. The third column indicates the vector containing the
corresponding
clones. The fourth column shows the ATCC deposit designation for each libray
clone as indicated
by the deposit information in Table 6.
Definitions
The following definitions are provided to facilitate understanding of certain
terms used
throughout this specification.
In the present invention, "isolated" refers to material removed from its
original
environment (e.g., the natural environment if it is naturally occurring), and
thus is altered "by the
hand of man" from its natural state. For example, an isolated polynucleotide
could be part of a
vector or a composition of matter, or could be contained within a cell, and
still be "isolated"
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
because that vector, composition of matter, or particular cell is not the
original environment of the
polynucleotide. The term "isolated" does not refer to genomic or cDNA
libraries, whole cell total
or mRNA preparations, genomic DNA preparations (including those separated by
electrophoresis
and transferred onto blots), sheared whole cell genomic DNA preparations or
other compositions
where the art demonstrates no distinguishing features of the
polynucleotide/sequences of the
present invention.
In the present invention, a "secreted" protein refers to those proteins
capable of being
directed to the ER, secretory vesicles, or the extracellular space as a result
of a signal sequence, as
well as those proteins released into the extracellular space without
necessarily containing a signal
sequence. If the secreted protein is released into the extracellular space,
the secreted protein can
undergo extracellular processing to produce a "mature" protein. Release into
the extracellular
space can occur by many mechanisms, including exocytosis and proteolytic
cleavage.
As used herein, a "polynucleotide" refers to a molecule having a nucleic acid
sequence
encoding SEQ )D NO:Y or a fragment or variant thereof (e.g., the polypeptide
delinated in
columns fourteen and fifteen of Table IA); a nucleic acid sequence contained
in SEQ ID NO:X (as
described in column 5 of Table 1A and/or column 3 of Table 1B) or the
complement thereof; a
cDNA sequence contained in Clone >D: (as described in column 2 of Table 1A
and/or Table 1B
and contained within a library deposited with the ATCC); a nucleotide sequence
encoding the
polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as defined in
column 6 (EXON
From-To) of Table 1C or a fragment or variant thereof; or a nucleotide coding
sequence in SEQ ID
NO:B as defined in column 6 of Table 1C or the complement thereof. For
example, the
polynucleotide can contain the nucleotide sequence of the full length cDNA
sequence, including
the 5' and 3' untranslated sequences, the coding region, as well as fragments,
epitopes, domains,
and variants of the nucleic acid sequence. Moreover, as used herein, a
"polypeptide" refers to a
molecule having an amino acid sequence encoded by a polynucleotide of the
invention as broadly
defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide
sequences which result
from translation of a polyA tail of a sequence corresponding to a cDNA).
In the present invention, "SEQ ID NO:X" was often generated by overlapping
sequences contained in multiple clones (contig analysis). A representative
clone containing all or
most of the sequence for SEQ ID NO:X is deposited at Human Genome Sciences,
Inc. (HGS) in a
catalogued and archived library. As shown, for example, in column 2 of Table
1B, each clone is
identified by a cDNA Clone ID (identifier generally referred to herein as
Clone ID:). Each Clone
ID is unique to an individual clone and the Clone ID is all the information
needed' to retrieve a
given clone from the HGS library. Table 7 provides a list of the deposited
cDNA libraries. One
can use the Clone )D: to determine the library source by reference to Tables 6
and 7. Table 7 lists
the deposited eDNA libraries by name and links each library to an ATCC
Deposit. Library names
contain four characters, for example, "H'TWE." The name of a cDNA clone (Clone
ll~) isolated
16
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
from that library begins with the same four characters, for example "HTWEP07".
As mentioned
below, Table 1A and/or Table 1B correlates the Clone )D names with SEQ >D
NO:X. Thus,
starting with an SEQ )D NO:X, one can use Tables 1A, 1B, 6, 7, and 9 to
determine the
corresponding Clone >D, which library it came from and which ATCC deposit the
library is
contained in. Furthermore, it is possible to retrieve a given cDNA clone from
the source library by
techniques known in the art and described elsewhere herein. The ATCC is
located at 10801
University Boulevard, Manassas, Virginia 20110-2209, USA. The ATCC deposits
were made
pursuant to the terms of the Budapest Treaty on the international recognition
of the deposit of
microorganisms for the purposes of patent procedure.
In specific embodiments, the polynucleotides of the invention are at least 15,
at least
. 30, at least 50, at least 100, at least 125, at least 500, or at least 1000
continuous nucleotides but
are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5kb,
5 kb, 2.5 kb, 2.0 kb, or
1 kb, in length. In a further embodiment, polynucleotides of the invention
comprise a portion of
the coding sequences, as disclosed herein, but do not comprise all or a
portion of any intron. In
another embodiment, the polynucleotides comprising coding sequences do not
contain coding
sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest
in the genome). In other
embodiments, the polynucleotides of the invention do not contain the coding
sequence of more
than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic
flanking gene(s).
A "polynucleotide" of the present invention also includes those
polynucleotides
capable of hybridizing, under stringent hybridization conditions, to sequences
contained in SEQ
)D NO:X, or the complement thereof (e.g., the complement of any one, two,
three, four, or more of
the polynucleotide fragments described herein), the polynucleotide sequence
delineated in columns
7 and 8 of Table 1A or the complement thereof, the polynucleotide sequence
delineated in
columns 8 and 9 of Table 2 or the complement thereof, and/or cDNA sequences
contained in
Clone >D: (e.g., the complement of any one, two, three, four, or more of the
polynucleotide
fragments, or the cDNA clone within the pool of cDNA clones deposited with the
ATCC,
described herein), and/or the polynucleotide sequence delineated in column 6
of Table 1C or the
complement thereof. "Stringent hybridization conditions" refers to an
overnight incubation at 42
degree C in a solution comprising 50% formamide, 5x SSC (750 mM NaCI, 75 mM
trisodium
citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution, 10% dextran
sulfate, and 20
~Cg/ml denatured, sheared salmon sperm DNA, followed by washing the filters in
O.lx SSC at
about 65 degree C.
Also contemplated are nucleic acid molecules that hybridize to the
polynucleotides of
the present invention at lower stringency hybridization conditions. Changes in
the stringency of
hybridization and signal detection are primarily accomplished through the
manipulation of
formamide concentration (lower percentages of formamide result in lowered
stringency); salt
conditions, or temperature. For example, lower stringency conditions include
an overnight
17
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
incubation at 37 degree C in a solution comprising 6X SSPE (20X SSPE = 3M
NaCI; 0.2M
NaH2PO4; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm
blocking
DNA; followed by washes at 50 degree C with 1XSSPE, 0.1% SDS. In addition, to
achieve even
lower stringency, washes performed following stringent hybridization can be
done at higher salt
concentrations (e.g. 5X SSC).
Note that variations in the above conditions may be accomplished through , the
inclusion and/or substitution of alternate blocking reagents used to suppress
background in
hybridization experiments. Typical blocking reagents include Denhardt's
reagent, BLOTTO,
heparin, denatured salmon sperm DNA, and commercially available proprietary
formulations. The
inclusion of specific blocking reagents may require modification of the
hybridization conditions
described above, due to problems with compatibility.
Of course, a polynucleotide which hybridizes only to polyA+ sequences (such as
any 3'
terminal polyA+ tract of a cDNA shown in the sequence listing), or to a
complementary stretch of
T (or U) residues, would not be included in the definition of
"polynucleotide," since such a
polynucleotide would hybridize to any nucleic acid molecule containing a poly
(A) stretch or the
complement thereof (e.g., practically any double-stranded cDNA clone generated
using oligo dT
as a primer).
The polynucleotide of the present invention can be composed of any
polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or
DNA or
modified RNA or DNA. For example, polynucleotides can be composed of single-
and double-
stranded DNA, DNA that is a mixture of single- and double-stranded regions,
single- and double-
stranded RNA, and RNA that is mixture of single- and double-stranded regions,
hybrid molecules
comprising DNA and RNA that may be single-stranded or, more typically, double-
stranded or a
mixture of single- and double-stranded regions. In addition, the
polynucleotide can be composed
of triple-stranded regions comprising RNA or DNA or both RNA and DNA. A
polynucleotide
may also contain one or more modified bases or DNA or RNA backbones modified
for stability or
for other reasons. "Modified" bases include, for example, tritylated bases and
unusual bases such
as inosine. A variety of modifications can be made to DNA and RNA; thus,
"polynucleotide"
embraces chemically, enzymatically, or metabolically modified forms.
In specific embodiments, the polynucleotides of the invention are at least 15,
at least
30, at least 50, at least 100, at least 125, at least 500, or at least 1000
continuous nucleotides but
are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.Skb,
5 kb, 2.5 kb, 2.0 kb, or
1 kb, in length. In a further embodiment, polynucleotides of the invention
comprise a portion of
the coding sequences, as disclosed herein, but do not comprise all or a
portion of any intron. In
another embodiment, the polynucleotides comprising coding sequences do not
contain coding
sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest
in the genome). In other
18
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
embodiments, the polynucleotides of the invention do not contain the coding
sequence of more
than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic
flanking gene(s).
"SEQ ID NO:X" refers to a polynucleotide sequence described in column 5 of
Table
1A, while "SEQ ID NO:Y" refers to a polypeptide sequence described in column
10 of Table 1A.
SEQ ID NO:X is identified by an integer specified in column 6 of Table 1A. The
polypeptide
sequence SEQ ID NO:Y is a translated open reading frame (ORF) encoded by
polynucleotide SEQ
ID NO:X. The polynucleotide sequences are shown in the sequence listing
immediately followed
by all of the polypeptide sequences. Thus, a polypeptide sequence
corresponding to polynucleotide
sequence SEQ ID N0:2 is the first polypeptide sequence shown in the sequence
listing. The
second polypeptide sequence corresponds to the polynucleotide sequence shown
as SEQ ll~ N0:3,
and so on.
The polypeptide of the present invention can be composed of amino acids joined
to
each other by peptide bonds or modified peptide bonds, i.e., peptide
isosteres, and may contain
amino acids other than the 20 gene-encoded amino acids. The polypeptides may
be modified by
either natural processes, such as posttranslational processing, or by chemical
modification
techniques which are well known in the art. Such modifications are well
described in basic texts
and in more detailed monographs, as well as in a voluminous research
literature. Modifications
can occur anywhere in a polypeptide, including the peptide backbone, the amino
acid side-chains
and the amino or carboxyl termini. It will be appreciated that the same type
of modification may
be present in the same or varying degrees at several sites in a given
polypeptide. Also, a given
polypeptide may contain many types of modifications. Polypeptides may be
branched, for
example, as a result of ubiquitination, and they may be cyclic, with or
without branching. Cyclic,
branched, and branched cyclic polypeptides may result from posttranslation
natural processes or
may be made by synthetic methods. Modifications include 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 cross-links, formation of
cysteine, formation of
pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor
formation,
hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation,
proteolytic
processing, phosphorylation, prenylation, racemization, selenoylation,
sulfation, transfer-RNA
mediated addition of amino acids to proteins such as arginylation, and
ubiquitination. (See, for
instance, PROTEINS - STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E.
Creighton, W. H. Freeman and Company, New York (1993); POSTTRANSLATIONAL
COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New
York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990);
Rattan et al., Ann.
N.Y. Acad. Sci. 663:48-62 ( 1992)).
19
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
"SEQ )D NO:X" refers to a polynucleotide sequence described, for example, in
Tables
1A, Table 1B, or Table 2, while "SEQ >D NO:Y" refers to a polypeptide sequence
described in
column 11 of Table 1A and or of Table 1B. SEQ 1D NO:X is identified by an
integer specified in
column 4 of Table 1B. The polypeptide sequence SEQ B7 NO:Y is a translated
open reading frame
(ORF) encoded by polynucleotide SEQ )D NO:X. "Clone >D:" refers to a cDNA
clone described
in column 2 of Table 1A and/or 1B.
"A polypeptide having functional activity" refers to a polypeptide capable of
displaying
one or more known functional activities associated with a full-length
(complete) protein. Such
functional activities include, but are not limited to, biological activity
(e.g. activity useful in
treating, preventing and/or ameliorating diabetes mellitus), antigenicity
(ability to bind [or
compete with a polypeptide for binding] to an anti-polypeptide antibody),
immunogenicity (ability
to generate antibody which binds to a specific polypeptide of the invention),
ability to form
multimers with polypeptides of the invention, and ability to bind to a
receptor or ligand for a
polypeptide.
The polypeptides of the invention can be assayed for functional activity (e.g.
biological
activity) using or routinely modifying assays known in the art, as well as
assays described herein.
Specifically, one of skill in the art may routinely assay secreted
polypeptides (including fragments
and variants) of the invention for activity using assays as described in the
examples section below.
"A polypeptide having biological activity" refers to a polypeptide exhibiting
activity
similar to, but not necessarily identical to, an activity of a polypeptide of
the present invention,
including mature forms, as measured in a particular biological assay, with or
without dose
dependency. In the case where dose dependency does exist, it need not be
identical to that of the
polypeptide, but rather substantially similar to the dose-dependence in a
given activity as
compared to the polypeptide of the present invention (i.e., the candidate
polypeptide will exhibit
greater activity or not more than about 25-fold less and, preferably, not more
than about tenfold
less activity, and most preferably, not more than about three-fold less
activity relative to the
polypeptide of the present invention).
TABLES
Table 1A
Table 1A summarizes information concerning certain polypnucleotides and
polypeptides of the invention. The first column provides the gene number in
the application for
each clone identifier. The second column provides a unique clone identifier,
"Clone )D:", for a
cDNA clone related to each contig sequence disclosed in Table 1A. Third
column, the cDNA
Clones identified in the second column were deposited as indicated in the
third column (i.e. by
ATCC Deposit No:Z and deposit date). Some of the deposits contain multiple
different clones
corresponding to the same gene. In the fourth column, "Vector" refers to the
type of vector
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
contained in the corresponding cDNA Clone identified in the second column. In
the fifth column,
the nucleotide sequence identified as "NT SEQ ID NO:X" was assembled from
partially
homologous ("overlapping") sequences obtained from the corresponding cDNA
clone identified in
the second column and, in some cases, from additional related cDNA clones. The
overlapping
sequences were assembled into a single contiguous sequence of high redundancy
(usually three to
five overlapping sequences at each nucleotide position), resulting in a final
sequence identified as
SEQ >l7 NO:X. In the sixth column, "Total NT Seq." refers to the total number
of nucleotides in
the contig sequence identified as SEQ >D NO:X." The deposited clone may
contain all or most of
these sequences, reflected by the nucleotide position indicated as "5' NT of
Clone Seq." (seventh
column) and the "3' NT of Clone Seq." (eighth column) of SEQ )D NO:X. In the
ninth column,
the nucleotide position of SEQ ID NO:X of the putative start codon
(methionine) is identified as
"S' NT of Start Codon." Similarly , in column ten, the nucleotide position of
SEQ )D NO:X of the
predicted signal sequence is identified as "5' NT of First AA of Signal Pep."
In the eleventh
column, the translated amino acid sequence, beginning with the methionine, is
identified as "AA
SEQ >D NO:Y," although other reading frames can also be routinely translated
using known
molecular biology techniques. The polypeptides produced by these alternative
open reading
frames are specifically contemplated by the present invention.
In the twelfth and thirteenth columns of Table 1A, the first and last amino
acid position
of SEQ m NO:Y of the predicted signal peptide is identified as "First AA of
Sig Pep" and "Last
AA of Sig Pep." In the fourteenth column, the predicted .first amino acid
position of SEQ ll~
NO:Y of the secreted portion is identified as "Predicted First AA of Secreted
Portion". The amino
acid position of SEQ ll~ NO:Y of the last amino acid encoded by the open
reading frame is
identified in the fifteenth column as "Last AA of ORF".
SEQ >D NO:X (where X may be any of the polynucleotide sequences disclosed in
the
sequence listing) and the translated SEQ >D NO:Y (where Y may be any of the
polypeptide
sequences disclosed in the sequence listing) are sufficiently accurate and
otherwise suitable for a
variety of uses well known in the art and described further below. For
instance, SEQ ID NO:X is
useful for designing nucleic acid hybridization probes that will detect
nucleic acid sequences
contained in SEQ >D NO:X or the cDNA contained in the deposited clone. These
probes will also
hybridize to nucleic acid molecules in biological samples, thereby enabling a
variety of forensic
and diagnostic methods of the invention. Similarly, polypeptides identified
from SEQ ID NO:Y
may be used, for example, to generate antibodies which bind specifically to
proteins containing the
polypeptides and the secreted proteins encoded by the cDNA clones identified
in Table 1A and/or
elsewhere herein
Nevertheless, DNA sequences generated by sequencing reactions can contain
sequencing errors. The errors exist as misidentified nucleotides, or as
insertions or deletions of
nucleotides in the generated DNA sequence. The erroneously inserted or deleted
nucleotides
21
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
cause frame shifts in the reading frames of the predicted amino acid sequence.
In these cases, the
predicted amino acid sequence diverges from the actual amino acid sequence,
even though the
generated DNA sequence may be greater than 99.9% identical to the actual DNA
sequence (for
example, one base insertion or deletion in an open reading frame of over 1000
bases).
Accordingly, for those applications requiring precision in the nucleotide
sequence or
the amino acid sequence, the present invention provides not only the generated
nucleotide
sequence identified as SEQ )D NO:X, and the predicted translated amino acid
sequence identified
as SEQ ID NO:Y, but also a sample of plasmid DNA containing a human cDNA of
the invention
deposited with the ATCC, as set forth in Table 1A. The nucleotide sequence of
each deposited
plasmid can readily be determined by sequencing the deposited plasmid in
accordance with known
methods
The predicted amino acid sequence can then be verified from such deposits.
Moreover,
the amino acid sequence of the protein encoded by a particular plasmid can
also be directly
determined by peptide sequencing or by expressing the protein in a suitable
host cell containing
1 S the deposited human cDNA, collecting the protein, and determining its
sequence.
Also provided in Table 1A is the name of the vector which contains the cDNA
plasmid. Each vector is routinely used in the art. The following additional
information is
provided for convenience.
Vectors Lambda Zap (U.S. Patent Nos. 5,128,256 and 5,286,636), Uni-Zap XR
(U.5.
Patent Nos. 5,128, 256 and 5,286,636), Zap Express (U.5. Patent Nos. 5,128,256
and 5,286,636),
pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600
(1988); Alting-Mees, M.
A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Along-Mees,
M. A. et al.,
Strategies 5:58-61 (1.992)) are commercially available from Stratagene Cloning
Systems, Inc.,
11011 N. Torrey Pines Road, La Jolla, CA, 92037. pBS contains an ampicillin
resistance gene and
pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the
Lambda Zap
and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express
vector. Both
phagemids may be transformed into E. coli strain XL-1 Blue, also available
from Stratagene
Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained
from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All
Sport vectors contain
an ampicillin resistance gene and may be transformed into E. coli strain
DH10B, also available
from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59
(1993). Vector
lafmid BA (Bento Soares, Columbia University, New York, NY) contains an
ampicillin resistance
gene and can be transformed into E. coli strain XL-1 Blue. Vector
pCR°2.1, which is available
from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an
ampicillin resistance
gene and may be transformed into E. coli strain DH10B, available from Life
Technologies. See,
for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D.
et al.,
BiolTechnology 9: (1991).
22
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
The present invention also relates to the genes corresponding to SEQ )D NO:X,
SEQ
ID NO:Y, and/or a deposited cDNA (cDNA Clone >D). The corresponding gene can
be isolated in
accordance with known methods using the sequence information disclosed herein.
Such methods
include, but are not limited to, preparing probes or primers from the
disclosed sequence and
identifying or amplifying the corresponding gene from appropriate sources of
genomic material.
Also provided in the present invention are allelic variants, orthologs, and/or
species
homologs. Procedures known in the art can be used to obtain full-length genes,
allelic variants,
splice variants, full-length coding portions, orthologs, and/or species
homologs of genes
corresponding to SEQ m NO:X and SEQ m NO:Y using information from the
sequences
disclosed herein or the clones deposited with the ATCC. For example, allelic
variants and/or
species homologs may be isolated and identified by making suitable probes or
primers from the
sequences provided herein and screening a suitable nucleic acid source for
allelic variants and/or
the desired homologue.
The present invention provides a polynucleotide comprising, or alternatively
consisting
of, the nucleic acid sequence of SEQ m NO:X and/or a cDNA contained in ATCC
Deposit No.Z.
The present invention also provides a polypeptide comprising, or
alternatively, consisting of, the
polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ m NO:X,
and/or a
polypeptide encoded by a cDNA contained in ATCC deposit No.Z. Polynucleotides
encoding a
polypeptide comprising, or alternatively consisting of the polypeptide
sequence of SEQ >D NO:Y,
a polypeptide encoded by SEQ ll~ NO:X and/or a polypeptide encoded by the cDNA
contained in
ATCC Deposit No.Z, are also encompassed by the invention. The present
invention further
encompasses a polynucleotide comprising, or alternatively consisting of the
complement of,the
nucleic acid sequence of SEQ >D NO:X, and/or the complement of the coding
strand of the cDNA
contained in ATCC Deposit No.Z.
23
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
w ~ O ,~ ~ Ov oo N N N oo .~ p due.
O v1 ~ Iw 0 ~ .r Ow
O N ,~ N . .
b
N
~
4, N ~ ~ ~O M ~ ~ ~ ~ ~ d\ ~ O~
O ~ ~ M M N d' N N N N N N N -~
y O
w
O~~ ~ OM N ~ N N NO N N N ON
a
~,
d ~n M vo c~ oo ~ a\ O ~n .~ N M
W ~ O o~ ~ o~ o~ o~ ~ ~ O ~ O O O
~.
M ~O M M M ~ M ~ \O
4~
c~7 ~ ~i o~0 W O M ~n ~ N N ~ N
r, M ,~ ~ .~ N ,
~
m p Q
C/~
O l~ l~ O~ (~ ,--mn ~' v.7 N pv M o0
M
O
O ~ 000 M '~ M N ~O
o ~ ~ ~ ~ ~ ~ o
N N
p O ~ .--i,_,N .--rM ~ ~ ,~ .-a
M M ~ M
~
O ~ ~ ~ ~ l~ M M ~ ~ O ~ vp
~ ~ ~ ~
C~
N N ,~ .-,,~ ,~ '-,
E-~ a ~ ~ N M ~ O v~ ~D '~ t~ oo Ov
au au
N ~ ~ N ~ N ~ ~ ~ ~
fx tx tx P: f~ fx fx Q' f~
~
:, .'.,.:.~.~~ .:.~.:,~.:.x..;x
~ ~ ~ ~ x
~ P~ ~ ~ ~ ~
a. ar
'b ~ a\ ~ ~ ,~ ,~ 0o a\ ~ N vp D\
00 oo t~ oo oo 00 t~ t~ t~ oo o0 t~
00 0o N N I~ l~ 0 ~ ~ o0 N O
Ov Ov O~ O~ 01 Ow O~ Ov Qv Ov Ov Ov
U O cd oo oo M v0 O O M N N I~ v0 O
~; c~ N N c~ ~ ~ ~ ~ ~ D C~ o'0
~ ~ ~ ~ ~ M M ~ ~ ~ ~ ~ ~
., O.N N N O ~ N N ~ N N N ~ N
~ O O O O O O O O O O O O
w w w ~ ~ w w ~ ~ w w w
N N N N N N N N N N N N
~n ~n O N t~ (~ O O~ O~ ~t N O
O O ~ O O O ~ O O O O
oc~'ooMO~ OV ~ ~ N M M N
z ~ ~ ~ ~ v v ~ A A w
~ U U W U U U ~ ~ ~ C7 .-
~1
o
_ x x x
U
N M ~ <t V7 ~D ~O t~ 00 01
24
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
O o ~ ,~ c ~ ~ o ~ o~oN
v~ ~ ~t N N
'b
N
w N O O ~O ~O O ~n ~ O~ O~ o~ O M ~o
'-' O M --a~ N M N -~ ~ N M N N N
~ ~
~
s.
. ~ O
w
w ~ Q' OW n v7 Ov ~ M o0 00 00 O~ N ,~ V7
O ~ ~ N ~ ~ -~ M N ~ ~ N N N N
w ~
w
O ~ o
~
~. o o ~ o o ~ o
G
~
z
'-' w
O ~ : ~ ~
'dG, N O ~ ~ N Ov d'. ' ~ ~ o
N ,_, N N N ~ o
' M
in ~ d
W
O ~ Ov O N y 0 ~ O N ~ ~ oo v7
M
O
w00' ~ ~ o~o '~ N ~ ~ M ~ N O ~
p O N l~ pp N ~ ~ Iw 0 W ~ ~ O ~O
N N ~ d' M ~ ~ ~ ~ N N
N
p O ~ ~ ,~ .~ ,~ ,~ ~ ~ .-r ~ .~ .--r,~
~n U ~
~ ~ N ~ ~ ~ 0 ~
O~~ o N ~ ~ ~ ~ ~ ~ ~ N N
o N ~ M ~
N
x NO N N N N N N N N N N N N
C
O ~ ~ a ~ o., c. o. r~. ~ d ~ d
r N ~ ~ ~ ~ ~ ~' ~ N N N N N
p; o o o o o o o ~ c~ o4 c~ ~
' ? ? M M ?
~
.~, M M ~ ~ M ~M ~M
X z z ~ ~ z ~
,
U U , U ,U U ,U
U,~
a. a, a. a. a. r~. a,
N N N ~ ~ ~ V7 ~n ,--iOv 00 00 O
DO Ov Ov 00 00 00 00 o0 oO o0 00 0o Ov
~ ~ ~ ~ ~ 00 ~ l~ 1
~ O\ ~ ~ I~
U O .r O~ M M N ~O ~O D ~O V7 00 O O 0
ctS o0 O~ ~ ~ ~ O O O O ~ I ~O ~
l~ ~ ~ f~ M M ~ 01 ~O ~ 00 00 M
Q\ Ov O~ ~ Ov O~ ,--.~,-.~~ 00 ~
d d M M ~ ~ ~ ~
N O O O ~ --~ ~ .~ .~ p N ~ ~ ,-i
O y , O O O O O O O O O O
w ~ w w w w w w w w w w ~
N I~ I~ N N N N N N N N N N
v~ N O O v0 v0 M v1 v~ v~
O O ~ O ~ ~ O O O O O O O
O
00 M M Q\ ~ ~ N N M ~ ~ ~ 00
~ N N
d ~, ~ ~ ~r C~ ,7-~~ ~ U
~ ~ ~ ~ ~ ~ z
A o a~ o 0
a
O O O ~r ~~ N M M ~ ~ v7 ~D l~ I~ 00
~z
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
Q~, 4--n ~' O1 M O~ O O V~ 00 01 ~ ~ M O
~
O y 0 ~ N v~ N ~D ~ ~ N M ,~ ,~ N
'b
+. N ~O ~ O O
~ ~ O M N ~
0~~ ~ N M N N M M M
O
~D o0 O ~ M M N N ,~ 00 ~ N N
c,..,
~p ~1 --i.~ ,~ ,-a,~ ,~ ,-, .-r
ur
M ~ O ~n ~D ~ l~ N M o0 O~ ~ v~
,m n ,~ ,m n .~ ~n v~ .~ ,~ ~m n
z ~ ~ .~ ~r
f~ N N v~'7~ ~ ~ .-,N_,~~ N ~ ~i l~
O
'O ~ ~ ~ N N N ~ vW ~ ~' O
~ ~ v l~
O N N M .~ ~ .~ l I ~ r,
U
o
~ M ~ ~ M ~ M ~
z p O ~' o0 ~ N o0 M ~O ~t V~ p ~ ~
~
p
j ~ 00 00 ~ 00 ov a\ oo ~ oo ,~ oo ,~
in ( ,
0 o
~ ,--~.-. .~ ~ ,~ .-r ,~ ..,
0 M o0
~'
in U
:j H ~' ~ ~ ~ N ~ ~ ' ~
o0 r1 o
O
x N p M M M M
M N M N N N N N
~ C
p., p., p., A. A. Or
~ N ~ ~ ~ N ~ ~ ~ o o
~C ~C ~C o ~C ~C ~ ~C ~C ~C > > '
~ ~ ~ ~ ~ ~ U U U
~
r~.o. a,
M M M
~O ~p ~D M 00 00 I~ l~ t~ d' pippip pip
00 o0 00 00 00 00 O p O l~ Ov Ov Ov
O O O
U ' N N N oo I~ l~ O O O N pp op pp
:~ O~ O~ ~ O~ ~ O~ N~ Np N0 O~ O~ O~ O~
~O~~O~ ~D~ ~Op00 00 ~O ~ ~ ~O
~ ~ N O\ pi ~
t~. N ~ ~ ~ ~ p p d ~ 1 O O p O
~ .-i,-, ,~ N p p O ' Q' ~ d ~ d
~ ~ O O N N N N
~ ~ Q O
A O O O O O O w , w w w w w
w w w w w w ~ w ~ N
N N N N N N O ~ O O
O O O O O O O
z
V7 M M ~ Ov O~ ~O ~D ~D ~p o0 00 00
z~ ~ ~ ~ ~ ~ ~ ~ z z
~
U
O Ov O O ~ N N M M M ~ V7 v7 ~n
N N N N N N N N N N N N
26
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
v' ~ O O v0 ,~ OW O t<1N p~ ~ N ~ M <t
~ M M ~ N ~ 00 in V~ ~O I~
G
Y O
,., ~p ~O 01 O~ r1 r1
O ~ ~ M M ~ O ~ N M M N ~ N M
~
w
~'' a\ ~ t~ O~ O~ Gv O ~n V~ 00 00 O O
~ M M M ~ -i ~ N M M N ~ N M
Y Q
r.,~ ~ ~, ~ ~ ~ ,~ ~ r,
~ ON N N N N ~ N N ~ N N N OM
z
Y
~ O ~ ~ ~ ~ ~ ~ ~
w b N o ~ ~ ~ N
Dp O .-.,~ .~ ,~
p~
O
O
~ ~O v0 ~ ~ ~ N
~ ~
DU
~' Ov N '~ ~ o~O ~ ~ ~n O '~ Ov O
p O N ~ l~ O N O O l~ ~ W n ~ M o0
~ 00 00 ~D 0o ~D l~
M U .~ N N ~ N N ,~
N
~n U ~
~ o o
z ~ ~ N
~
, N N ~ N N
'' M M M M ~ N ~t ~ N ~ ~ ~ ~t
a~,O.
~'
~f
~
A, P..~G, f~, ,_, O
~ N ~ N N N ~ ~ ~ ~ 0
f~ ~ C~ L~ cx C~ rx ~ ~ G4 ?
i i i i i i i i i i o
' ' '~ ~C X~ '~ ' ' ~
' ' X~ ~
.., ....., ..,, .,..,.,.,, ..,. N
,~ ,~ , , ... , , ,
, ,
' U
a.
a'
U ~ ~ ~n ~ N ~ 00 00 0 ~ vo ~..r0 ~ t~
t~ oo t~ 00 00 00 00 o o o0 ~ t~ 00
N ~n d' N l~ l~ 00 O O ~n O N N
~ O~ O~ ~ d\ O~ O~ O O ~ ~ O~ O~
:~ ~..~WD N v0 00 00 v~ CV N ~O M M 0
~ O ~ N f~ 0~0 0~o~ Ov O~ ~ ~ (W N
~ ov ov a\ ov ov a\ ~ Q. ov ov
E-~ a. ,-,o .~ .-.,,~ ,-,,~ d ~ o N o ,~
N o~ o~ o~ o~ o~ o~ o~ o o o~ o~ o~ o~
~ ~
A
O N N N N N N N ~O ~O N N N N
~O M O~ N ~1 v~ ~ ~ ~ M G~ O N
0 0 0 0 0 0 0 o o 0 0 ~ o
00 ~ ~ ~ ~ ~ M O O
00 O o0
U ~ N M M
~ ~
A _ ' ' Z U U U U U U U U U U
x x x x x x x x x x
O ~O l~ oo Ov O O ~ N N M ~ ~n
'Z N N N N M M M M M M M M M
U,
27
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ N N
a
O ~ ~~ N ~t ~ N N N ~ ~ M ~ O
w
c,.., ~ ~ r, ~t I~ ~ 00 OM N N
b0 C~. N ~ ~ N N N
O ~ ~
w
0o av N M O ~ Tw o t~ o0 ov
~
~z~
~
~w
o _ _
~ ~r N ~ ~O N M ~ ~ V7 ~ M O M N
~n o a
rn
H
o ~ oo t~ O
~ N '~' ~ ~ ~
N O~ M M N
N ~1 N
O
~ ~ ~ O O
p O M ~h ~ M N M N ~ ~ I
~ t~ w o ~ ~ M ~
cn U ~ N '.,,~ .-.
00
0 O ~ ,~ ,~ ,~ .-~,~ M .-i M .-r ,~ Q r,
U 'n ,~ M N
~n o0 N 01 M I~ V~ O O N Ov
C/ ~ ~ ~ I~ ~ N ~ o~oM _
l~
~
N N
a' ~ ~ ~ !/~ t/~
C~ Cd C~ .~ ~ ~ N O N N N ~
"'L'd 'b ~d "d ~ it it i-n Ir
~ I-~-I1-~-1 1-~-1~ O
1-~-I
, ~.y ~' ~ o
~ ~ ~ ~ W W W W W A~ a.
~ ~
N ~ "'a '~ ~ a '~ ~ d ~ ~ c.
''~~ N pa N N ~ ~
N
N N N
~ ,~ ~ N pip pip~ ~ N dW l~ ~n v~
Q\ O~ Ov I~ a\ Ov O I~ oo ~ 00 o0 00
0 O ~ Ow O O~ O~ ~ 01
O O w
U O c~ 00 00 00 ~ 1 pp ~~ N ~ N N O~~ 0
y ~ ~ ~ Ov pp ~ M~ n M~ ~D~ -~.,
~ \ ~ NN ~ ~ 00~ ~
~ ~ ~ ~ O~O
H ~.N O O 0 ~~ O aN aN ~O ~0 ~0 ~~ ~~ .
~ O 0 0 O, O , ~ O~ O~ O~ O~ O~ ~-
a~ a.~ a~ aN O~
, ,
a ~ O ~ ~ ~' N y' ~ M N N N N N N
O O O O O O ~ O v7 O N v0 v0
~ ~ , O ~ ,--~Q .-~p .~ O O O
. , r .
a~ ~ ~ ~ ~, H H ~
~ ~ ~ ~ z a a ~ ~ 3 3
o
Z Z
_ x x x x x x x x x x x ~
"~
O t~ I~ t~ o0 ~ O~ O ~ N M ~ v~ v~
'Z M M M M M M ~ ~ ~ ~ ~ ~ C~
28
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M t~ O
~ ~ N M ~ N ~ t/7 00 ~t
Q 0 M
1
b
N
wN'O M M ~ ,~ ~O ~ Ov ~ I~ N N M
O V O M M M M N V7
M
w
4 ~ a' N N ~ O m o0 00 (~ O oo O O~
~ M M M M M N ~ ~ ~ N N M
..s.., ~i r..i.~ .~ ~ .~ ,~ ..~ ~ '.r
p ~ ~
w
~~~o~
~
v'1~ M O ~ ~ M ~ O ~ ~ N v7
~ N
~ C/~
O
-~,~'O ~ ~ ~ O ~ M ~ ~ ON0 00 ~
'
U N ~D M ~ V7 ~, M N ~ N V
7
O
0~ ~ O M N V~ ~ 00 ~ M
0
O M ~ ~ _ W _ O N ~ ~ N l~
~
M ~ O M
U
0o v~ oo ~ o0
O O p~ ~ .~ ,~ ,~ .-r ,~
O ~ M I~ M
~n U ~
yH0' ~ O ~ ~ O M N ~ ~ O~ON M
C/ M ~ ~ ~ n _ O N ~ I~ N l~ ~O
W
~ ,- , ~O
, -
O O O O O O O p O O O O O
~. ~. ~. ~. ~.
v~ rr~ w rn vy o v~ v~ v~ v~ cn rn v~
o o p p 'M o o o p p p o o
M 'M M 'M 'M 'M '~M 'M M 'M ~M 'M
U U U U U U U U U U U U U
a. a, a. a. ay a. a. s~ ay a. a, ra. a.
U ~ ~ ~ ~ ~ ~ ~ ~ ~ 'n ~ N N N
~ ~ ~ ~ ~ ~ O O O ~ ~
cd N , , p~ pp pp pp ,--~,~ ~ ., O ,-, ~
G.N ~ w_ w_ w w w w w_ w_ y_ w w w w
~O ~O ~O ~O ~0 ~~ 'N Q'N dN ~~ MN ~
O O O O Q w w O O O O
~ A"i~ w w ~ w w ~ ~ ~ w w N
O O N N N N ~ O O N N N ,-"N-"
O O D O O O O O
, ,
N N M M M O~ ~ ~ ~ N p ~' O
M
p", p.r G. A..iG, p..,p~ p.,p..,A..i~ p..,
O ~G ~O I~ l~ I~ 00 O~ O~ O~ O -i N M
29
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
fn '+, Oy ~ N v0 ~O v0 ~ ~ I~ l~ ~ O
O ~n ~ ~ et ~t vo ~O
O
'b
O
wN~O ~--~M ~ M l~ Ov 00 O O O
O ~ ~ N N ~ M N ~ ~ ~ N N N N N
O
~r
O ~ N ~ M N ~ ~ l~ ~i ~ Ov Ov O
~ ~
w
~~~o~. ~ ~ ~ ~ ~ ~
z
~.
O 'd G~. Cv ,n OW ~ I~ M ~D N V~ 00 M N
N ~ N -' '~ v~ ~n -~ 0
~ N ~' ~ ,~ ,~ ,~ ' ~ M ,~ ,~ N
~ ...r
O
O
'O ~ ~ ~ N ~ N v~ ~ ~ 0~0
O N .-, ,~ .-~ ,~ .-.,,~ N
U
o
N ~ ~ ~ O ~ ~O
O O O M I~ ~D N O ~ W n ~ ~O ~ ~ M
M ~ '~
c~ U ~ ,~ ,~ .-. vo N M ,-, ,~ .~ N
O
O ~
p ~ ,~ ,~ ,-.i,~ ,--a,~ ,~ .-.,-r ,-,,~ .-,
~n U ~
E-~ a' ~ N ~ ~ ~ o ~ '~ ~ onoQ
O O M I~ ~O N O ~ O ~n ~ ~O ~D ~ M
C/~ M ~ ~
,~ ,--m.r ~O N M ,~ -.r ,~ N
~~ ~ ~ ~ N ~ N N N ~ N N
x
z N
Z,
O O O O O O O O O O O O O
~" p. G~ P~ S~.P. ~L C1 ~L A~ GL GL Aa GY
O ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
O O O O O O O O O O O O
N ' ' ~ ' ~ ' ' ' ' ' ~ ~ '
M M M M M M M M M M M M M
U U U U U U U U U U U U U
o. a. a. c~,a. s~.c~. a, ~. a. a. r.~ a.
b M I~ 00 ~ ~ ~ ~ ~ ~ ~ ~ ~ V~
~ 00 00 01 O~ ~ 01 O~ 01 O~ ~ O~ 00
~ v ~ ~ v Ov Ov ~
U
U y ~ 0 N Q1 pp pp pp pp pp ~p pp 00 pp t~
y ~ ~ I O ~ O O ~ O ~ ~ ~ i
O .r ~n ~ o0 ~o ~ U ~ ~ ~ ~o ~ ~
o N 00 ~ ~O ~O ~o ~o
~O
N ~ o ~ ~ d Q ~ d ~ ~ ~ Q~ ~ ~
~ ~-.i.~ N N N N N N N N N O
.-, O O
A O O w w w w w w w y , w w
Q,'~z w w Nin ~'O~O ~O ~O ~O ~O ~O w ~'O N
NN NN O .-i.~ ,.-i,-a ,~ .~ .., O ,--iO
-, O G~
...~
00 ~O ~O 00 00 00 00 M M M
M d' O 00 00 ,~ .-i ~ .-iV'7 ~ V~ Q
~ ~
z ~ o
~
U
O M ~ V7 ~ ~O l~ l~ I~ I~ 00 00 00 O~
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
O ~ ~ N N
~
O M ~ v7 ~ ~ M ~
,~ d
'b
N
~+-~ N ,~ d1 N 01 ~ ~ l~ 00 00 O I~ M
y N ~ ~ ~ w-~ N ~ M M .-~ ,~ N N
O
~ O
~+. ~ O o0 .-~ 00 00 M ~D l~ ( w 0 N O
'' N ~ d' - ~ N ~ M M ~ ~ N N
O ~ ~
w ~
w
z
~ o o ~ ~ M M ~ p~ ~ N
d ~1,~ N M ,~ ~ ~ .--~,~ N M
~ N
v
n o d
~
N
b N M ~ ~ ~ '~ '~ N M N c
~ ~ M n
U N N ,~ ,
O
O ~ N oo O
p ~ p M Ov ~ N N ~ ~ ~ -v N
~ ~ ~ ~ ~
M U .-i M N ~ ~ N ~ N N
N
p O ~ ~~ ~ .-~ ,-i,~ ~ ,~ ,~ ,~ ~ p ,-,
' o0
~n U N
~
~ M oo O
O ~ O M Ov ~ N N ~ ~ ~ ~ N
p ~ ~ ~
M N ,~ ,~ N .-~N
N ~ ~ ~ N ~ N N N ~
T~ t',
O O O O O O O O O O O O O
u.. a. a. a. a, a a. a. a. a, c. a. a
~o ~o ~o ~o ~o ~o ~o ~o ~o ~o ~o ~o ~o
M ' M ' M ' ~ M ' ' ' ~ N
M M M M M M N
M
U U U U U U U U U U U U U
c~. a, a. p. a. ai s~. a. a~ a, ar a. ai
b V7 N N ~ ~ N N ~ ~ ~ ~ O ~
00 o0 o0 Ov 00 o0 o0 O~ Ov ~ Ov ~O 00
G U O~ O O 01 Q1 01 O~ ~ W
O Q\
~ ~ 00 00 ,..~M 00 00 pp pp pp pp l
~ D\ 01 ~ ~ M ~ v ~ d d d
I~ I~ ~ ~ pip ~ h ~
~ p Q d p p d
N
O O O O ~ ~ ~ ' N ' N ~ Q
d A z ~ v N y0 O N ' ~ ~ ~ ~ N N
~ N N N O N ~ N O O O O N ~
~ ~ ~ O O ~ ~ ~ ~ ~ I~ O
O O O ~ O O
00 <t ~ ,--i,--i.~ ~ t~ M
3 ~ x x x
~
A as a~ a, a, a, a.~a. a. as a. a. H H
O O~ O O -~ N M M ~? ~ ~ ~ V~ ~O
~z
31
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0
w N .O ,--~,~ ,~ M (~ N v1 I~ I~ ~t
0 N N M N M N N N N M
w ~ A'' O O O N v0 ~ ~ ~D ~O M
O ~ ~ N N M N M N N N N M
v 4. tU
CL
~'~o~.
. ~ .
z ~ ~ ~ ~ o ~'~' O. o0
~
0o v~ ~ N Oy ., M ,_,
O
O o0 00 00 v~ ~ ~ ,_, -~ ,~ Q'
'b ~ ~ O ~--~ ~O N
~ N Qy M
00 ~!1 ., ,_,
~O ~D N v~ ~ oo OW ~ N Ov
' O O O~ O
~ N IM ~ ~ ~ O M
N ~
M U ~ M ~ ~ N
rr
zoo
i N
U ~'
n
~ ~ M O
O N N ~ ~ ~ ~ ~ O
O ~
C
/~ N N M ~ ~ N
N N ~ N ~ 000 00 ONO OMO
~. ~, p,
~ ~ ~ ~ ~ ~
~ >~ SC Nx ~C N~C~C N~C ~C ~C
V
r~. a.
b V'7 V~ ~,,~ ~.,~ t~ M ~ ~ O I~ O
U ~~, 00 00 I~ I~ 00 00 O l~ ~ ~ O~
~ ~o ~o ,~ ~ l~ ~ o ~ ~n ,~ o~ ~
o~ a\ (~ o~ o~ o~ o~ o o~ a~ o~
o~ o~
~' Q\ O~ ~ ~ ~ ~ ~ ~ ~ ~ O 0~0 ~
~ ~ O N O C~ 0~0 ~ ~ N O O~ M
I~ O I~ O ~ ~ N ~ ~ N .-i
a\ Ov ~ N ~ Ov
N N N
~ ON~~MO~ ~MO~ ON~ ONEE-iMONN ONV\O~ NO
N N N
O O O O O O p., ~~ O O
O O O O
a a ~ ~ M ~"~ ~O O
x ~ o ~
~ A A ~ N ~ ~ ~
_p Q
O ~O ~O I~ l~ o0 O~ O ~ N M
32
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
pip ~ pip~ ~ OMO
w N v ,~ .-, ~ ~ O\ OW E N M o0 Ov
O V ~ M M ~ N N N N N
w
w ~ ~ O O oo M o0 0o v0 ~ N t~ 00
O ~ ~ M M ~ N N N N N
a M ~ 00 ov o ~n ~ N M ~r Tw o
~w~o~, ~o
z
~',a O ~O Q\ ~ M M l~ M Ov N l~ ~ O~
~ C~.
w
P-~ ~ ~ 'n ~ l~ ~D ~n O~ N ~ ~. O
C/~
O
a_\
'b M N
,r N ~ ~ ~ ~ M ~ O
O ,~ ,~ ,~ ~ N
w
U
wGa' ~ ~ oOo M ~ N ~ ~ N N O
O y O~ O ~ O t~
V c~ ~ ~ ~ ~ ~ ~ ~ ~ ~ oo d
00
U ~ M
~
n
~ ~O ~D ~O M ~ ~ ~ ~ ~ ~ ~ 00
C/~ ,-..~.~ ~ ~ ~ ~ ..M-~~ ~ o0 d 0~0
~. ~,
~ ~ o N ~ ~ N N N ~ ~
~
rx C~: G~ fx c~ fx C~ fx f~ C~
~' .:. .:. p.
,~ ,~'
a
O O ~ M M M ~ I~ l~ 00 t~ N ~
O~ ~ ~O t~ l~ I~ O I~ I~ (~ I~ l~
~ ~
U I~ I~ d' ~ N N O O I~ O O~ ~ N
~ O~ O~ ~ O~ O~ O~ ~~ O~ Q\ O~ ~ Q~
~ ~~ Oo\OOOvN(~ No~O
N ~ M Ov O O~ Ov Ov ~ ~ ~ ~
U A ~~ ~~ ~0'O~O ~0 ~M NO'O
c M r,, O y,,M M ~' N .-,N ~ .~ N
. ,-, N N
A
'
o ~ : ~ c o o EM o o. ~ n o. o
d
O O O .~ ~ .-.p., .~ O O O O O
O
ON ON N ~p 00o o00 ~ v M ~n
~, 3 3 W
~
Ao ~ ~ W ~ ~ ~ ~ U
p
O M M ct v7 ~D ~O l~ 00 ~ O
N
z
~
33
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M M M ~ 00 N l~ I~ 00 N
N ~n M ~D ~ ~D ~t W
C
w ~ ~O O O M Ov ~ M ~n l~ O~ O l~ Ov
'-' O ~ ~ ~ ~ N ~ N N N M .-, N ~ N
s.~. ~ O
~ ~4
w ~ ~ Ov a\ N oo O N ~t v0 0o O~ ~O o0
O ~ ~ M M N ~ N N N M ~ ~ ~--a N
y Q
0~0 O~O l~ l~ O~0 00 ONO 00 O~O O~O O~O 0~0
z ~ ~ ~O ~ ~ ~ ~ ~h ~h ~h ~
"w
°0N° ° ~ ~ ~ ~ N V
0
z ~ ,b ~n N O ° °"~° ~ ~ ~ ~ ~r ~
w U ~ own r, ,_, ~ ,-, N a\ ~ oo N
O
O M M M
p _0
M V ~ '-' ~ \D ~ I~ I~ ,-, ,-a
N
z ~ p ~ ~ .-r ~ ~ ,~ .-~ M
"v~ U ~ N
O" ~ ~ I~ ~ ~ ~ O M l~ OHO ~ M
V~ ~ V~ l~ l~ ~ ~O 00
N M
o ~ o ~ ~ a o°~, 0 0 o O
z
Q d -d ~--~ -~ b -o ~ -d ~-,
°o. °a. a. A. N
o. a. p. a. ~ ~ ~ ,~ ~ ,-~ N ,~ N ~ ~ ~
.~ 'b ~ o~ ~ oy ow~ t~ c~ oo O c~ O t~ .~ oo O oo N oo ~ oo M c- ~ t~
O op O~ op O~ op O~ ~ ~ N O~ O O~ D ~ t~ ~ oO O~ oo O~ ~ ~ N O~ O O~
O y ~ M ~ M ~ M N 00 ~ (~ M ~7 M V7 O l~ ~ ct ~ O ~ 00 ~ O ~ M
w w O w O w O w O w O ~ O w O w O ~ O w O w
Q'~z ~O ~O ~O NO NNO NO NO NONO NO NONO NO
a '~ ~ ~ M
ao ~
~ x x
O M M M ~ V1 ~O (~ 00 Ov O ~ N M
z 00 00 00 00 00 00 00 00 00 O~ O~ Q\ O~
34
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ O O p
C
N
w N ~ l~ l~ l~ OW t o0 N O O~ ~
OV.~ N N ~ M --~ N N M N M
w
w ~ O'' ~O ~D ~ 00 M I~ ~ O~ 00 M
O ~ ~ N N ~ M ~ N N N N M
w ~
N .-r~ ,~ ~ rr ~ ,~ rr
w
a o0 0o a, o~ O O ~ N M ~r
z
'-' w
o ,o ~ 0 0
~ ~
'~ o ~
v~
0
0 0 ~ ~ ~ o
0
z ~ o
o ~
o_ N ".'~"'~ N ~O ,-,N ~O I~ ~
U ~
M
H
zoo ~,
in U
~ n o ~ o ~'' ~ ' '-'
cn o ,-. ~ N ~ ,~ N ~o ~ ~t
o
N
o o ~'o o o ~o o o ~o
~
~
z~ ~. M M ,~ M ~ ~, ~ ,~
z
-~b b~
~ x ~
U U U U U U 4 4
~ ~ '" "
c~.r~ s~. ar a. ay
b ~ ~ ~ M M 00 (~ l~ l~ N l~ I~
U~ U ~ Ov 00 00 I~ 00 ~Ov~Q~ l~ ~OV~Ov
~ p~pOVp~pOvp~p01v>0W OU NOV ~Ov
Ow
~ ~ ~ ~ ~ ~ M ~ a\ ~ N 00 ~D
~ M M M l~ l~ ~ (~ O Q\ c~ O
U O ~' ~ ~ ~ ~ ~
~
t~. N ~ ~ ~ O O ..~.-~ ~ O ~ l~ N
Q,'~zA ,-.~,~ ,~ ON ON~iONOONN Ov ONE ~
~O ~D ~O ti O -~ O N O ENO
,~ .-- m, O ~.~0~ O N
O N O
O
00 00 O pp Ov ~ iM
~
U U U ~ ~ ~ ~ 1 U
0.
~ C7
' O
o ~r ~ ~ ~n ~n ~ ~ oo a\
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
--, ~ ~ h O~ O~ O ~--~
M
.b
O_
~ N ~ N N N N N N N N
O
ar
O ~ ~ N ~ N N N N N -' '~ N
a.
~'~o~. o a. ~ ah.o~, ~ ~ o ~ ~ o
z
~,
N
O
U N N
N
O
N
V1 ~ ~ t!7M M ~ Oh0 h
O O N ,~ ~' h .~ tn h ~ ~n ~D O N
U ~ h h o0 N ,~ tn ~ r.,,~
c
h
0
y H ~ ~ ~ M r1 00 V~
~, z ~ ,~ ,~ h ,- ~ h ~ ~ ~ o
h h oo , ~n ~n
N
a O ~--~ h N M ~t V1 00 ~O Ov O h
o ,~ ,~ ,~ ,~ o ,-,o ,~ ,-,
~
z ,~ M ,~ ,--V,~ .~ M .~ M M
'
,...,...., ~ .J .~
O b ~ GL 0.WL f-~GL G. _
~ p U U U U U U A~
U
~"~ ~ p~ ~ N ~ ~ i i i i
~ p. p~ R: ~
x
a~ ~~C~t~ ~v~~c~ ~v~~v~ ~c~ ~v~
a ~ A A A o
. . . .
'b h h h h O ~O OWE tn ~ ~ ~ ~ h
U ~ ~ Ov ~ O~ h o0 .-i h h ~ Ov U o0
N Ov N Ov O ~ Ov ,--~,~ Ov ~ Oy ~
O~ O~ O~ Ov Ov
at O ~n w W ~
U O ~' h h M h ~ N N ~ ~ ~ ~
Q~ M O\ M V1 h ~ ~ ~ M M M 00
O ~ O ~ ~ ~ Q
E
ANA ~~o~ ~~o~ os o os os os s s E os
M ~n M ~n N N N N N ~''~ .,s N
01 ~ vD o0 o0 O O O
A O N O N O O O O O A-'
O O
h h t/1
N ~ N N O O O
a z a ~
u
A ~
o
U
N M d ~n VW p vD v0 h
z o 0 0 0 0 0 0 0 0 o O
36
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ ~ O ~ N N O ~ ~ ~ ~ ~ M N ~
~
, M
O
G
O
~+. N O o0 00 v0 ~D .-.,O N N -W ~ ~O
M ~ ~ N N M M ~ ~ M N
O
~
~
v~ cf.., ~ l~ (~ ~ t~'~O Ov ~ ~ O ~O V7
by t3, N ~ ~ N N M N ~ ~ M N
O ~ ~
a,
W
~ o o ~ ~o ~ o ~ o~ ~ ~ o o o
z
~w ~ o ~' ~ ~ ~ ~ N ~ o
~
~
~ m n
o c
w
0
~, ~ ,b O I~ a\ 00 ~n ~p O~ O O M I~ O
U ~D I~ ~O M M ~ ,~ ~ V7 N ,-,M ~O
W
O
O ~ Q~ ,~ M ~O ~O ,~ ,~ r,
O O ~ N ~ ~ ~ ~ M O O ~ ~ ~ N
~ ~ ~
M U ,~ ,--i.-a M ,~ N N ,~ .-i ,--i N
N
z o ~ ~ ~ ~ ,~ ,~ ~ ~
~
U ~ N
v7
a\ - M ~O ~O ~ ,~ ,-.-~ N o0
~ M 00 01 V7 N ~ V7 O O ~ ~ ~ M
V1 ~ ,-~r~ M ~ N N ~ ~ ~ ~ ~ N
0o Ov ~ O N ~ M N ~ v~ M v0
~ N ~ N ~ N ~ ~ N ~ N
x
z ~ ,~ ~ M ,~ M -v M ,~ M M -i M
z
'
p.,O O O O O O O O O O O N
GL C~ GL ~4 G3~f3~ GL . ~ ~L ~L
~.,~ ~ ~ ~ ~ ~ ~ ~ ~
..'.,'~O O O O O O O O O
'~N '~N '~cV~N '~N'~N '~NN '~N
U U U U U U U U U U U
a, a. a. a. ar a. ~. Q. ~. a, ar
,w, 'O .~ M M ~p ~O l~ l~ ~ ~ ~ .~ ,~ N
U 'N ~ 00 00 00 I~ l~ 00 00 O~ O~ d\ 00 00 00
~ oo oo ~ ~ N N op op op n we oo
Q\ Ov a\ Q\ Ov Gv O~ Ov Ov Ow O Ov Ov
U O ccS ~O ~D ~O M M ~O ~D i i i ~O ~D I~
~ ~ O Q O~ O~ N N M M M ~ ~ O
c~ U O~ O~ O~ O~ O~ Q~ d ~ ~ ~ ~ ~
N N N O O ,~ ,~ r, ,--a.~ O O N
A O O O O O O O ~ ~,, w O O O
Q,'~, ~ w ~ ~ w w ~ ~O w ~O w w w
0 NN NM NM NO NO NN NN ~ O ~ NM NM N
O O O -i ~ O O ~ O O O
~
~
00 00 ~O ~O ~O ~ ~O ~ I~ M
' ~ ~
Q ~ N N ~1 ~-1 ~ j W W U
z ' ~ U U w'
~
U
0o Ov O~ O O ~ ~ N N N M M
O ,.~.--r.-i,~ ~ ~ r .~ ,~ .-.r
O
~z , , r
O O
37
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
O N ~ V ~ ~. ~ ~ ~ ~ M
M ~ .-
-a
N
O~ d' ~ O N V~ N ~ Ov ~ N
.~ ~, N N
,~ M M N N M M N ~ N N
O
v~ w tU ~ M M Ov ~ '~t ~ O 00 M
G, ~ "' '"~ M M .-~N M M N ~ N N
O ~ ~
N M a\ ~ O -~ N ~n M ~ ~w 0
0 o O O O .~ ~ ~ O
~ w
O
b~O~ ~ M M ~M ~ ~ ~ N ~ M ~ ~ O
~
Q
.
,b .~ M ~ ~ O M V7 ~ ~ 01 O
~
v~ n ,~ N N ~ M ~ ~ M
,~ w
O
E'' W O I~ v~ N O Ov ~ ~O vD N o0
w ~ ~ O oo N ow n M O~ ~t ~ ~n ~ o0
O O ~ pv ~ ~ O O ~ l~ M N
E
z ~' ~
~ ,
~ ,-,,~ ,~ ,~ .--a,~ .-i ,~ ,~ O N , .
N
U
OW ~ W N O N ~ ~D O N N o0
et o0 N v1 v~ ~ Ow t ~D l~ 00
V7 ~
t~ 00 Ow n O v0 l~ oo ~ Ov O ~ N
N N N N N N N M M M
z
M M M ~ M ~ ~ .-r M
O N N ,~ --~ ~ ~
~L ~ T~ !~ G~
O .i ~. ~. O o ~ ~ C/~ C/~C~ C/~C/~ x
C O O O O O ~
y ~ W W ~ O, O ~ 'M 'M ~M 'M ~M f
W :
u..t'" Gq pq U U U U U .,
N N N .' ~'' A ai a. t~.ss.
~ ~ N N N l~ I~ M M t~ I~ 00 I~ ,~ ~O
00 o0 o0 00 00 o0 I~ l~ l~ 00 00 00 o0
~
U 00 00 o0 I~ I~ O ~D t~ I~ N N O~ ~
c~ O~ O~ O~ O~ ~ O~ O~ O~ O~ ~ O~ l 01
~ ~ n n
U O l~ I~ l~ 0 00 v0 ~ N N ~O O O I
~ D O O o0 0 ~ ~ o o c~ ~ ~ Ov
~ Ov a\ Ov 0 o Ov Q\ o o U M M
Q\ a\ Ov Ov
E-i f3, N N N .~ .-r N .~ .-, .~ ,-, N N O
N c O O O O O O O O O O O O O
A w w w ~ ~ w ~ ~ w w w ~
N N N N N N N N N N N N N
~ ~ d' ~n ~n ~ .~ O~ Ov N v0 I~
O O O O O O -~ O O O O O O
M M M ~O ~ ~ ~ ~D ~O M N C~ 00
M M ~ 00 00 N vD I~
U U U a a pq ~ ~ z x
a ~ ~ ~ ~ A
o
_
W n vW O I~ 00 00 Ov O ~ N
.-.,,~ ,~ ,-.~N N N
~ z ,~
38
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
001 ~
'b
~ N
O~.OMOMNN.MNNN~MNM
w
O ~ O M N N N M N N ~ ~ M N M
~r
d d ~ o0 0~ ~o O .-~ ~ oo N M ~ ~wo
° °
C/~ ~ N O N N ~ <t ~~-r
w
O
O
bO~O~~MV1NN M000MV7
N N N ~ N
O
~_O~~~o~O~NO~~~Mp'~
M U ~ ~ .~ ~ ~ N ,~ ~ .~ ~ N N ~ M
N
~n U ~ oo N
O ~ ~ O ~ ~ ~ N N ~ M ~ M O ~ '-'
~., z C% ,~ ,~ ~ ~ N ~ ~ ~ ~ N N ~ M
M ~ ~n N ~D l~ M ~ 00 Ov O ~ N
z~~z~c
M ~ ~ M M
o~o~~~~~ a~a~~ 0 0 0 0
o -d ~, -d ~ ~ ~ c~, a. a. a,
f~, ~ ~ . fx N R; N C~: fx
N
U U ''a ''~ ~ ~ ~ ~ U U U U °"
a. ~. s~. ar ay o~
,,, 'b .~ 00 l~ 00 M 00 M 00 N 00 I~ O I~ O ~ O ~ 00 ~--i 00 I~ 00 ~O l~ .~ 00
U ~~ ~ O l~ ~ ~ O~ O O~ O ~ 00 01 O O ON p O O N ~ M O~ ,--i O~ N O~ I
p .r O I~ ~n O ~O ~ ~O O\ ~ O N Ov ~ ~ ~ Q\ ~ c~ M oo '~ O '-' Ov O t~
O. N c~ M N M .~ O~ N U N O~ N ~, O ~, O d O Q~ ..~ M O M .-, O~ ,~ M N
O A O w O w O w O w O w w w ~ O w O ~ O ~ O w O w
O N I~ N N N .-t N ~ N ~ ~D vD v0 N N N O N N N ~ N I
O ~ O O O ~ O ~ O ~ O O ~ ~ O O
00 O .~ ~ ~ ~ '~ ~ ~ D
o'a~~~~~~a~a~vQ
~ U
M ~ V1 v~ ~O l~ l~ I~ 00 ~ O ~, N
z N N N N N N N N N N M M M
39
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
oMO ~ ~ o~o~ O ~ ~ N M
, M
_,
G
'+~ N .--iO O M V1 N l~ l~ 00 M V7 O 00
- ~ ~ M N N N N N N . M N N
O ~ ~ M
O
O ~ ~ ~ M N N N N N N N M M ~ N
au
~.1 r-1r-1 r1 v-1 ~ r1 r1 r-1r--1r-ir1 r1
N O M W v0 l~
M M M M M
~aa~z~'
~.
M
d.~p~., M N N ~ ~ N ~ -~ N M M
~n Odv~
O
M ~ O ~~ l~ ~ M N
~ M M M
U M N N ~ ~ N ~ N c
O r1
4~ ~ Q' 0 N ~ N ~ ~ ~ oho
UvW - ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ w o
M
a~
p
p ~ ~ ,~ ,~ ,-.i,~ ,~ ,~ r.,
~
in U ~
~ O
O N N N ~ N N O ~ ~ M ~ N
~
M V7 ~ VW O t~ 00 ~D O~ O ~ N M
.
N ~ ~ ~ dw t N ~t m W n v~
M .~ ~ ,~ ,~ ,~ M ~ .-i
--i~ ..~pr C~, ar ~ c~ c~ c~
~ ~ ~
O ~ ~ ~ ~ d d d 'b -d -o
~ N N ~ N ~--~~
0 0 0 o N k ~ ~ ~ ~
~ ~
o a a a ~ ~ ~ ~
N N
. .. . . ~ ~ ~ ~ ~ , , ,
~m n
b ~O ~D ~O M 00 M l~ ~ 00 00 00 M M
l~ I~ l~ 00 l~ I~ O O 00 l~ l~ I~ t~
~ w ~ ~n vo wo 0 0 N vo w ~t v
o a\ o, o, o a~ 0 o a, o a' a' a.
~ M M M 00 M V7 N N ~O M M N N
O ~ ~ ~ ~ ~ ~ ~ ~ W~ ~ ~ C~ N
~s Ov O~ O~ l~ ~O o0 ~ ~ a~ ~O ~ ov ov
ov ov ov ~ ov ~ Gv O ~ ov
E-~ ~ o o o o .~ ,~ d d .~ ,~ ,--~.~ .-,
N o o o o o o o o o o o o o
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
d NO NO NO NO NO N~ ~O ~O NNONO NO NO N
N pv ~ M ~ ..fir~_ ~ V~ ~ ~ U
d v~ x va
~ w
~ ~ ~ ~ Q ~ ~ w ~ C7
A
o ~ ~ ~
_
M M ~' V1 ~D I~ DO 00 O~ O ~ N M
O O
M M M M M M M M M et ~t ~
~z
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N ~ ~ ~ ~ ~ M ~ ~ l~
C
O rr 00 N M
O ~ .t'..~N N ~ N M M ~ ~ ~ M N N
O
w
O ~ ~ N N ~ '~ M M ~ ~ QM N N
au
N M Ov O ~ d' N M ~ V1 ~O
~ -, ,~ M d' ~ ,~ ~ ~ ~ d'
~
~'
~
z
~w
00 ~7 N O N vD v'7 ~ ~ 00
LZ, ~ ~ ~ ~ N N N M ~ ~ N
p,r
~
O
O r.. oo ~n O N ~O ~n ~t M o0
~ 'b M N ~O N l~ ~ ~ M N ~ ~ 00
U v) n v~ ~ N N N ~ N ~Y
O
4-. O p~ ~ N ,~ N o~o
C3'
M O U N ~ l~ '~ ~ r.rM M ~ l~ ~ O O
C%
--i [~ ~ ~ .--~,~ r, O .~ ,~ O
O
~' N ,~ N
in U
~ ~ ~ N ~ ~ ~ ~ M o 0
o
z N ~ ~ ~ ~ M M ~ ~ ~ ~ N
~
t~ oo Ow n ~O I~ O o0 Ov O ~ N
v7 N N N m v~ ~n M ~m n ~D v0 v0
~
~
z .-~ M M M ~ .~ ,~ M ~ ~-.a
G~ 0.. A. ~ p, ts.
N ~ N N ~ ~ ~ o N N ~ ~
~ fx C~ ~ ~ Q o C~ rx ~4
C, .:..:.,.:,.:. .,~M '~
~ '~ ~ ,~C,x M /~
G ~ ~ ~ ~ G
U U
a. a.
'b ~ ~ ~ ~ o0 ~D N N o0 v0 oo O f~
Ov Ov Ov Ov I~ I~ ~ Ov 0o (~ lW I~ 00
O~ O~ U O~ ~D I~ O~ O~ N N ~D ~ N
00 00 00 00 ~ 01 M M O~ O~ C~ O~ O~
U ~n cC w w w w M O w y 0 .~ M M O
N ' ' ' ' w ~ ' ' (~ w w w w
O M r1 M M ~D ~ Ov Ov ~ O W U v0
N ~ ~ .-, ~ -~ N Q~ ~ ~ ~ O ~ M
~ ~ ~ ~ ~ O O ~ ~ O N
~
~ . . . , . O w w . O . O O
Q'AZ ~O ~O ~O ~ O w ~O ~O O w O w w
O ~ NO ~ NQ w NO N
NO NO NO
l~ ~p oo vO ~O '~ N ~ ~ M
A w ~ r~ c4 a ~ ~ W U
~ U
~' v'1 ~D t~ I~ 00 Ov O - N
41
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M M ~ M N O v0 ~O N I~ t~ M
O O ~ N ~O ~ 00 Ov M ~ oo ~n V7 Ov o0
b C
N
w N ~O ~O v~ N O ~O ~ l~ l~ 00 wW O v~
O V ~ ~ M N N ~-~ N ~ M N M M N M
w
w ~ Wn d~ ~ a\ ~n M vo ~o ~ ~ Wn ~t
O ~ ~ ~ M N ~-~ ~ N ~ M N M M N M
w b0 Cl,
~N rr
~r
l~ 00 0v O ~ N M ~t W O ~n ~O I
~~~z~ ~
.~ w
vp ~ N ~ M t~ ~ I~ I~ ~ I~
op ,~ l~ ,_, '-, l~ M N N ,n v1
O
z ~ b p N ~ 0~0 ~ O M ~ ~ N N ,!
c,", U N N .-, ,-i .--r M
O
4", .~". p~ ~ rN., ~O ~ ~ ~O ~D M ~ N ~ ~ 00
O O O M N ~~ N O M O~ O ~ ,~ I~ M
cn U ~ ,~ ,~ '~ ~n ~, ~n t~ r., oo N
~n U ~
N ~t M ~ M
v7 ~ ~ ~ ~ ° ~n ~ ~ oo N ~
M ~r ~n ~ t~ oo a~ O .-~ N ~ N M
~O ~O v0 ~D ~O ~ ~O l~ l~ ~ M M (~
y
o ~ '~ ~ ~ d ~ ~ ~ d ~ d
N rx N N rx N fx N C~ N tx N tx N ~ N tx N t~ N L~ C~ N fx
.:,~C.:,~C.:.~C.:,~C.:.,~.:.~C.:,x.:,~C..:~C..'.,~C.:.~C
a
,~ 00 00 0o M ~ ow~ t~ r t~ wo t~ oo ~ 00 a, ~ ~ ~ a\ ~ ov o0 00
U -~ I~ O~ N O~ ~O ~ O~ O~ 01 ~ O O~ M O~ ~O O~ ~ O~ op ~ pp O~ pp ~ N O~
U O c~ ~ O ~ ~O N 'ch ~ N ~ .~ ono ~ M N ~ M ~ ~O Ov . M ~ M i M v0
N c~ M N Ov ,~ O~ ,_, Ov N Q\ O Ov N Ov O Oy, M O
A O ~ O w O w O w O ~ O w O ~ O w O y, w w w O w
Q,'~z NONNO N~ NO NO NO NO NONNO~O~O~'ONNO
O ~ Q I~ O M M ~ M ~ ~ ~ Ov
A _0
M et v~ ~D I~ 0o O~ O ~~ N N N M
O w v~ v~ v~ V~ ~n ~n ~D v0 ~ WO v0
~z ~ ~ ~ ~ ~,
42
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
O N
~O oOoI~ ~ o00O ~ M -, ~
O .- ~ .~ N
-"
w N ~O ~ N ~ w O VO ~D ~t ~ Ov O ~
O V ~ N N N N M M M N M N N M M
w
O~~ N N ON ON M M M N ~ N ~ M M
w b4
r, ,~ ,~ ,~ ,~ .-, r, ,~ .-i
w
~ a ~ ~, o ~ N ~ ~o M ~ ~, ~ ~ o
W A O m~ ~ ~ ~O vD ,~ .-m 0 ~ ~ ~O ~O N
,~-
~
~z
~
~~ oo ,-r O N o0 N ~ ~ ~ ~- o 0
~ M I~ d' ~ N M ~~ ,--w.--~~ N M M
(/7
O
p M I~ ~ ~ N M ~ ~ ~ ~ ~ O O
oU
E"~ ~ ~ ~ V7 N I~ 00 M M O~ l~
~ ~ ~
z~,
O
_ ~D 00 M M M M ~ l~ O~ O
O N ~' ,~ ,~ ,~ .~ ,~ ~ N ,~ ,~ N
~
U 'r'
M
N
~
in U
y h ~3' ~ 00 O~ V~ 00 O~ ~D ~D ~D ~ 00 l~
O ~ ~ ~p 00 M M M M ~ ~ t~ O~ O N
z C/~ N ~
~., ,~ -.r ,~ .~ ,~ ,~ N .~ ,-~N .-r
~D l~ 00 M ~t O~ O w ~ N ~O
W A O (v [~ ~ [~ (~ M M I~ 00 M 00 00 M
'~ .~ ,~ ~ ~ ,~ M M ~ ~ M ~ .--~M
~"~ z
z
~
t.' ~.'
~ CL P. f~ GL CZ.p,, 0 0 0
~ ~' ~ ~ ~ ~
N N N C~ o o o o o 0
C~ ~ C~ M M M M M M
~ ~ C/~ C/~
U U U U U U ~ "' '
a. a. a. ay a. a.
M
U ~ "d M M N ~h M M M ~ ~ ~ N N N
o0 o0 O~ O t~ I~ (~ I~ O O 00 o0 o0
0o oo Ov ~ ~D O 0 N ~ '~ oo oo o0
Ov Ov O O aw Ov Ov O O a\ ~ Ov
~ ~N ~ ~ ~ a0 ~N ~ ~ ~ ~~ ~~ ~~ ~ ~~ ~a
H ~ ~~ d~ ~ N ~
Q o~ o~ ~ ~ o~ o~ o~ o M M o o O
A N N ~ NN NN NN NO N~ N~ N
~z D O O ~p O ~ O O O
~1,~ .-ir, , ~ O
~ f~,
O N ~ N N N O O
0 ~ ~ ~ a W W U ~ Z
~ ~ U ~
A o E
" -
U
~ N N
~
(~ l~
~ z .~
43
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~oO o~o ' o~o ~ c~n ~ ~ ~ N ~' o~o
~+. N N -, ~ (~ N in v~ W W
~ M N N N N N N N N N N
O
~
~
~,
O ~ ~ M '~ ~N N N N N N N '~ N
w V~ 0~ ,
N \O ~ ~ t~ I~ N N N N l~
~n t~ v~ ~n ~n ~n v~ t~ t~ t~ m n
au
E"' ~ N
O c~
z
~
wQ N ~ ~ ~ M ~ v ~ ~
~'a
oQ
a,
l~ ~
,.
'~' o ,
4~ ~ d" pp ~ ~ O M ~ O O ~ 0~0~
O ~ ~ M M l~
O
M
C>
p O ~ ~ ~ ~ ~ ~ ,--i,--i
~ N l~ N o0
.~, E'~ .-i ~ ~ ~ M M ~ O ~ 00 .-i
~
a
. ~ ~ o0 ~ l~ N N o0 ~n M
H z ~
-~
.
E., d M t~ ~ ~n ~ ~ o0 00 ov o - a\
~ ~ 00 M 00 00 00 00 00 M M ~ ~ 00
x
z ~ z .~ M ~ ~ ~ ~ ~ M M M M
." o, o. a. a. a. a.
a ~ ~ ~ ~ ~ > > ~ ~ >
~ o
. a. a. ~ ~
a ~' U U U U
. " ' ~ ~ ~
ay ay a. a. c~. a,
~ ~ ,"'r,,';o ov N ~ o ~ ~ ~ ~ ~ ~
ov a\ a' oo ~ ~ ov o, ov ov ov av ov
U ~ ~ ~ O O 00 ~ ~ ~ ~ ~ ~ W
U O ~ pp 00 ~ I~ O ~ ~ M M M M M O
Ow N ~ Q ~ M ~ N M ~ d ~ ~ Q~ ~
A ~--i,~ M N O~ ~ .-r,~ .~ ~ rr N
..~ O O O ~
O ~ O ~ ~
~ ~
n~ ~ ~ N N ~ N ~ ~ ~ ~ ~ ~'
Q' ~ z ~ ~ .~ I~ N W ~ O O O O O O
O O D O D O ~~ ~ ~ ~ .~ ~r
O N
O
~ ~ ~ ~ w z ~ a a a a a
~ . . ~
Z ~ A w
O O
p
x x x x x x x x x
M M ~ V7 ~D I~ 00 00 00 00 00
O
l~ l~ l~ t~ I~ I~ I~ t~ t~ h f~ I~
~z
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ V~ l~ ,_, "'~M
o~O ~ ~ M ~ ~ d' ~ ~ N ~ W
'b
N
4-. N N V~ ,-~Ov ~ N ~O O~ Ov N
O N N N N N ~.,~.~ ,-rv~ ,~ ,-a..~ M
~
w c% A:
4. ~ A .~ ~. 0 00 00 ~ ~n o0 00
O ~ '-''~ N N .--~M ,~ .-,~n ~~ ~~ ,~ M
N
~
w pp GL
w
..~ N N ~ N N ~ OM ~ ~ ~ M OOo
z
0 0
0
c _
~ O O N N M
d
' ~O ~ ~ ~ ~ ~ ,~ ~~ ,~ N
O M ,~
pU "."
M 00 O N V7 '~ 00 M 01 O~
4r ~ O" ~p I~ M ~ ~' ~ ~ V7 O\ ~ M M t~
U p ~ M '~ ~' ~ N ~ ~ ~
M oo O ~ ~n ~ oo N O~ O~ l~
O" ~ ~ ~ M M M t~
~
O O ~ ~ ~ M ~ N N I~ ~' l~ I~ ~O
~ ~ r., M ~ ~ ,-iN .~ ~ ~ ,~ ,~ ~-,
E., z
C/~
N v0 M ~ ~n tW O
H ' ~ ~ ~ ~ a\ o, ~ a\ a\ a, ~ a\
~ ~ ~ -~
~ ~ '
x
, M M -~ M M .~ ~ M , . M
,~,
~ ~ ~ ~ ' ~ N ~ ~ N ~
N
0 0 ~ fx fx ~ ~ fx C~ f~ f.~ fx
N '~ '~ .:. .,1..~ ..,G -,..,.,~ .,..,.,...,~ ...
N N ~ ,'Y~,'~ ,~ .., ,'~','~ x ,'X~,,'X~,,'
',~C,
V
ar r~.
yo ~ ~ ~ ~ ~ .~ M M o ~ M M av
Q, pv ov ov ov t~ t~ tw t~ t~ t~ t~ o0
Ov pp pp pp pp W N N 00 '~ W WO 00
~ Ov Ov O '7 O~ 01 ~ O D Ov Ov
~ O
~ pp ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
O ~ ' ~O M M M ~ O O Q~ ~ 00 00 (~
~O ~ ~ ~ ~
GL N ~ N ~ ~ ~ ~-~M M N ~ ~ ~ N
p A N ~ ~ ~ w O O Ow O O O O O
~ ~ ~ ~ ~ w w N ~ w ~ w N
O O O O O N N O N N N N
~ O O O ~ ~
oNO ONOOO N ~ ~ ~ M
'-' "''''' ~ h ~ Oi O O
-,
O ~
~-1 ~ ~ ~ p O O O O p
U~ x x
x x x x x x x
~ Ov O~ O O O ~ N N M ~t ~ N ~O
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
d '+~ p~ 00 00 0 ~ o o ~ p O ~ ~ M o
,...a d ° p ~r ~ "~ °° oo ~ N N ~ M
'b
O~ ~O ~O ~O ~O O O M 00
''' ~ ~ ~ M M N N N M M ~ N
N O
d ~+. ~ ~ 00 00 ~n ~n r., ~n ~n a~ a, N t~
O ~ ~ ~ .~ M M N N N N ~ N
w G,
N M ~ N W O M t~ ~ 00 Ov
..i pp M M M 00 M M 00 M 00 M M 00
v~ z ~ t~ t~ t~ ~n t~ t~ ~n ~ ~n t~ ~- V,
H tmy, O cd
zw ~~ N ~ ~ O ~ M
~n p ~ V7
z ~ .00 ~D ~ ~ ~O M ~ oo N O
O ~ .~ ~ ~ ,~ ~D V1 ~O l~ ,.~
oU
~00~~ONl~,n,_, ~MN V7~
p _O N ~ ~ M ~ ~ G~ ~ O O O ~ ~ N
M U 'n N ,~ M .-~ .~ N
p _O ~ '~ ,--i ,--~ ,~ ,~ ~ 0M0
m U
00 ~ ~ N I~ ~ ,~ '~t I~ N V7 ~
~ ~i' ~.,~ ~ "1 O ~ ~ 00 ~ I~ I~ ~
v'7 ~ a\ M a\ l~
E.., Or I~ oo Ov O o0 ~ N Ov M O ~ ~n
~ ov ~ ~t m own ~n a~ ~n o mn O
"""~ ',Z, ~ M M M ~ M M ~-n M N M M N
p., p., O
fx ~ f~ ~ fx ~ ~ ~ fx ~ fx ~ C~ ~ R: ~ rx ~ fx ~ fx N ~ ~ o
. ' ,'~f,' .:. ,'~t,' ..: ,'X,' .:., ,'~(,' .:. ,k,' .:., ,'X,' . r, ,'X,' .:.
,'X,' .'., x .:., ,'X,' .:., ,'~(,' .:, ,'X,' ~ M
U
a.
"~ ov '~' ov "' ov '~' o, ~ o ~ o ~ 0 00 00 00 00 ~n ~ ~n c~ ~n ~ w o0
~ ~ o~ ~ o~ ~ o~ ~ o~ 0 0 0 0 0 0 ~ o~ ~ o~ o~ o~ ~ a. a~ o~ ~ a~
O ~ 00 00 0~0 00 ~ Ov . Ov . 0v N ~ ~ ~ ,.-m~
a. N ~ d .~ d .~ d .-~ d ,~ d o d o d o °' .-~ a. ,~ °' o o, o
c' o a. N
~ O ~ O w O w O ~ O w O w
dAZ ~O~ O,~ O~~O~ ~O~,O ~ONONONONONONO
-N-a~~NNNNN t~ 000
~1 0 ~-~, ~ ~ ~ ~ ~ ~ ~ ~, d
o t~ t~ t~ ~ 00 00 0o av o, 0 0 0
z o0 00 00 00 00 00 00 00 00 a\ a\ ov a\
46
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ O ~ ~ N ~ M ~
a
p ~ ~ I~ N M o o
,~aO '~ ~ ~ ~' M ~'' M 0 0
N N
a ~ G
O
O ~ .~' N N N N N M ~
.. ~ ct M
O
~1,
~
O~O N ~ ~ N N ~' N oMO O OM ~ ,-v7,
--i ,--a,--i,--~,--~~ ,~ ,--~,~ ,--~.--~.-,
w
a'
o
~
~,
a ~, z
N N ~ o ~ o 0
~n o
'O ~M ~ ~ M ~ O O
N N ~ N
O
~ w ~' M M ~n I~ ~O M O ~ N ~D ~h p O
a'
, ~ ~ ~ o o ~
jv o
t ~
~
~ p yy ,~ N N ,-~oo ,~ ,~ oo ~ N ~' N
U '~
~n
a' M M 00 t~ ~O M O ~ N ~O ~ p O
N ,~ ,~ N
~ ~ ~ O oo ~p ,~ ~ o0
CJ~ ,. ~ N ,_, .-,
..,
o o ~ o ~ ~ o
~'
x M N M N M M N M M M N M M
~
'Z,
a a ~ ~ a
~ ~ ~ ~ ~ ~
o o o o o o N N N N N N N
rx C~ rx ~ c~ ~ C~
M M M M M ~M .~~ . -~'JC~~~,-
'~,
~, ~
U U U U U U
a. c~. a, a. ar a.
o\ o\ a\
'b Ov N N 00 00 00 ~ ~ ~ ~ WG ~ ~
o0 o0 o0 00 00 00 ~ O~ Cv O O O O
00 v7 wl ~ I~ ~ pp pp pp pp O O D
:j Ov O OW Ov OW Ov Ov Ov ~ Ov p O O
O o0 00 oo oo oo o0 ~ ~ ~ ~ N N N
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~
(~ [ 00 00 00 M M M M i i i
~ ~.N ~N ~o ~p ~~ ~~ ~~ a~ a~ a.~a~ ~ O\ O~
~ o o o o o o ap ap ao
~ ~ ~ ~ ~ ~ ~ ~ ~,
a A z N N N N N N ~ ~ ~ ~, ~ ~ ~
D O O O O O O~ ~ ~ O O O
V~ v7 V~ ~ 00 00 00 p~ O~ Ov
z a A ~ ~ ~ U ~ ~ ~ a
~
~
U
N N M M M d' ~ ~ ~ V7 V'7 V7
47
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
O O ~ ~ ~ M 0 N ~ ~ ~' M N ~ v'1
, ,
_, -,
b
O ,~ ~p 00 00 V M
O ~ .~ N N OM ON N N ON N N ~ ~ ~ N
N O
4. ~ ' N ~O ~ O~ .-~ O O~ O ~ I~ I~ M N
O ~ ~ N N N ~ N N ~ N N -~ -~ ~~ N
w
Ov N O M ~ ~t ~n ~D N I~ 00
~ N ~ N O N ~ ~ ~ ~n ~ N ~ 00
~ ~ ~
ar
.-r,--Vr.r .r N M
O
N ~ ~ N o0
O ~ ~ .- ~ N Ov N M ~
~ ''"' r
U
0
z ~ ~ ~ ~ ~ ~ ~ o
o~
o ' ~ ~ .~ .-.~.~ ,~ ,~ ~ 00 00 ,_",,.-
U U'
i-n r
p O ~ ~' O ,~ ,-~~ N .~ .-, .~ ,~ .-~.-i
v U ~
E-~ ~ o ~o o o o o ~ 0
~
o ~ v ~ ~ ~ ~ 0
z
~
~
N oo M
0 0 0 ~ o ~ o ~
~,~~zx N N M N M N M N N N M N N
~, 0.~ G, ~, ~L C~.
~ ~ ~ N ~ N ~ N ~ .~ .~ ~ ~
~ C~ R.' G~ ~ tx C~ ~ f3: tx fy
j '~~~~~ ~~x ~~x~c~ ~~~~~x ~~~ ~~x~ ~ '~~ yDC
, ,
~ ~O ~D M M 00 00 ~ 00 V7 tn M ~
y 00 l~ I~ 00 00 O~ ~ 00 I~ I~ l~ 00 l~
Ov N N O O ~ d' o0 ~ ~ ~ n wl
Ov Ov Ov ~ Ov Gv Ov Ov Ov Ov Ow O O~
~ ~~ ~ ~ ~ ~ O ~' r' """'op n
C M p~ p~ p~ p~ o p~ p ~ ~ ~ y cV
Ov ~ O~ O~ M M M O~ O~ ~ Ov O~
E'~ ~L O ,~ .~ N N O O M .~ ,~ .-rO ,
N c O O O O O O O O O O O O O
A w w w ~ w ~ w w w ~ w w w
N N N N N N N N N N N N N
N ~O ~D ~ -~ N N l~ I~ I~ I~ v~ N
O O O O
-~ O O O O O O O
00 ~ ~ ~ y p v0 ~ M O O N
Q Q
A o o A A A ~ A ~ ~ ~
~ x
"v ~ x x ~ x x x x x x x x
W p I~ (~ 00 0o Ov Ov O ~ N N M
O
Q\ Ov Q\ Ov Ov O~ Ov O O O O O O
N N N N N N
48
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
O ~
d O ~ M .- ~ ~ ~ ~ N 00 M V~
r
b G
N
w N v ~t O ~ ~n N N d Q' ~O O Ov
O N N N N N N N ~ N N
~
~
w
O ~ ~ N ~ N N N N N N
~ ~4
O ~ ~ O ~ O O O
d ~n ~ ~ ~ ~ ~ ~o c~ ~ ~o
0
zw ~ ~ M
~~
~
O
0
l~ V7 ~ ~ N M (~ ~t O v~
M ~ ~ '~ M ~ ~t N N
O
N N M N
p~ I~ 00 ~D .-r01 l~ M 00 M ~
O 00 0
O O G7 ~ vo ~n ~ I~ ~O d' O M
W
cn U ~. ,~ .~ ,~ N
~ r"~\O ~ ~ M .--iV7 M ~' ~ .r
-i .-.a M
~n U
~ 00
O ~ ~ ~ ~ ~ l~ ~ Ov O M 00
(~ C/~ ~ ,~ ~ ~ ,~ ,~ ,-, N ,_,
~ N I~ M o0 Ov O
~,a ~ ~ o ~ ~ ~ ~ ~ ~ ~ N
N M M N M M N M N N N
~ a~ ~ y
A..I~ A-1A-1 A-1 ~ ~
N N N N ~ ~ ~
C~ ~ rx C~ fx C~ fx C~
.~x.~x .~x .~x.~x .~x~ ~ ~ .~x .~~c
~ ~ ~ ~
, ,
'b I~ I~ I~ N N N I~ l~ I~ I~ ~O O~ O
V N ~ N N N Q\ C~ Q~ ~ ~ l~ I~ I
~ ~ ~ M <''~M N N ~ M O
~ ~ ~ ~ ~ ~ ~ ~ ~ Ov
N U O~ O~ ~ ~ ~ o o M ~ M
U O ''' t~ l~ l~ O~ 01 O~ O O O~ M ~
p. N ~ t~ t~ t~ d d d O~ ~ O~ et ~ ~ N
O O O O O O O O~ O O~ O O
I~ O l~ O
O~ N O~
N
A ~ ~ ~ w w E,.,~ w p p~ w O O O
d ~ z w w w ~ ~ w w p w w w w
M M M I~ I~ t~ ~ N v~ ~ N N N N
~ ~n O I~ Ov
O O O O O O O O O O ~ O O
d ~ ~ ~ z z "
~ a. a a
z
A ~ ~a ~a
~ x x x x x x x x x x x
~n ~n Tw o vo ~ t~ t~ 00 a\ O
~ O O O O O O O O O O
Z N N N N N N N N N N N
49
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
ti ~
b
oo M Ov N Ov N ~ N ~ ~n M ~t
M ~ M ~ N M N N N M M
O
~- ~ a' I~ N o0 ~ 00 --~ O ~ ~ ~ N M
M ~ M ~ N M N N N M M
y,..,
ao ar r, ~ ,-..m.r .-rr, ,--i
~
w
' o y~ n o o ~o o 'o
z~~~ M ~ N
p.., N ~ oo r, N oo ~t N ~ '~h'n c
O
O
N ~ ~ N ~ ~
U ~ N
O
H ~ v1 ~ ~O I~ l~ 00 01 ~
G' ~ O l~ I~
p O N ~ N N N ~ ~t O M M o0
O t~ ( '
~ ~t
cn (~
v U ~ ""
~ a,
O ~ O N N ~ ~ N N ~ M
O ~ ~ ~ ~ ~
C/~ ~
~ .~ ~ .-i M ~ ..~ ~ .--w
N N N N N N ~ N ~ N N
M N N N N N N M N M N N
(1, (1, O O O O p..,
N ~ ~ ~ N ~ ~ ~ ~ N ~
fx C~ fx tx C~ f~ Q o o o f~ RG
.~~C,.~~C,.~,~c',.~x .~~C,.~~C, ~M ~M ~M ~M .~~t',.~,SC,
U U U U
~
a. a. c~. a.
b O ~O N t~ l~ M ~ ~ ~ M M ~ ~
~ l~ h ~ M I~ o0 ~ U O~ (~ I~ O ov
ov a o av o w o wo ~
o, a o o~ o
U y o N ~ v v q ,~ w, ~
a~ ov ov , o ~ r-~ ~ ' ~ ~ , '
U O ~ ~ ,~ W'V o ~ ~ ~ ,~ .-i ~ '~t~--~M
N M ~ d oo O~ d ~
~ O ~
00 O
Ov
H~ o~ o~ o o~g~ o~ ~ o o g~ o~ Q~ ~~
A N N ~ N ~ N ~' v0 yp N N ~ ~
Q,' ~ Ov v0 Q\ N v~ ~ oo O ~ ~ O O
z O O O O O O O O
O pv ~ ~ ~ M M ~ N
~
U N 3 ~ ~ N N C7 C7 3 W
A ~ a ~ ~ > x
o
_ x x x x x x x x x x ~ ~x
"~
O ~ N M ~ ~w 0 ~D t~ I~ oo Ov
. ~ ~
.-r ~ , , ,~ .~ r, ,
z N N N .- N N N N N N N N
N
SO
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o O ~ oho
b~
w N ~ ~ M ~O vD v0 M
'-' O M N N ~ ~ ~ N N ~
~ ~
v.~. ~
O
w
O ~ ~ M '~ N ~ ~ ~ N N ~
.,
-, ....
a~
a o ,~ N
d
~
~
~
z
~ w
M ~ N N ~7
w
C/~ ~ M
O
-M~ N N
w
O
w ~ ~' 00 l~ ~ M N N
O O ~ M O I~ 00
~ c~ 00 ov o0 00 00
cn V
z o o ~ ~ ~ .~ ~ .~ o
~
~n U ~ ~"
~ o M N Ov ,~ .., O
O
M M l~ 00 O O v7
Q1
O
M N M M N N N
a, a, ,_, a, ~r ~r a~
~ ~ ~ ~ ~
~C 3C ~C N~C N~C DC
a. . ...,
~ ~C N~C
U ~ ~ ~ ~ ~ ~ I~ t~ t~ N t~ ~ ~ t~
O Ov D\ O t~ 00 oo oo O t~ I~ N
pp pp ~ Ov E E E N Ov N ~ ~
Ov Ov ~ OW OW OW O~ ~ ~ Ov ~ 01
U O ""' ~ ~ O~ ~ ~ ~ ~ O~ I~ M O~ M
t~. N M M O 01 00 00 00 O C~' C~ O N
~ Q ~ ~ O ~ ~ ~ l~ O ~ t~ ~
.~ .~ Ov ~ ~ ~ Ov O ~ N
N N
~nzA a ~o ~,ooo oo Do oo ~,ooo oo ~,ooo
o
W W ~ U U U
~ ~
~ ~ ~ W W W W W
o
_ x
0
O N N N N N N
Z N N
51
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
v~ o n ~ ~
~
N ~ ~ N N
b
N
~O ~O O N ono~ ~ O O
'"
>
., ~ O
w
W ~ ' v7 ~ Ov O t~ M 'cYO~ O~
O ~ ~ .~ ..~ ,-~ N .-wt ~ N N N
~.
ON N N N N ~ N
z
o
o
o~ ~
V~ N
O
,.., \O M ~ ~ ~ M ,.~~ O 00
t~
0
~+. ~ 0~1 ~ M ~ ~ ~ ~ M G1 00
C" O
O
~ ~ ~ ~ o0
v~
V ,~
0 0 ~ ~ ~ ~ ~ ~ ~ ~ ~ o
in U '~' N M
Ov ~ v7 M 01 00
C/~ ~
N v0 l~ oo Ov O M
x M 00 00 M M M M ~ 00
z ~ ;~ N M M N N N N N M N
p, A, 0.. C~. P.. ~1,
o ~ N N N N ~ ~ N N ~
~., f~ tx c~ ~ ~ fx R: tx G4
N .~ ',~C.~ ',~C.~ JC .C .~ .~ .~ .~ .~ .~
JC JC JC JC ,5C 'J~,~'C
'b I~ l~ l~ I~ l~ I~ 00 ~t .-~ N M M ~
N ~ N O~ O 00 00 I~ l~ U
N ~
Ov Ov O~ ~t V7 ~ n N N 01
U O '~ Ov Ov D1 Ov 0 OW Ov Ov ~ ~
~ ~ M O~ M ~ M ~ 'i ~ ~ ~ ~ ~
G O (~ O C~ O (~ O~ ~ N ~ O O
N ~ M ' ~ ~ ~ ~
. ~ .-r I~ .~ I~ ~ O N N O M M N
~ N O~ 01 ~ d ~ ~ ~ ~ O
01 M N N N M N , 0 O
O , 01 M Q\ M ~ ~
~ D ~ O ~
~'' ~''
0 0 o O o O O O
O o
~ ~ ~ ~' N
Q p~ V~ (1r Cl~ C/~
~, z z z o
~ ~
~ u~ w u~ w w a a o
o . ,
_
0
N N N N N N N O O
z N N
52
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
'a-~ O v0 l~ M N N v0 d' ,.~.., rte,., v0 00 00
0 0 ~ oo M ~ ~ ~ ~ ~ r., ,~ ~n t~ t~
d v.. ~ ' ° v-, ~n M o0 00 ~ ov o, a\ ov ov
" O ~, ~ N N M N ~ ,~ N N ~-~ .-, ~ N N
w
W cue, tp ~3. ~ d' N I~ t~ v1 00 00 00 00 00
O ~ ~ N '~ M N .~ ,~ '~ N ,~ .~ ,~ N N
w
N N N ~ I~ N ~ ~ M M
w do 0o M~ ~ ~ o ~ o o ~ °° o. o. M ~ o
o ,_~
O M "~ O ~n ,~ ,~ oo ~ o
.M-i 01 O ~ Gv ~ M ~ M
O
vD ~_-~ 00 00
p _O ~ pM p W l~ O ~ O O I~ l~ M ~D l~
M U ~ ~ ~' ~ .~ N o0 W ~ ~ ~O N O~ 00
in (, ~ M N ,~
E~ a' p ~ N ~ ~ Q' '-' ~ '~ ~n yn
~°.,z~;n~ o~~ o°°~~NO~.o°°o
z~~'zxMMN NNMMNNMNN M
a,
fx ~ C~ .~ N fx ~ C~ ~ fx ~ fx ~ p, ~ ~ N N L~ ~ ~ N ~;
° ' x.:,~C.' ~.:.x ~ :.,~.:,~.~~.'
~ ~ Ov 00 I~ ,~ 00 ~ Ov ~ Ov ~ O~ ~~ 00 M I~ M I~ O o0 N Ov N 01
O pp 01 pp Ov M Ov ~ Ov pp 01 pp Ov pp Ov V 7 Ov N Ov N Ov o0 Oyp Oyp Ov
U O ~ ' vp ' vp ~' M Wn ' M ' M ' M ~ ~t ~ O ~ O ~ ~ ' c~ ' N
G. N ~ ~ N ~ N ~ O ~ N ~ ~~ ~ ~-~ d ,~ ~ O ~ M ~ M ~ ,-~ d O ~ O
w w O w O ~ y, w ~ O w O w O w O ~ ~, w w
O ~ O N I~ N N ~ O ~ O ~ O N M N O N O N ~~ ~ Q\ Ov
D O O O O O
OMOOMO~ ~~ ~~,-N-~.-Nr00~
~ as ~ 3 x ~C x x x
N M ~ ~' ~t ~!1 ~ ~O I~ 00 00
M M M M M M M M M M M M M
z, N N N N N N N N N N N N N
53
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
w ~ N O V~ ~ M ~ M ~ ~ ~ ~ ~ N
d' O O v~ ~n ~ ~ V~ ~ d. O ~ ono ono~
b
N
w N y M O ~ - ~ ~ N N ~D vD
O N M N M M M N N N N N N N
~ ~
ON O O ~ ~ N N N N r'
r. r.
M ~ M ~
'..i M M M l~ M M l
Q
z
~
~ w
0
' N -' M M ~ N N ~ ~ ~ N
A"' ~ .-,-' M
~ .i
v7 p
C/~
O
N M ~ N N N_ ~ M M
M M M ~ N N ~ ~ N
O
V1 N 00 ~O ~ O~ 00 00 O~ O~ ~D l~
w ~ ~' O ~ O O O O~ ~O M M N o~ o~
O U ~ ~ ~ ~ M M ,~ l~ ,~ ~-.i
~ M N
M M M N ~ ~ ~
O
p ~ ,~ .-r
~
U ~
~
n
~n ~ N 0o ~D ~ ~ 00 0o Ov O~ ~ t~
E-~ ~ O O O O N C~ N
o ~ ~ ~ ~ ~ ~ D\
M M N ~ ~ ~ \D M N
N N N N M M N N M N M M N
(1, O O O O O O O O O O
w GL Q. f~.G1~ CL CL p. GL C. G7.
N o N ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
C~ f~ o o o o o o o o o o
c~7 .:.,~~ .' '~M'M M '~M '~M'~M ~M '~MM ~M
"' '~C,
'
.t ~
. t
' ~ U U U U U U U U U U
a. n. a, a, ai c~. a. cL o~ r.~
'b o0 ~ M O O O Wt ~ .~ ~ ~ ~ ~
U y ~ Ov 00 00 Ov Ov O O 00 00 Ov ~ Ov O
~ ~ o ~ t- ~ ~ ~ ~ ~ ~ ~ ~
~ ov o~ ov ov o~ o o~ o~ o~ Q. av o
~ vo ' ' 'r''r' ~' . ~ 'D ' ' '
o ~, a~ ~n ov ~, ~.~ .~ .~ n V, vo vo vo '
U M ~ ~ M M M N ~ ~ Q ~ ~ N
N ~ N ~ ~ -~ N N N N N
[- O N O O ~ O O ~ ~, w ~
, ~ O O ~ O w O w ~ w O ~ O w
O ~ w N ~ N w M N N ~ O ~ M
N N .-t N ~ N N N
N N ~ .~
AZ o 0 0 0 0 0 ~0 0 0 ~ ~.~~ ~o
O y 0 ~ ~ ~ ~ ~ ~ 00 00
M ~ O, 0..i x
~
U ~ ~ ~ ~ U
~_o x
~ Ov O ~ N N N M ~ W n v~ v~ ~D
M ~ ~ ~ ~ <h ~ ~ ~ ~ ~ V' ~t
z N N N N N N N N N N N N N
54
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M .-n
b .t'.
N
W N .O ,-i
O V M N
~
w
+, ~ ' O M
o ~ ~ M cv
da~z~'
~w
M
O M 01
~ M .M-as
O
'+
~
oU
o U
E
zoom ,~
~
U 'n
n
M
H
zapx N N
z
~.
~ N
o f~
a~ ~ .
ri x
U
o~
Y
U
a.N ~ ~ ~
~AZr~ ~ o
a 00
o
N ,~'
z~ ~
U
00
~z N N
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
Table 1B (Comprised of Tables 1B.1 and 1B.2)
The first column in Table 1B.1 and Table 1B.2 provides the gene number in the
application corresponding to the clone identifier. The second column in Table
1B.1 and Table 1B.2
provides a unique "Clone ID:" for the cDNA clone related to each contig
sequence disclosed in Table
1B.1 and Table 1B.2. This clone ID references the cDNA clone which contains at
least the 5' most
sequence of the assembled contig and at least a portion of SEQ DJ NO:X as
determined by directly
sequencing the referenced clone. The referenced clone may have more sequence
than described in the
sequence listing or the clone may have less. In the vast majority of cases,
however, the clone is
believed to encode a full-length polypeptide. In the case where a clone is not
full-length, a full-length
cDNA can be obtained by methods described elsewhere herein. The third column
in Table 1B.1 and
Table 1B.2 provides a unique "Contig ID" identification for each contig
sequence. The fourth column
in Table 1B.1 and Table 1B.2 provides the "SEQ ID NO:" identifier for each of
the contig
polynucleotide sequences disclosed in Table 1B.
Table 1B.1
The fifth column in Table 1B.1, "ORF (From-To)", provides the location (i.e.,
nucleotide
position numbers) within the polynucleotide sequence "SEQ ll~ NO:X" that
delineate the preferred
open reading frame (ORF) shown in the sequence listing and referenced in Table
1B.1, column 6, as
SEQ ID NO:Y. Where the nucleotide position number "To" is lower than the
nucleotide position
number "From", the preferred ORF is the reverse complement of the referenced
polynucleotide
sequence. The sixth column in Table 1B.1 provides the corresponding SEQ ID
NO:Y for the
polypeptide sequence encoded by the preferred ORF delineated in column 5. In
one embodiment, the
invention provides an amino acid sequence comprising, or alternatively
consisting of, a polypeptide
encoded by the portion of SEQ ID NO:X delineated by "ORF (From-To)". Also
provided are
polynucleotides encoding such amino acid sequences and the complementary
strand thereto. Column
7 in Table 1B.1 lists residues comprising epitopes contained in the
polypeptides encoded by the
preferred ORF (SEQ ID NO:Y), as predicted using the algorithm of Jameson and
Wolf, (1988) Comp.
Appl. Biosci. 4:181-186. The Jameson-Wolf antigenic analysis was performed
using the computer
program PROTEAN (Version 3.11 for the Power Macintosh, DNASTAR, Inc., 1228
South Park
Street Madison, WI). In specific embodiments, polypeptides of the invention
comprise, or
alternatively consist of, at least one, two, three, four, five or more of the
predicted epitopes as
described in Table 1B. It will be appreciated that depending on the analytical
criteria used to predict
antigenic determinants, the exact address of the determinant may vary
slightly.
Column 8 in Table 1B.1 provides a chromosomal map location for certain
polynucleotides of the invention. Chromosomal location was determined by
finding exact matches to
56
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
EST and cDNA sequences contained in the NCBI (National Center for
Biotechnology Information)
UniGene database. Each sequence in the UniGene database is assigned to a
"cluster"; all of the ESTs,
cDNAs, and STSs in a cluster are believed to be derived from a single gene.
Chromosomal mapping
data is often available for one or more sequences) in a UniGene cluster; this
data (if consistent) is
then applied to the cluster as a whole. Thus, it is possible to infer the
chromosomal location of a new
polynucleotide sequence by determining its identity with a mapped UniGene
cluster.
A modified version of the computer program BLASTN (Altshul, et al., J. Mol.
Biol.
215:403-410 (1990), and Gish, and States, Nat. Genet. 3:266-272) (1993) was
used to search the
UniGene database for EST or cDNA sequences that contain exact or near-exact
matches to a
polynucleotide sequence of the invention (the 'Query'). A sequence from the
UniGene database (the
'Subject') was said to be an exact match if it contained a segment of 50
nucleotides in length such that
48 of those nucleotides were in the same order as found in the Query sequence.
If all of the matches
that met this criteria were in the same UniGene cluster, and mapping data was
available for this
cluster, it is indicated in Table 1B under the heading "Cytologic Band". Where
a cluster had been
further localized to a distinct cytologic band, that band is disclosed; where
no banding information
was available, but the gene had been localized to a single chromosome, the
chromosome is disclosed.
Once a presumptive chromosomal location was determined for a polynucleotide of
the
invention, an associated disease locus was identified by comparison with a
database of diseases which
have been experimentally associated with genetic loci. The database used was
the Morbid Map,
derived from OMIMTM and National Center for Biotechnology Information,
National Library of
Medicine (Bethesda, MD) 2000;. If the putative chromosomal location of a
polynucleotide of the
invention (Query sequence) was associated with a disease in the Morbid Map
database, an OMIM
reference identification number was noted in column 9, Table 1B.1, labelled
"OMIM Disease
Reference(s). Table 5 is a key to the OMIM reference identification numbers
(column 1), and
provides a description of the associated disease in Column 2.
Table 1B.2
Column 5, in Table 1B.2, provides an expression profile and library code:count
for each
of the contig sequences (SEQ ID NO:X) disclosed in Table 1B, which can
routinely be combined with
the information provided in Table 4 and used to determine the tissues, cells,
and/or cell line libraries
which predominantly express the polynucleotides of the invention. The first
number in Table 1B.2,
column 5 (preceding the colon), represents the tissue/cell source identifier
code corresponding to the
code and description provided in Table 4. The second number in column 5
(following the colon)
represents the number of times a sequence corresponding to the reference
polynucleotide sequence
was identified in the corresponding tissue/cell source. Those tissue/cell
source identifier codes in
57
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
which the first two letters are "AR" designate information generated using DNA
array technology.
Utilizing this technology, cDNAs were amplified by PCR and then transferred,
in duplicate, onto the
array. Gene expression was assayed through hybridization of first strand cDNA
probes to the DNA
array. cDNA probes were generated from total RNA extracted from a variety of
different tissues and
cell lines. Probe synthesis was performed in the presence of 33P dCTP, using
oligo (dT) to prime
reverse transcription. After hybridization, high stringency washing conditions
were employed to
remove non-specific hybrids from the array. The remaining signal, emanating
from each gene target,
was measured using a Phosphorimager. Gene expression was reported as Phosphor
Stimulating
Luminescence (PSL) which reflects the level of phosphor signal generated from
the probe hybridized
to each of the gene targets represented on the array. A local background
signal subtraction was
performed before the total signal generated from each array was used to
normalize gene expression
between the different hybridizations. The value presented after "[array
code]:" represents the mean of
the duplicate values, following background subtraction and probe
normalization. One of skill in the
art could routinely use this information to identify normal and/or diseased
tissues) which show a
predominant expression pattern of the corresponding polynucleotide of the
invention or to identify
polynucleotides which show predominant and/or specific tissue and/or cell
expression.
58
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
O O O I~ N
O
~ O~ O O O~
I~
N M O o0 ~O
O
~D ~ Ov O
'~'
O ~n ~1 O O
O~
O O ~n ~ N
~n
N
-.~
M 00
01 N
N v~
M O
~ ~ ~O
O N
O C"r
~'
~ ~
O ~ O O~ O O
~ ~
,~ r, vD ~ .y0 ~
,~
N
O O ~ O ~ ~
~ O
~ N
N v~ ~ 00 O
~O ~
O ~
~
~ _ N _
_
_
O
O ~n M o0 O
~ ~
,~ ,.-m.-, ,~ N .~ ,~ ~p ~O
~
N ~ N O vi O vW p Ov
v'i
O
(~ I~ 00N O V1 ~ Ov o0
~-'
l~
t~ N o0~O ~ O O v~ O
~D
O
N l~ O M O ~ O~ ~ N
O~
~
O O O N o0 N l~ O O
I~
O~
V ~
.~ M N
C.ln M M
O LC ~ '~_
~ V~
U ~ ~ M N
00 ~ ~ ~ v7 O~ M D\
O " " O
~ ~ ~
~ ~ ~ pp pp pp l~ pp
~ N N ~
M ~ <h
O ~ ~ M M ~ ~ 00 ,--i O
\O 00 v~7V~7 ~O ~ CL O i. O
~
G7w _ r ~ N ,
~' ~ _
' ~J
~. ~
~
'
_ p ~ , >,
, [~ ~"' ~ f~,P-i C/~ ~
~ V" E--~E-~ ~ d U
H ra C7
~ ~ '-~
O
fl O O
~ ~ O O O O O
y y
y
y p "' 0 ~ ~ y y y
~ ~ ~ y
~ O O
y O
~ O O ~
~
~ l~ V~ M M ~ N 00 O~
~ ~ ~O M M
~ b-0 ~ ~ ~ ~ ~ O A" ~ N ~ ~
O O ~ N ~ ~
~
a~~c~ ~ ~ ~~ a~ ~a ,
a~d~~~a~vc~
~ ~ ~ ~~ ~ ~ ~ o ~ 0 00
~a
A
z M ~OMM M ~ M ~
O l~ ~
~ M~D V'7M O ~ p '/~~O
M I~N ~ M ~ ~ ~ ~ N'~
i i ~~ ~ i i , , ' i~
O M MN
~i ~ ~ M~ ~ ..N ~ V7 ~ O
~ 1
~ NM ~ ~ vWO ~ l~ 0oOv
'-''~'~ '-~'~
N N N
z
D d' ~ a\N ~ Iw0 ~ l v~ NN
~
e M N _ ~ ~ _ _
~ o N v0
~ 0
~ M _ _ _ ~ ~
0 ~ ~ U M ~D ~ MN
U 0 ~ ~~ oo~ ~ ~ ~
oo t n t n n
C M M ~~ [~[~~ V'1~ N ~p1
~ ~~ x x a ~ ~ ~ c~~
U U ~ ~
N ~U C C C7
7 7
x~ ~ ~ ~ ~
a x x x
v
NM ~ v~~O t~ o0~
59
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o ~ o
N M N
M O M
~n O M
N ~D
O
t~
v7 M
~O O
00 O M
~
~t O ~ N O
N ,-~ ~O
1
O O O
0
o oo O
0
N N
~ 00 ~
~0 O
00
N ~
~
M ,..,
M ~ N
~'
C O. ~O
v7
~ ~ Wn N O ~ O M oo ,<j a V7
a~ N ~ ~
N Ov ~ v'i ~ O ~ I~ Ov N N
00 Ov N ,~
N
~ "~ a ~ O ~ N N N N M ~M M ~ O
M ~ M ~ ~~ ~
~
i O O a.. ~, .~ i _G v_~ _~ ~~ i M
a. s.. ~ Q. o N ~~ ~
~, ~ i cd ~ N ~ ~, f3~ f.3~
~ N N
N
'~~"a,r~ ~,-~Hv~v~ ~ HC7x~7aaa.~
C7 0 0 0 ~, 0 0 0 0 0 0 ao 0 H o
0 0 0 0 o g 0 o
g
o 0 ~ o 0
0 ~ .r ~ " ~O V1 ~I V1 am' ~' N
o .~ 00 vp 00 ~ ~p vp
" ~ " ~p ~ V'1
N '~ O ~D
M
Op ~.,~ pp O~ M M O~ ~ t!7 00 p~l~ (~ O M
~D ~ p~ pp .~ ~ O ~ '.r
N .-~ 00
N ~ p~ ,-, N oo Q\ ,~ .~ N N MN N M N
,-, .-~ M ~. N M ~'~ ~, ~' ;'
v~ ;'
G ~ ~ N~ ~ '~ y'~ ~~
~ ~ ~ ~~ ~
~ ~G4~ ~
~
~,
.. , ' ' C%
r. a"~~Ha~ , ~d~. aH~
c~~~c~~ ,
'
~c~~~ac~~H~a
a, o
O O ~ o O ~O ~ O .-
M ~ QvM ~ ~~,~ ,~ I~ ~ I
~
~ N M~ N _
00
~ M
i
O
N O N ~ N~ ~ N ~ N
N N M M~ ~ ~ ~ l~
O
N N N N N NN N N N N
M ~ ~ ~ ~ N
M v~ I~
N
~ ~ ~ N~ ~
o Oo
o O0
~N N
N N ~ ~
z o
~ ~
x
p ~ N M ~t ~1 ~Ot~
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0
a\
0 0
0 00
o .-: vo
00 0 ~
a, a\ ~
O O N
~O o0 O
~n O o0
M O
Wit' ~ G1
N O
M l~ O
O O O
O OO
~O WO
N o0
N l~ ~
.-, .-i N
O ~O
O M I~
N ~O N
.-~ N
M
N
N
Cr
o0 O V'1 1n Vj V'i ~!j ~
t~i NM ~O O t~M ~ t~ ~ tri ~ (~ .~(~t~
~ ,M-, ~ ~ ~ ~ ;' ;' t~
~ N
,- O ~N ~ cC~ ~ M ,01~~~ M ,0~~~~ M NMOO
~ Q _ ~ v
~
t3,. fn t1, _ " _c~ ~' _c~ v~
d N _cti T .C ~ W_,
~, ,~ N ~
U o H a,-~ ~~' ~ o o 0 0 ~ a~x
U o o ~d~ Q~~ o
o o
~ _ _ ~ O O
_ ~ O ~
~ ~ ~
vp'~ ~'~t~ N O~ N O I~ O O ~ ~ M ~ NN ~
-~ ~ v~ Ov ~ ~ O ~ ~ Ov O O
p M N N o0 N ~ ~ .,
O Wn M I
~O~ N M~ v ,~ ~ :,.L~.. ~ pp ~.-, , N~ r
r, ~c~ p 7, ~ ~ O O ~ .~ , ,
~ O y~~ ~ ~ O O ~
~
a ~ ,=-,dd 0., H E-~ ,~ a, E-~ ,~ a. ~ ~nC7
U C7 a., v? A.., v~ C7
a.., ~ a., v~ C7 U E
t~ N M o0Ov
N m ~o ~ ~
r v~w n
O ~ ~~ ~ ~ 00~0
0
00 00~ M~O~n~ ~ --,~
o0 v
N ~p ~ ,7
, , , ,, , , ,
~ , ,,
N ~v
M N N~ ~ ~ ~ ~
O
N N MN M M N M N N MM
~ ~
0 V'7~ OO~M ~ ~ ~ d' V1 00
0
N ~ ~ ~M ~
M
o ~ ~ ~ ~ ~ ~ O
O
MM '~ j~~00
00~Odd ~O v0~ V'7 NVJ
'7~ L1~ Pa~
r ~~ ~ ' '
G.H r ~ C7C7 U U
0oO~O ~ N M ~t~n
.~.-~N N N N NN
61
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
'
o
~
N
O O O
~ O
O
O N
pv M
O O M
O O~ N M
0o O N
~D N O O
O~ O N
~n O O
M O~ O M
00 O ~O
~ N ~O O
OWE N
N ,-r
O O O O N
v7 O~ O l~ ~O
0o O Ov O M
M N V7 O
O O~ ~ N O
M
N
O
v0 p
N
O~
M
~
~
p
~ ~ ~D ~ p OvN
-- ~ o 0
N 0~
~ ~ ,~ .~ ,-.i
N N
.~ .~ i .~ ,_, M ~Do
l t N ~O t r;
M 00 , O Ov v ~O
~ M 00 ~
'
'
~ c ~ ~ ~ ~ ~
~ ~ ~ >, ~ ~
c~
~
. Qj , '~a~aH~
~ ~ o c~~a~~ ~ ~ ~
~
0 ~ x o o o o ~ 0 0 0 0 0 ' ~
0 0 ~ 0
0 0 0
0 p p .' ~ ~ 0 ~ p o
' , ~, ~ ~' ~, y' ...~ a~ ,..,
' , ' ~, F., ~' ~..~ ...~
,..~
. . ''' Q ~ ~ .r
W N v'7 ''' ~' " '-' ''' ~' N ~ O M
O ~t N v7 M ~ ~ ~ v7 ~ M ~
N o0 O N o0 ~ O -~ yn O pp O M ~
~ ~ O .-~ p~ ~D O vD O
-.,M l~ ,~ M l~ ~ Ov ~ ,~ ~n ~p ~ ,~ ~ N
.-i.~ ~ .~ ~ ~ N ,~ N N M ~ v0
,~ ~ ~ ~
i ~ ~ i ~ ~ ~ ~ i
.
>, ~ w ~ ~ , , v~~
p N >, ~ ~ ~ p ~ D c~
t-. w D ~ t-. N p
p cd p
as C7 C7 C7 C7 ~ C7 C7 vW . 1 a; C7 C7 a ~
a H a. H a. w C7 ~ w ~ a: E-
a
v7 O ~ N M ~ ~D~n
N ~ ~ N
~ 00M
U M ~ N ~O~i ~ Ov
I~
v7 ' ,-,N N ,_,., ,-, ~ i
O ~ ~ ~ i ~
O I~t~~D v~
I~ ~ N oot~~O ~O
M ~ N V'
M M M
~ ~ M
N ~
~ ~ ~ ~ ~ N
N O o o ~
O o
_
~
_
~ w ~ w
~ 3
~ ~ z w W w w
~ ~ ~ x x x x
a, p
N N N N M M
62
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M
M
M
N
N
00 ~ N o0 N M '~'
I~
M
~
ON
_ ~ N ~ ~ N ~ ,~
_ ~~ U ,-i ~i
N N Ml
aN ~ pp" ~ ~ N ~ ~ M ~ ~ pp ~
c~
~
~,~'
_ ~ ~ ,~ E-i
_
_
_
O O ~ O O d' d'~ C7 r F.E ~
O O a -~, ",,
'"~
.'Y .~~~'~' O O O O O O O OO
O .WO ~ ~ O O a y, a.,a~O .N ar au au y,,
N Vl ~ ~ ~ 00
.N
a,
M ~ ~ ov .~ O ~ .-. W p oo O twp ,-.,
,~ dw0 O N M
~
~ .-r ~' Y ~ M ,~ l~l~;'N N D [v ,~
,~ N CV v~ M
N t
~
~ON~ Ns!O ~ ~"'~ 0 0 ~ O ~' ~~ O
dHQa.~~7H ~~ia~~ H v~ a:aaa a; ...a a~~aa~7~
~O l~I~00OvO~ 00O~N M O ~VWO t~00Ov
N ~ N N N MM V1V7M M ~OMM M M M M
O
M N I~N OvOW--~ O t
~ ~ M M ~ ~
~ N ~ vp N ~ ~t
N ~ ~ ~~ ~ i i i i ,i , , ~ i
i _ _
~ ~ N MN ,WO N M ~ ~~ ~ M O M
N M M ~~~ ~Gf~~ ~ 00O~~ O~~N M ~ V'1
~t N ~ ~ ~t'~~ N N ~ ~tN m~n~ y ~n~n
M I~O N 00~ I~00M ~tV7O00M ~ l~
O ~ M I~00l~'~C~N ~ N 00d'O M N M '-'
~ M v1O~ ~D~ ~ OvN ON o0~ O
M ~
00M M \O~ M ~'~O_~~O(~O I~M O~O
~ ~
O ~ V~~O~ O 00V~Q~Q~O~ O V~~
O O
O O o0ON00~(~I~l~~-~V'7,nplop~ ~ ,-~-r~ N
p p ~
p~q ~ ~~ ~ ~ ~ E E ~ rnU
~ ~ ~ ~ -~-~7~ ~ x
U U
w w w w O ~~Z~Z~Zz a a C~ ~ 3 ~ ~a
w w ~
x x x x
x x x xx x x x x x x x x ~
N M ~t~n~l~ 00pv O~ N M ctv~
M M M M MM M M
63
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M
a'
V7
M ~O ~ N ~ pp" .-i o0 ~ O ~ p~ ,-i 0 N Ov pp ,-.i
~ C,j N O~ ~ ~ oo pp"
~O ,
N N
~
N M ,~ N ~ ~ O r.
t~ ~
p~ O v~ ~ O ~ M o0 O N ~
M ~ ~ ,~ pv ,~ N ~ ~ ~. d~ ,~ ~; vp ~ t~ ~ .~ N ~ ~
,--~ ~~ I ~ op o0 pp oo Ov a' d~ ~ ~n
aQ c~ i ~ ~' GU ~ C
~ ~, ~ ~ ~ ~, ~ ~ ~' ~ ~ ~ ~ ~ ~' ~ N
>, ~ ~ ~ N
~~~ ~c~~>~c~a~c~H~c~a~~a~,~~~ ~c~~>c~c~~~
0 ~ o g o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0
0 0 o 0
.,u a.. .,., ,~ Y' ~ M l0 I~ ~ p 00 '~' ~' '~ ~ ~ M
y, ~ ~ [~ ~ ~ 00 .-r O~ ~ ~' ~D l~ l~
p~
O I~ ~p M v0 t~ ~~ N M v0 Q\ ~ oo ~ ~ M v0 l~ ~ N
.-r N 00 ~ O N ~ Ov M M ~O Ov
M M ~ O ~ ~ ~ ~ ~ y ~p ~ ~ I ~ ~ M
M ~O ~ pp ~ pp 00 O~
.~ ~ ~
GD~p7,~ C~~t~nc~c~j ~y~cticti~
~ ~.,
~~~N~NN~N~~
, ~
a~>a~~a ,, .
~~~~aa.~~~~a~H~H~~ ,.~
~~~~aa,
O N
O
d- M
N
i
i
a\
N N N
N ~ N
N
O
N o0 00
l~ N N
64
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
O ~ O
d'
M
G1 00 O
~
p ,~
N .
00 O O
~-~
N
O O ~t
O
O O O
~ ~
~1 V~ O
v~
~
M V~
O~
Ov -~ O
O N
M M
O O
N ~D
~D
O O O
o0
0o
tn l~ O
O N
M O 00
00
Q1
O~ 00
O
M ~t
O O
O M ~1
~O
G~
~ M M
~O
a\ D 00
~n
t~
M 00
O
N ~t
O O
--i O
ri
p~
h d'
M ~O
l~ O
N l
~
_
O ~ O
O O
~ ~p
N
a"
0 00
t~ 00 ~ ' 'i
p ' ~O
~ 00 M Ov p M~ , ~O M "
~ ~ N O ~ ,--.i ; ~ o0
~ ~ N ~ ~~ ~
~ ~ N O
~ ~'
.~ .~ v~ . n O w
_>, ~ O ~ t-.
~ >, A
0 0 ~ o C7 rn C7 aa U 0.. ... ~ v~
o ~ o ~ ~ o o a .~ 0., ~
y O ,., O O O O O_ O O ~' U"'
ay0 ''' ~ U" i'' y0 '
~ O ' '''
' '
'
O op .~ .' ~ ~'- - O M '-'
,n .~ MO O ,~ O '' ,r
'~ oo ~ N v~ O N oo N O ,~ Y oo N
~ o0 ~ ~ M V7 N ~ p ,~ N
~~ I~ O~
~
l~ ~ [w ~ M I~ O~ M .-r 00 M
~~ N ~~ .~ ~
~ ~ ~ ~ ~ ~ ,
~ ~
~ -'~ , O ~ O
~ ~ ~ ~ O O
~ O O ~ ~ ~
O ~
~ C7 ~ ~ a.. w H~ a a d a.. w U
d a v~ v~ a.. C7 C7 v~ E-~ v~
v~ a.
w
M ~ NM ~n ~O 'W n
~O ~D~~' ~ ~ d'
~ ~ ~
.- 00 M ~O
r
~ N~ l~ 01 M l~
i N
M .-~ O v~ N
O ~ MM ~ O 00 00
N vp
a\ O .~ N ,_,
'n N N ~~ N N
N O O~ ~ ~ O
N O
~ ~U U U U
~
00ov o
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o ~o
Q\ o0
,n
~N
N
~
O
0
0
O ~O
N
.-~
N
O O
M O
~n
Q\ o0
N O
~t
O ~
N N
-
N
~
N
-
O O
O O
N
O~ d'
O O
t~
O N
~D ~
O
N O
v0 ~O
Q\ N
I~ M
O
N ~--~
N
~D
O O O
O ~n
~n
O~ N O
O o0
~
O N
O~ ~O
O
N O N
~ O
O
a\ ~ N
~ ~
~
M M
N M
N
N M
.. l~ O~ O
O
v'i.-~~ ~' ~tI~ t~ oo d' t~ O
M N wj ~rj ~ ~ N .
~ i M M ~N ~p N ~ (~
~ ,~ ~
,~ C~ ~, J, ~,
~ d C7
C7 > ~ Q E-~ a C7E-a E-~ C7 H U ~
w H C7 C7 Q o
0
O O p Y'O O O~ ~ ~, O O
O O p O p Q p O
"'
.~O ~ O ...~ O
~, ,., ....~ ~
,J ,~ r
~ ,~O O M (~" N ~' N ~ v~ t~
oo ~ ,~ ~ N N ~
_ _
N
>, d0 p ciS~ ~ ~N ~ N ~ p c~ ~
c~ p p v' ~
~7~ a~ a~~ ~..~ a~ a~~a~ ~~a:~a:U ~a c:7~7~H
~O l~ I~00U Oo0~~ Q1O ~N N M M
~ V'1~OV7 ~Ol~l~V'7 l~ l~ V~
W O wtd'~Odw D ~D~O~ ~O ~D
t~ M o0U l~I~l~M l~~O~O ~O ~ M
~O M M ~ON ~Ov~N O V~~OM M 00
M
M v0 ~ '~~1NN M M -w0~ ~ ~
~ i
tn ' O~~ ~ l~I~M ~ ~ V'700 M N
Ow n vwn N~ N ~ N W ~n ~' 00
N ~n N .~.~,~.-~.~ .--mnM.-i .~ N ,-,
N ~ ~ ~N ~ N N N~ N N
Q\ ~ h 0
~ o ~ ~.~~ ~ ~ ~~ 'n ~ 0
o 0
~
M ~ OO '~ ~ V~
v0 l~ O M ~ ~Ov~ O O
~ ~ DD D\~
a0
O O ~ ~ ~O~00 O 0 OOM M M
O 0 O
~n M M ~ ~ _ _ _
zz ~ asascax x x
N M d'V W I~ 00 O~
p
m ~m ~n~n ~n ~n ~n
66
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
O cri
~o
r,
~
N
O v~
O ~O
d'
O
O N
O .-,
O ~~
.-a
O
O v~ O
I~ O
~
~O O~
M
O~
N
O O O
~
~t o0
~
N
O ~ t~
O
,~
,--W
p
N N
i i
r r-
N
C ~L
.~ N
~t wi N N ~
N y0 N ~ O M
i ~
O ~ Ov vp _ r
Q ..
N N N M r; M ~ C~ ~.,~j ri ~ ~ ,~ '~ ~ ~ ~ ~ ~
~ V~1 ~ M M ~ ~ V7 t~ N ri
~ ~ by ~ ~ n ~ M ~'' V' ~ ~ y
~ j ~ ~' ~ ~' ~
~ ~ aD ~
, r . s,
a~~a> ~ , , G1~ GL
~~~ ~ ~~~~a~aQ~ '~ ~~ ~~a~H~
~ , 0.
a 0
0
0 0 ~ o g 0 Q i o 0 0 0 0 0 0 0 0 0 B o
o 0 0 0
O~ M N O O ~D ~'~ ~ y y O ~ ~ ~' a, y ~
I~ ~ l~ N ' M
V7 M l
N ~ f~ N M ~ Ov _ N ~ ..N-,
~ _ Ov O M
O O N
~
oo
oo ~ d. M ~
~n ~D l~N ' .-
N M W"; ~ M .~
M ~ V~ ~ , ,--~
~ N M
c'; , , ~
N
~ ~ ~ ~ ~ ,
~ ~ ~ ~ , , ~, cti ~ GO
~ ~ N ~ , v~ C C
~ ~ ~ O O ~ >, ~ ~
Q. ~
, , a~ ~c~awwac~~~dH~ .-
~~a~a,dHa~~ ~ ~>c~~x~~
M
O~ MO~ O
N M
O O
~t
O ,~..-, N
G~O NM l~
N ~ I~M M
~
0 ~ O~O
0
O ~ N
67
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
a.
0
N .. . .
N ~ ~
_ _ _ _ t!j
O M V1 ~ ' M M M
~ ~ N ri ~i
~
N ~ , N ,~ ~. '' ~ dU by ~;
~ ~ ' ~' W o ~ ~, ~
~ ~, w v~
~
~'
~
~
~ o ~ rig a
C7 ~ C7 ~ o C 1 d
o ~, ~.
7 ~-
OO y~~'0 7 E-~E-~ p [~p [7 p
O~ a0
O
'O
~O
Y
O
~ pp p pp ,., p p '''O
Y O y '' 0 ~'
~ " ' ''' O
p .'
'-'
'''
~
00 M O .~ ~O y, .r..~ ~ y ~ ~
00 M ~ V'1 G~O~ ~ N ,_, ~
~ M C~ M l~ l~ p M
N d' O ,-a '-' M 00 N
~ r-~ V~ ~ V7
M ~ ~ N M N N N MM m M ~ ~ ~~ N N N O~
~ ~ M M M ~ y ,--~ N N M M
v ~ ~ ~ ~ i ~
' ~~ i i M
~G
L ~ bDi
~ N N 0~ ~. ~ b0 pp ~ v~ fn ~ v~ ~ p ~ N
~ ~ p O~D ~ ~ c~ cC ~ ~~ a
WC7 ~~c7 ~ ~~ ~~~
~ dx'>
vav~v rr~ v~ wa, a.
a, a
.o 0ot~000~a\ o o ~
O N ~ O ~ ~
N N ~ ~ r M I M
", ~
MM N N
~
i ' ii ' ' ~ i i
'~ NM M Q\N M ~ ~h
.~ V~,--aM .--~ ,--i.~
M ~ ~ ~ ~
~ ~ 1 Ov Ov ~
N ~N 0 N ~ ~ N N
N
00
~ ~ H ~ ~
M O~ O I~O O 00
O
O O
M O l~O C~Ov00 l~ v~~
~p l~ 00G~0000l~ ~ 00 C~~O
~r (~..~P..y..~Gl.H H E~ E~N
M ~ v7 ~D l~
68
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
00
~o
N
o0
N
~O t
O~ O
M
M O
O
N ~O
Ov N
~
Ov
I~ ~n
O
~t
O ~O
W
D
0o O
O
~
M O
o0
O
O~ O
O
N
l~ O
'ct
I~
O Ov
N
~
M O
~D
O
,w0 N
~O O
O
O
I~
N
~O
O O
~O
~
~N
M
O
(~ O ~ M ~ ,-i~ ~ ,-i M N 00 M N
N N ~ ~ [W
N
.- M O~ M V7 V'7 ~O t~ WD l~ ~
r ~ ~ 00 pp
t/7 N N
,~
i
0, ~ ~ ~ N ~ N _7, ~ ~ ~, ~ ~ v~
N N C. ~,
...:
C7dH d C7 > P~~ o ~ ~UC7~ ~UC7> a
o o o o
o
0 -~~ Y
o_oo~ 0 0 o o o ooo~ oooo o
~ ~ O "
~
00 N ~ ~ M ~ ~ ~ 00 ~ ~ 00 V7 ~O
N D O O ~
' ~
'
00 ,~ M pp M ~ ,~ ~ ; ~ M
N ,~ V7 ~D y0 [~
N [~ ,~
~
d G; ~ ~ ~ G~C7 C7 ~ C7 C7 ~ C7 C7
C7 C7 C7 H E-~ C7
H E-~ E-~ E
-~
N NM ~ vW D I~ M ~ o0OvO ~n ~ N
00~Dv0v0v0 v0v0 00 0ov0~I~ oo t~~
M 'd'
O~N O ~ ~D~ O M Q~~M M
MN M N ,~,~ ~ ~ ~ N~ ~ M
ii i ~ i i n ~ i ~n i n
O~ M O~
N O~~ M N M ~ v ~
0oO~O ~~ N M ~ ~ ~ ~~ ~ l~00
~ ~ ~~
N ~~ ~ ~ ~ N M M
V7OM O ~ M ~ 00 O ~ MO 00 M N
N ~O vDN ~ M ~ O ~ M~ ~ f~-~
O n~ O oo O N ~n ~ n ~n~ O O .
l~ N t~
N OO I~~D O ~ ~ ~ ~tMO O l~~D
00~l~~'~ N M M 00O (~
M l~v700v~ ~ ,M_, 00 00~ ~D,M_, v7 00v'7
M p
~ ~iM ~ ~ O NO ON ~ N ~p~ 0
. 0
~. 0
~ ~N oAO~ ~ O O ~ [ ~~ d d
~La
..pn.
.
00~ O ~ N M ~ v'7~ l~00
69
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o°o°0 00
00 0o I~ mD l~
N oo N d' O N
O O ~--~ O l~ O
M M M ~ W p
O O O o0 O O O
m O I~ I~ ~n N O
M o0 .~ O ~-~ 01 O
N l~ N N ~ ~ M
O O ~~ O O ~O v~
M M M ~ .~ ,~ N
t~ O O ~t ~ O ON ~ O
~O N O O ~O ~O Q~ ~O M
,W O N ~~ M ~t I~
M O O ~ O O ~O N l~
N M M M ~D ~ .~ N
O C~ O O O O O ~n O
O l~ O O o0 O N ~n
O O O ~~ M p ~ v~'7
N M M M
O ~1 v7 O O O O O O ~ O
O t~ M ~ O O O O O ~n ~O
00 O ~ ~ d' ~'a ~ V1 O~ V'7 N
O~ O V7 Ov M ~D M ~ O ~ O
00 O O O ~-~ O O O O V7 N
M M M M ~ ~ ~ ~O ~-m
M N ~N M N
N_
N N ~ '~ ,-M- p, N M v0
G. a' ~ ~ Q,
d' ~~ O~ ~ ~ viN vj~p~NC~IN vj00
~ M M ~ ~ ~ y, ~ p~ A. ~ ~ ~, M
W ..~ x a ~ ~ ~ ~ a ar ,~ ~ _c~
O O ~ O U
O O 4 O O p p O p ~ N M oo N .,p
O~ M ~ ~ O~ ~ M ~ O ~ l~ ~ ~D 00 O M
~O ,~ N M .-, ~ N ~ ,~ O~ ,--~ N N cV ~ ( ~ N
r.~ ~ ~ ~ ~ x ~ ~ G~ r~ V' V' ~ ~ V7
M ~ tn ~O l~ ~O l~ 00 Gv O ~~ N M ~' ~ ~O t~ 00
l~ I~ (~ I~ l~ 00 00 [~ l~ 00 00 00 00 00 00 00 00 00
d' ~ ~ ~O ~ ~t ~'
N O_1 ,_, M ~ M o0 ~ ~ N M O O ,_, O ,n ~O
~n ~ ~-~ ~ ~ N ~ N N ~ ~ ~ N N
N I~ ~ Ov ,~ N O O O o0 I~ N t~ pp
M 00 ~ ~-n ~ V~ 00 ~ .-i V~ ~' V'7 <h ~ ~ 00 M O
N ~ O N .~ .~ v~ .--~ N N
Ov O ~~ N M N M ~t Wp t~ 00 Ov O ~ N M
O O ~ ~ ~ ~ ~ ~ O O O O O
N v~ Ov Ov ~ M oo O M N v0 O ~O o0 ~ N o0
~D ~O °~ ~ WO ~ ~ N l~ N o0 ~O ~ M N
M M ~D ~ ~ N O l~ O I~ O o0 ~ ~ N o0
O M ~, ~ C N ~ ~n v~ 00 Qv ~~ ~ O ~O O
M ~~ N ~ ~ I~ M M d' ~ I~ O O M I~ ~O
l~ ~ V~ V7 ~ 00 00 tn ~D V'7 V~ I~ ~O I~ ~D V'1 In
N O N O vp M M ~ l~
fi a ~ ~ ~ o ~ ~ ~ ~ N a ~ ~ ~ M
U ~
x x
Ov O ~ N M ~t v~ ~O I~ a0 O~ O ~ N M
00 00 00 00 00 00 00 00 00 00 a\ a\ a\ a\ a\
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
00
N ~ ~ ~
~ N O
O oo ~ M 1 M ~'~ cfi~
~ O ~ O ~ ;' ~ ;' N
~ N M ~,
~ ; l ~ V M~ M W_, ~ _~ b-0
M ~ i ,--i Vi N M ail
~ ~ ~
;
a ~,~ ~'~~ ~~ ~ ~C7 ~C7dx~d
~ C7
Hda.~ ~Hdw _ aa. v~C7dc7v~C7 0 0 0 0
~
0 0 0 0 0 o 0 0 00 0 0 g ~
0 0 0 0 0
o ~. .~.~ ~ O oo a. ..,
M .~ ~o o a~
~ ~
~O M ~ ~O O\ N ~ (~ NM \O~ ~ M ~ ~ N
N M N M ~ O V~ M M M
m v M v~ ~ N
00 00 ~t
~
~ N , , , ~ ,
,.._, , , ~ O~' ~.,~, p ~ '~ p
0~0 ~.. ~ ~ s.. N
p ,.., do ~ ~ O O O
s.. O
C7~C7v~ri~C7~C7ri~ d d~ vW.~:c:0.~~l ri~
_
~C70.~~jUC70.~
0o OvOvO O ~ NM ~ v~w 0 l~
00 000oQ\Q\ O~ a1O~01a\O~Q\a\
~O ~OW O ~ d' ~~!'~ ~ ~O
O _
M ~ IrO~ ~ OM00~OM O ~
M N ~ V7N M V1M N ,
_,
i i ~ ~ i ~ ii ~ i ~ , i
. M NO O O O
~ M
N oo_ y 0 ~~ N N N ~ 0
o
M
0 pp O ~ ~ N M
O 0 0 0 O O
M M .~M .--i~ .~.~.-~~ M
(~ M ~ 00N ~ No000OWE v1
N ~ M o0(~ N MO ~ N ~t~ M
v
_ _
M t~00M N ~ ~O O N M d'V'1
00 ~ M N v0 M ~N W O oo~YOv
00 00~O~OV1 ~O ~V'1M ~OM V1~D
~~M v0~O~ N
~
M M O O ~ ~ W
U U ~ ~
~ ~ ~ ~ ~
O -~ N M
~~ O O O O
71
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M 00
M
~O O~
N
O ~1
~
O d'
O
O ~O
l~
O M
V~
N o0
O~
O ~O
O
00 M
O
O ~
O
I
O t~
l~
I
N ~
O
~
O M
o0
N
00 M
00
O
O O
M
~D
O O
v7
.~
N l~
O~
N
00o ONO
O ~
~
~O
O N
~
~
N t~
~
00
O 00
I~
00 O
~
O
M M
~
M
N
M
p V'i c'~j l~ ,-i ,-i ~ -i 00
o0 tn N ~O ~ O
_.. ~~_p0_~~ _..V_1M..V_~M_M_~_O
N
~ ~ ~ ~. ~ O M t; M ~ ~ y >,
O N ~ ~. i.i ~
~
o 00~~~~>c~~, ~,~~~Q ~~~ ~ ~~c~~~
.x ~ C
0 x d d d p.,~d O O O U d O ~ 7
o C7 O p p w
O p p
O p O
O O O O O py y y p _ ~ _
O O pp '.' ~ 0 ~ ~ _
~ O ~ '
~ ~
~ O ,--~,~ M d
00 ~ W O l~'~'n N ~ ~ Ov N N ~ tn 00 Ov
M O ~ ~ M ~ N o0 O N
--a N v0 M V7 00
N y n N v~.~N ~. N .~ N ~ l~ ~ ,~
~ M ~p ,-, ,~ N ;' .-. ,-~
, N
p" ~ ~ ~ ~ p 'n~ ~ O ~ GU p ~ ~ ~
v~ p ~ ~ ~ v~ p
dd , , ~"~a. wa ~nC7~ v~C'7xH>C7dHC7
dw H a. c7v~a;C7~dc~
0o Ov N O M ~~ N M v~
O~ O~ O~O O~O~O O O O~ O
~DvWO vov~ vm vo m
O O~ (~~ M ~ 0
~ M 0 00 01
M M M 0
i i i ' i 'i ~ i i i
O
~O
v~ 00~O01Ot~ 00 Ov ~ O
O .~...r ~-~r, ~~ N
M .~M M~ ~ ~ M .-i
00 O
~ O ON M O N
~ M N
~ ~ N ~ M
0 O l~I~ ~O ~O
0 O
C7C7C7>'' L N N C.~
d d d d d~
~n ~ c~ 00 0~ o
0 0 0 0 0 0
72
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
v0 ~ Ov ~ ,~ l~ 00 M wi N ~ N_ ~ M ~ ~ ~ N
N ~rj v0 r; ~ O ~ ~ ~ M M M ~ M I~ l~ 00 N ~, '-' ~ -i N ct 00
00 a.n ~ M 00 ~ i ~ ~ i ~ y'n V'1 ~ N ~ ~ ~ cC ~ ~ ~ cn
W n ~ ~ N ~~ ~ ~ ~ ,~ N ~ ~' ~ ~--~ i i ~ b0 cd ~ ~ N ~ ~ ~ c~
~, ~ H ~ ~r ~ r~ ~ ~"~ ~ ~ ~ ~ ~ ~ ~ ' H ~ Q d ~ ~ ~ r~
O O O O O O O O O O O O H H ~-' p O O O O (~ O
a, i' ~ O O ''' a.n E'~ O au a-' ~, a.u .w au ~ O E'~ O G~ O a.~ '-' ''' '-'
y' O O a,,
~. M ~ O y N M ~O O~ ~ .-i V~ 'J O O .~O ''' O .' (~ N N N ~p
N ~' Ov N 00 O N " ~n ~ M d' ~ ~n O~ O '~ ''' '-, ,~ M ~' l~ .-~ ~ ~O I~ N o0
N N
N N N ~ ~ ,~ ,wp I~ ,~ ~ ,~ M M M ~t N ~D ~ ~ N ~ ~' ,-.~ ,.--~ ,~ ,~ N M v~
~ ~ d E-~ ' C7 ~ E-~ E~ E-~ ~ ~ C7 ~ r~ ~ c~ H v~ rn C7 v~ ~ ~.,'~' C7 ~ C7 E-
~ ~ E-~ ~ E-
~n two 00 ow~ 0 00
o~ o o~ o a, o~ 0 0 0
~D ~n ~o mo vO m t~ ~n
o ,~ ~ t~ a' o M
MoM00MOMa~O
i i ~ i i i i
t~ 00 00 ~ 00
M O Gv O O N
N .-r M N ~ v~ M
N ~ N ~ ~ N ~~ N
M .-~ M ~-v M M ~ M .-
V~ O~ t~ t~
v0 ~ 00 ~ ~ ~O M
j ~ ~D vo W W U
N M ~t
73
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o 0
" 0
o
o ~o
M
O O N
M M
O O O vD
~O ~ O ~O
O Ov .-a
,-,
O O O O
M M '-i
~O
O O O O O
l~ ~D O v7 00
O 00 M
O O~ N ~ O N
O O ~ O O 00
M M M ~ ~O
O O O ~D
(~ M V1 O N
O o0 O O oo d'
O .-, ,~ ~ 00 N
O O ~ O o0 t~
M M M
l~ O O O
O 00 00
O O 00 O O~ l~
O ~ 01 ~ 00 I~
O O O O M d'
M M M
N N
N
N ~O
N
~i
O
N ~rj ~ o0 00 N 'n -i O N vp O y0 yp" ~~
~ .N-~ ~ ~ N ~ ,-M.. gyp" '-'
~ ~ N ~
> ri~' ~.~ ~"; ~~~ i~pC.cC ~;~ci~y' ~
~~0 ~
, ~ ~ ~ , y , ~ c~ ~ , b0 cd
~, ,~' ~~ ~~ ~, N ~ ~" , ~,
~, c~
cC >,
N
0 0 ~ a o E-' E~ C7 ~ a C7 C7 ~ ~ ~ a a
0 0 0 0 0 0 o o o C7
>
' ~ ~
'
'-' '' O O O O O O '-' 0 p p p O O
'-' 0 p '-' ' ' y '"' .' ''' O ~ O
,~ '' '' " "-' W' u
'-' W' . a
u
N a
~D ~ a ' O r~ ~, a .
N .-.i O V~ O ' . p ~ au '
O . .
~ ~ ~
a-'
V7 O 00 O ~' ''' ~O ~ V~ ~ ~O ~t M 00 1
M ~O N ~ O O ~ ~O ~ M O N O ~ V~
O V
N ~ N M ~ ~ .~ M m o0 Ov M ~p o0 N M M
~ ~ N r-, .~ ~ ,-~ N ,~ ~ ~n v~
~ i ~ ~ ~ ~ ~ ~
i ~ ~
~ ~ i
>, >, ~ ~ ~ . , ~ ~
t~ ,~ .,...~~ ~ O ', cd a3 p p >'
~ . .'~ c~ p '~ N
~
~~~c~ a~~~c~ aa aa ~c~~~~~,a a~c~c~~H ax~.~ a
N M O~ ~t O ~ N
O O O O O
N
M N M ~ 0 ~ M
i ~ i
i i i
M M ~ ~ O N N
l~ 00 O~ v7 O v0 l~00
~ N N N N N
M M M .~ M
~ N o~0 0~0
Ov _ M ~ ~ N
M ~ -r
~
O ~ o0 t O N o0
I~ ~ M 00 l~ ~D V1M
M M M ~ ~D
'~ 3
v v v ~ a
74
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0 0 00
o ~n t~ t~
N O I
v7 ~h M
N N ~N
O ~n O M
O
O ~ own
oo
N ~t M
~
l~ V7 ~ ~D
O
N
~O
O O --~
~ O M
00 O l~ ~
t~ ~
~O ~O .~ ~
M 00
O N M
~
N
O 00 O M O O
O I
t~ ~O ~ 01 O l~
O ~n
~ ~n O ~ l~ ~O
O 01
I~
_ _ O
O
~n O N O N ~
~
,~ v0 ,WO ,~ WO
N
W O O ~O ~n O
O ~
00 O O~ oo N I~
O l~
~ O ~ ~ ~
~ O
o M 0
0 0
N
I~ N N O O ~
O
N N
N Q'' d" ~
I
N
~i a"
O
M Ov ~ ~n ~ ~ ps v-i
~ ~ oo O
,WO ~ ~ .~ ~ N d' o0M vp ~ t~ ~ ~ ,-i
~' N N M O ,~ ~ ,-i
~ \D ~ ~ O WO o0
~ ~ ~
cdG N N >, ~ >, N ~ U ~00
~ ~ ~" ~ ~ ''
~
~c ~,a>a~H~~ ~ ~ ~ ~ _~_~
~ ~ x~ ~ ~ _~ ~ ~
~ ~ U C7
o o '"'~ 0 0 0 ~ o o a Q. Q.
o 0 0 o a ~ ~~
p .' ~a~...~a~.~ pO p O oY''' o O o O
~' 0~ o
Na.~ar N ~' O~ O I~ a,a.yO .~, Q ~' Q0 au
~ I~ ~ ~ N ~, ,~, ~' a~
O V7 ~'
~ ~ O O O ~ ~ _
~M N .~ N N M M MM ~ n 00 '~ N ~~ M
Oy M 00 I~
v~ GO b-0 ~ i~.. _.~r ~~ p b0 _~ _~, __~,
~ v~ _~ _cd N ~ _~ _~,
i. _~ N _~
~~ ~HC7a~7~v~C7 a~ a.a,~c7>~ C7~C7a.C7C7C7C7
V'7M ~ ~n ~Ol~00 OW D O ~ l~00
O ~ ~ ~ ~~ ~ ~ O N N OO
t~~m n v~ v~~nvm n t m ~n t~t~
NO~
~ M
~M O ~ t~ ~ ~Ov
O
W N ~
i
O OV0 O
N ~ MO M m N NM
0
M ~ O~
Ov O ~ NM W n N ~Dt~ M~
N N M M MM M M N M M NN
M .~ ,~ ,~ ~i.-,,~ ~-a M ,~~ MM
O M N v~ ~~ N N ~ ~ M
l~ M ~~O
t~ t~ v7I~
O
~O I~ ~ ~O ~ O ~D~D~ ~,O-,
~ ~
N v0 v0 ~t
z o a a ~~ a A A ~ ~ F~
A
A
O NN N N
N N N N
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
.~ O vi v-i ~0 0
0 0 ~-~ o M ~o
0 o M ~ ~ c~
~ ~ o~ o o °o
o~o~ ~ o
~t O ~O O~ M O
U O 00 00 ~ ~O
v~ O~ N O N ~p
M v1 00 O O vD
.-r .-., r, ~p ~O N
O ~n O O ~ ~O O ~
O ~' ~ O O~ M O ~O
l~ <t o0 N ~ ~ ~ l~
O N N ~O N N O~ O
v~ 00 v0 O O ~ O
~ ~ N ~D ~O N ~D
O ~n O O N ~D O ~
l~ ~ ~O O v~ I~ 00 ~O
v0 ~ 00 00 ~_ N v7 I~
O~oNOOMO ~ 000
--~ ,-r ,~ N vp -.r Wp
O O ~n O N v~ O l~ O O O
I~ Ov v7 O ~~ O O ~' ~O ~O I
l~ l~ l~ 00 ~t ~ O~ ~ I~ l~ M
~ ~O O~ O ~ ~ O~ N o0 O 00
O ~h ~ M O ~ ,_N.., O
M ~-Mi M M
N ~ .-i ~ N
a' N N
.--i N p~ ~ 00
M ~~ ~ .. ~ Ov O .. ..
O_ M ,~ I~ I~ ~!7 v7 ~ p' ~D ~ N M ~ p" ~D .-r
', N ~ N ~ V7 ~ V7 ~p ~ ~ ~ ' vD O~
v c~ ,~,~~~,~~aa~ a
0 0 0 _o _o
~' O O p O O ~ ~ ~ ~p M M ~ ~ ~ O
~ 00 ~ N ~ M ~ 00 0~0
M M ,
fan ~ ~ ci~ p p ~ >, >, p G m ~ ~ >, p ~ G
da>~~7 a. ~ c7 ~7w~ac7~7~7a~~ C7
N M W vG (~ Ov o0 Ov O ~~ N O M ~ v7
N N N N N N O N N M M M ~ M M M
m ~n ~m ~n ~n r' ~n ~n ~n v~ ~n ~ ~mn ~n
N M ~ ~ M ~ ~ M N M v0 O
Ov ,~ ,-, M N ~ '~ V~ N ~O ~n O ~ M ~ ~p
~ ~ , ~ , , , ~ , , ~ ,
,
M ON ,~jNOMO~oOOW O ~ M ~I~
~ ~ M N N ~ ~ N ~ ~ N M
00 ~ O ~ N M V7 ~ tn ~O l~ 00 ~O Ov
M M d' ~ ~ d' N ~ ~ ~ ~ ~ N ~ ~n v~
N O O~ 01 ~n M I~ ~ N ~ .-~ ~ M ~ ~O ~n
v7 ~~ O ~~ t~ ~ O ~ ~ ~ M ~ N O I~ l~
v7 M v0 v0 O N v~ ~1 O Ov oo N ~ M ~D f
Own l~ O o0 ,~ M M oo w0 ~ ~ ~n O O
N ~O OWD l~ ~.,~ ~ V 1 M ~O Oy.,~ O M ~O ~O
~O l~ r' ~ l~ ,~ V1 V~ ~O ~n V'7 ,-, ,~ ~D V~ V~
(_~ ~ ~D V~ tn ~ O~ ~~ 00 M ~ ,~~,
f~, Q W
3 3~ 3~~,~.~~ ~A
0o Ov O ~ N M ~' ~n ~D l~ oo O~ O
N N M M M M M M M M M M
76
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M
O
O
M
N
N
O
N
N
00
d'
00
O
M
M
N
L1.
M
M ~ ~
~ M M ~ N ~
~
., N v0
N
~ ~
N
~'i p~V7 V'I .~ ~ .~ ~ N N N N M M M ~
M M ~O ~ tn V7 M
M M NN~
~ ~ ~
M~
~
~,c~ M ~~ ~~ l~, c~c~
~
~,
~,~,~~~
~
~
pp ~ _
p _
y
N ~ .~
m N .C ,.
~c7~~~7c7~c7~7v~a,a.~~~a..,
0 ~ a ~ C7a o o O p p o 0 0 0 0 0 o
0 ~ ~ O o 0 0
0 ~
O O O p ~
O O M
O O ~ O
~
~
~
~
~O
v1 ~ ~ ~t
v
.
,
~p I
py1 Ov o0 N
N ~ ~ ~ V~ 00 N V7 00 ~--~
~ N
~ '-' ~ ~
O ~ r, 00 ,~,~
N M l ~ i N ~; ~i "'~ N N N N M M M
00 I ~ ~ ~ t/1 V7
M M ~
'fit'V'
V'1 ~
O ~rs~.. i.~ ~ ci~ p
O p p ~ G.~ j, ~., 'p b0 dp b0 ci~
~ i, i.~ p ~ w.
N ~ ~-~
~--~ N ~ '
~ ~
~ >
,
; i v v ~ ,
H : ri ~ s.,
a v 0. , y,,
H a ~ C7 v~ n
Q~ ~ d a C7 a H H H a a
, ~ ~ ~ .
a ~ , ,
a
vpI~00 ~ N M OvO ~~
M M M ~ ~ ~ M
~ ~ N
O m N v~_ o0
O
~nM
i
M N A O
O M N N
M ~ ~ V7 .~N N
N M ~' t~ o0O W v0I~
v~v~~n N N N v1~nv~
'.r.~ M M M ,~
N
D O ~ ~ O ~ ~
N
V7~ 00 O WEV
~' '
w a a a a ~ ~ ~
c7A
w ~ ~
77
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0 0~ o
o ~
0 0 ~
0 00
o 0o t~
o
~
o
_
_
M ~ 00
V~ O
.~ N v0
O ~7 ~
O o0
O ~ N
O N
O l~ ~
~n
O N O
M ~O 00
M O
-i N v0
O O ~
.-t
O O v0
O .~
.~ l~
~ Q1
M
M 00 01
O
M V~ ~O
O O
-~ N v0
D O ~
v-i ~j
O ~n ~D
M ~
O ~ N
O
~ I~ 00
M O
O ~ ~O
O~ O
O O ~
~--~
O
O 00 ~O
00 (~
N l~ ~
~ I~
N M 00
~ Ov
O M ~O
a1 in
N
M
a'
'~ O ~O l~ O 00 00 ~ 00 V7 gyp" V7 O~
.~ ~ (s " l
V7 N ~ ~ ~ ~~"V N M N N M ~ M ~ ~ ~ N v~'1
N ~ M ~n N N ~
~n '
~O o0 , , , N fV , , , M , , ~ d' V
~ ~ ,~ , ~ ~O o0 Ov ~ O\
O~
OU~, M
y bD~,~ N
~~ ~T~~
~ ~ ~
~ ~
~
~
~
~ ~
C7 ~ ~
~ ~ ,
,
N
.
.
>, C7 H ~ C7 c7 ~ C7 C7 v~ a.. w ~ d
d ~..~ ~ ~ C7 ~ ~
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 o g ~ o
~
N~
~
~
~
~N~
NM
MNNM~ Ov~
o
o
o
o
~t
NNM
~ ~~
~D00~~; N ;~ i~'~NNNNMMM~ ct~~yp~D00~~Ov
Ov
t~.m~r ~ f3. >, ~:., ~p 04 b~ by ~ ~ W ., v~
C bD p t~ t~.~
~:.~ ~
v~ vW ~1 w v~ vW7 Q~ ci
~ v~ H a ~ c7 v~ a, Q~ ~ Q~ i C7 ,.~ ~ H
H ~..
N M N
,m n
N
M ~
N
M
,_,
N
O
M
M ~~ ~i
~p M l~
Ov O
~p M ~D
U
pq ~ A
r,
78
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o~
N
O
N O
O o0
d' O
O O
N O
O t~ ~O
~M
M
O ~O N
N N O
O O O~
~D
O O
N N O
O O O~
O O
N N O
N
M
O"
N
wt o0 O M O O
Ov O M ~ M ~~ ~ O ~!j ~ ~ O M ~rj ~ ,N_, ~ N M ~rj
N ,~ v~ , M N M ~ N v7 I~ M
W , y,, ~ ~ ~ ~ i ~ O~ O~ i ~ ~ ~ ~ O ~ ~.. ~ ~O
Q
0 0 0 0 0 0 0 0 0 o C7 C7 0 0 0 0 0 0 0 0 0 0
., ~ o o ., ~ .~ ~ r.
~ O V7 ~ O~ ,n pp ~p ~ ~ ~ l~ M ~D N ~ ~ O ~-~ ~O
N ~ ~ N "' ~ ,~ ~ '-' '-' ~O ,~ ~ D1 ~, .~ N M V7
i ~ N ~ i y au ~ ~ ~ N i i i ~ i
O O ~ O'' O O ~ N N ~ ~ O N ~ O ~ '~ O
0.~ 0.~ v~ ~ ~ A; ~ 0.~ d ~ ~ C7 C7 ~ P~ ~ vW. ~ ~ 0.~
v~ ~D t~ 00 Ov O ~ N M ~t ~W D v~ ~ l~ 00 Ov O ~~ N I~
d' ~ ~ d' ~ d' V1 V'W 7 ~ ~n V~ ~n ~ ~ v'7 V'7 ~ ~O ~O ~O
vm ~n v~ ~n ~n v~ ~n ~n v~ v~ ~mn t~ t~ v~ ~n v~ vmn v~ t~
00 ,~ I~ O~ ~ M O O ~n ~ ~ O O ~ N O t~ ~~ ~ O l~
M N Ov M N ~ N N o0 ~ ,~ M O O l~ O o0 O O ~ O~ d'
N ~ M M N N ~ N N ~ M N M N N a\
, , ~ ~ ~ ~ ~ ~ i
N ~ 0~0 O N ~ 0~0 N O M ~ 00 ~ ~ ~ l~ 00 ~ O N o0 N
N ~ N N ~ ~ ~ ~ .~ ~ M N N ,~ v~ M l~ ~ ~~ N M
O ~ N M ~t vWD t~ 00 Ov O ~ N ~ N M W v0 l~ 00 M
~O ~O ~D ~O \D ~D ~ ~O ~D ~D I~ t~ I~ M M I~ l~ I~ I~ l~ I~ M
M 00 I~ ~ ~ M O~ ~D N O 00 ~ N ~ M ~ l~ O~ N 00 ~ l~
~D v'7 M ~ ~n ~ ~ l~ v7 N ~O N M o0 00 v~ O O ~D o0 ~ O
O ~7 M M V~ O ~ O V1 ~ v1 N ,~ ~ N o0 ~ l~ <t ~ O o0
N M M o0 ~ l~ N O~ M ~ ~ O~ ~ 00 O~ ~h ~ ~D v7 M ,y0
~p V'1 v~ ~D M l~ M Wn w0 M O M M M v0 ~t ~ ~ ~.,~ Gv
V~ V~ I~ I~ ~ ~ ~ ~ ~ ~ ~ 00 ~ 00 00 ~O ~O ~ 00 00
N '~ O ~ p ~ O M M ~ M ~ ~ ..N.~ Gv '-' O N ~ N N
U ~ ~ ~' ~ ~U ~ C7 C7 ~ ~ ~ ~ ~ ~ ~ ~ H H
O ~ N M ~ vW O I~ 00 Ov O ~ N M ~t vW O l~ 00
V1 V~ v~ v~ V~ v'1 ~n V~ v~ vW O ~D v0 ~O ~O ~O ~O ~O v0
79
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M
~O
O
O
M
N
N
O
N
N
00
~D
O
00
M
N
M
O O~ M ~O .. v~
O~ O ~ N O~ p
N ~ N M M O 'j
~ ~ ' ~
~
W
00 00 -r .~ w O Ov ~ cri
Ov N ~O ' ~ ~ d I G1 ~ M
' ,- ~ v ~; " V~7~ I
V' p ~ ~D ~
1 ~D M ~ ~
' i ~
O ~ ~ ~ ~ b-0~ >,
~ y ~ '~
~ , ~
~ ~'
E...,~' ~'' >, a r-~ >' [~ H ~ ~
A... C/> ra ' C/> ~' Gl,, C7 C
~ , a ~'
E'' a ~'
C7 C7 C7
O C7 E-' ~' o o O 0 U v~
w o O O o 7
~' a' am ' ~
~
O O O ., ,., O y, O O O O
O y au _O _O O O O O O
~'
~ a~ Vl au a~
N N ~ ~ M N ~ ~ au ~,
~ ' ~ ~
~ M
~D V7 O d ~ M V7 .-r M M_ ~
.~ O ~ O O 01 N M l~ ~ (~ ~ ~
i tn ~ ~D O ~ ~
~ 00 N ~ N M O~ ~ i i i
"'~ "'i M M i ~
i , i i i ~ i i
i ~ ~ ,
N O ~ ~ u.y GO ~ bD ~ ~ ~ b0 cn p p ~
t~-~ N a3 .T'"~" c~ O
O ~
~v~a~w~~ a~Haa H ~a~~7~ ~c7~7~7a~~i a a~~a~c7a:~7
H
00 M ~i' O~ V'7 ~OO l~
~D v0 ~ ~D ~DN ~O N
' ~ ~ i
O ~ , o O O
.~ ~ 'n M M N ~
Ov O ~ ~~ N ~DM l~
M l~ 00 M 00 00M o0 M
M ~ ~ M ~ ~ M ~ M
In V'1 M
M N M
~
Ov ~ N O M Qv~ O~
N N N O ~ 0~0
z O O
U U z z
so
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0o cri ,-i ~ op ~ ~O ~ ~t .~ oo c-n ,--i ~
pWo p~ op y0 oWD
00 O v~ ~ O W p ~ Ov ., d' 00 O W Ov O W p
N ,n ~ Gv N
~' N N N M M M M M M ~h' ,~ ~ ~ N N N M ~';
~ ~ M M ~''~ M
~
~O O ~ ~ ~ ~ C ~ _~ ~ Q' ~, ~
~ ~ ~, ~ ~ ~' ~ ~ ~ s~ ~ po
V1 v~ b0 N H
t~ ~
>, ~ ., U U ~ E-~ ~ v~ ~ U U
~' a d ~ C7 E~ E-~ d ~' ~' ~ ~ ~ C7 H
v~ ~'
rsac~ ~ 0 0 0 0 0 0 0 0 0 0 0 ~ o o g o 0 0 0 0 0
,~ 0 0 0 0 0 0
~ ' 0
t~ 00 ~ N O ~O N M O '-
O .~ ,~ y l~ 0o ~ N O v0 N M O O
r., ,~
00 ~ M l~ ~ W o0 Ov N ~O I~ ~p M l~ ~ ~ ~ Ov N
~ oo p~ N v7 ~O ~ 00 p~ N
N M ~ ~ ~ N N (V M M ~,~ M ~ ~ ,~ ~i N N N M M
M M ~ ~ ~.,~ M M
~ ~ N ~ ~~ ~ N ~ ~ ~ m . ~ .~ ~ ~ ~ ~ ~ ~ .~ ~
v~ ~ ~ .~ ~ N
~ ~
G H aHddaddddxd~7a~7 ,
7 aa.Hddaddddxd~7a
Hv~
0o OvO ~ N N
~D ~Ol~I~I~ N
N
OvM N
O O
d'~n
~
d'M ~
V~~p(~OO 00
00 00000000 M
M
O ~ N ~ O~
O O
~ N
o0
M 00N M ~
00 v0~ 00, Ov
,_,
Ov ~ ~ N M M
~ ~r~ ~r Nr
OI
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M
M ~ ~D~ ~ 00 M M O i
O .r ~ 00 ~
O M O ~O 00 00 ~ ,-
: O ~D Q N N M
M ~ ~ i M ~O ~ ~ M ~O ~ M M
~ ~ i ~..~
i
si p~'~ j, ci~ .~..~ ~ ~ ' ~ ~ j., ~ v~ ~ s~-
N .~ v'~ ' ~ ' ~ ~
' N N ~
O
s..~, ~ O ~ V7 ~, O >, >, ~ N
% ', C/~ ~ ~- CJ 0-~ C/> .~ r. ~ V~
P-a ~ s-' 'U ~ a A"'
~ ~ r"~ ~ ~, ~ (J~ (~
O ~
a'~ C p ~ , ,. ~ 0
O O ~-I ~ ._, 0
~ Q 0 ar O Y ~ O p"'
a-' ~ ~ 0 a'
O ..~ a~
N Y ~ O 0 O~
O 0
l~ MNd'OM 'n~OO 000 00~ 00,~ ~O
j ,Q O
M
M N N ~ pp N M M ~ O~ M M l~ ~ '~ 0O
~ ~ ,~ ~ ..-i O~ ~ M M
Wn ~ ~ O ~ ~' ~~ ~, m
~ y ~ O O
~ ~ N ~
C7 ~ C7~HC7~a. U N ~ c;7a.~ ~7~ a
v~r~~7HC7v~N ~7a.
a v~7H~7
M <hV~M ~Ol~~' 00 01V7~O O l~ 00
N N N I~ N N I~ N NI~l~ M t~ l~
_ v7
~t~ N N p ~ oho N~ ~
I~M I~ M ~,~00 V7 ON ~ N M
~ i ~ N ~ ~ ~', ~ ~ ,
.~ N ' ~O ~O
0
N ~ M ~ ,~0 ~ ~ O ~n
0
OvO ~ O~ N M O ~ v7~ N ~O M
M ~ <t00 ~ d'O~ V d'~ 01 ~ 01 O~
M M M ~ M M ~ M M-~~ M
d'O~~O~ M ~O~ 00 M~ ~ V1 O~ N
N O
O~M 00~D ~ 00N M ~M M <t N N
v0v0~ N N o0 M ~~ N oo
~DN N M M W oo t~a\W O Ov O
~ ~ 0 M ~ ~o0v ~O N N
O O O l I 0 ,~ n nv~~ W <f' N
Ov~ I~00 00l~ 00 00 00
N
M M M ~ ~ O 00 00~ N N
a a a ~ ~'~.O ~ ~~,.~ ~ a
~
~ ~ ~ ~ ~ ~ o' a o,~ A
w 0 w 0 0 0 0 0 00 0 0 0
0 0
x x x x x x x x xx x x x
Q\ O -~N M
I~ OO o000 00 00
82
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M
N M
O
l_~ t~ O ~_ pp ~ ~ O ~ ~ N
00 te
O ,~ ~ ~ O ~ r-.i ~D ~O~DO~ O ,~ ~O '~ O
~ M r ~~ "'~ ~ ~ ~
., '~ '
~ ~ 0
~
~ ~ ~. ~ ~ ~7 ~ v~ O~ ~ ~ i ~ ~D
Vi ~O 7~~ 0
~O I
~?~~ N ~ ~.~~ba~
~
a~~o ~xo ~ ~ aa~o a~aaoooo a
o
o oo ~ ~ ~~ 0 ~ ~ ~ ~ i'
a.u .~, 0 ~ ~' au a, ~' a, ~
a..~ a.n w .~ ~ ~y y
O .~ O
~ O O N ,r ~ ~ M ,n ~ "
vpO ~ O M O p~ 00 O O OM oo O 01 N W
~ O O N ~ O v~ v~ ~1 M
M ~ ~ o0
M'~ ~ ~--~ ~ ~ ~ ,~ M V'7V1~ 00 ~ ~O I~ Ov
,-, ,~ ,-, ,~ ~ ,~
N
~ ~ H~ ~H~
~
~
c~~ ~ ~ ~ ~a ~aad~c ~
aHac~ ~a
r
~
Ov ~ O~ N M ~ N WD M l~
l~ M 0000M M M 00MM 00 M
MN N y n M Mv0
i i ii i ~ ~ ~ ~i
00 I~ WO ~ Ov~ ~N 00
N ~ ~ ~ ~N ~ v~
~
- ,~~
1
l~ ~Ol~00O~O 00--,N O~ M
M ~~ M M M ~ MM ~ M
O~~ ~ V~l~'~I~' I~ 00
~
Ov~ I~N 00~ _~ ~ .-r
00
O t~ ~O~ M 01V7~ '<h~D M
M~t
~
~~ N
N NN
N NN
~ ~ ~ ~ U UU
~ 0.
1
v y pf~ o0
00 0000 00 00
83
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
N
O
O
M
M
O
O
M
M
N
N
GL
M
~ N ~ ~ Ov ~ 00 O ~ ~ l~ ~ N
,-i
Ov ~ " "
~ 0 ~
0 N ~
O
'~
_, ~ ~ p ~ ~ p ~~ p gyp
~ ~ ,-i p -i
~ ~ ~
N N
M M
~
i W ~ ~ ~ i ~ G, ~ ~, N ~ ~ ~ j> >, V;M ~ M
c~3 ~, ~, ~ ~ 00
~
' ~ a" U _ , ~' '~ _>,
7 ~ ~ ~ ~' ~ ~ ~ C7 ~ 7 C7 d '~ ~
~ C7 ~ ~' ~ ~
7 ~
C , C ~V U U
~ 0 0 C , ~ C7
0 0 0 0 0 0 0
~' ~ ~ o H ~ ~ o
0 0 o 0 ~~ p ~ O
0 0 0 ~' 0 ~ p ~ ~ ~, ~ 0 o
~ ~ ~ ~ p ~ ay, au y ~ ~ ~' " '
~ ,,, y, '
'-' ''' Y .~ ''' '-' M N O Y ,"' y' M .~~' .~ '
O a\ N m O o0 v1 ~ ~p N O O ~ ~'
N N ~ .~
~ N ~
v~ v~ M M ~t oo ,~ p r-, ~v~ p O
~ l~ 00 ,~ N ~ N vp t~ ~ N ~p l ~O ~n
~ t~ Ow, ~,~ ~O ~ .~ ~, ,~ M ~ ~ ,~ r, M ~ M ~,
.~ ,-..~ N N N M ~ ,~ N ~O ~D
,~ 00
~ WD c~ ~ O ~ CD ~ p bQ c~ ~ ~a3 Q c~
~ J, p ~ p ~ b-0 ~ p A.
N a N ~ 0 ~
. ~,, W ~ Q a a. rn~ ~ ~ ~
, a. ~ ~ a a; C7 ~ C7 ~ a a.. a
7, C7 C7 a. v
a ~ ~ ~ c7
H C7
00 own o
00 M M00 ti'
~n OvN o0
N ~ MV~ M
M N M
ii i
~ 00 O
O ~ M
N I~ .--i.~ rr
~O
O ~ ~nw 0
O ~n v~O ~n
N M MN M
~
M
M_ ~O
N ~ dN
'n
~ o000 00
M 00 ~00 ~n
pp pp ppO O
d
O
O~ O~
84
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0
w
N
O
O
D\
00
N
(V
N
C
a0
N N
p ~~~o
~Dv'I~p O ""'' v0
N N ~
~ I~ ~
'
N ~ N .~ N M M N
l N ~O .-i
v ~
1 ~
~
ii ~ M ~ ~ N ~j _~ N ~ _~ M
~' i~.~ ~ V~ _7, ~,,
C l ~ ~ ~
~' ~ '
' '
~
~ ~ C7 >, ,~ ; ~ U C7 E-~ C7
~; [~ 7 ~ C7 ri ~ E-' E-
a ~ ~; ~ ~ ~ ~
~ a ~ ~
~
U o o '~ o 0 0 0 0 0 o 0
o o o o 0 0
~' ~''
u
.~-~ a, 0 p ~ 0 ~ a.~ a.u a..n 0 ~, o
~ a, a' 0 ~ a~
o a.~ a
,,, ~ a, [w .r ~ [v a, .~ N tn O O Y' '"'
~ O ~ ~ O ~ .r ~ <h d' ~ N
~ 00 ~ O~ ~ 00 ~ O O 00 N M 00 M ~O
~p [v ~ ~p [~ ~O ~ (~ 00 ~ 00
N
M
O M v~ ;' M vy' N in ~ ~ ~ .-~ N ~ -~ N
0o N N N N N ~ N N N M ~
~ N ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ N
~ ~ N ~ ~ N ~ ~ ~ ~
~
, , ~aH , ~r~Q
~ ~a~~~H a~dHa
QH ~a
~ Ha
a, ~ .
a ~
a
OM O l ~ ~
~ ~
_ _ _
d' O N a\
V~ M ,--i
ii ~ ~ ~ ~ i
~ ~ ~ ~ ~ 00
NN M O ~ O ~ O
" v
~
O O 1M M
NM N M N M M
N ~D ~ ~D M O ~ N
~ ~ ~ O
NM ~
~Ol~ O O O ~ ~ M
_
U
A~ ~ ~ ~ ~
~ ~ C C C C
7 7 7 7
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
00
~n o
V7 M
O .-i
M M
l~ O
N O
DM
O ~~
M M
O ~O
00 ~-w O
O O l~
N O M
O O ~
M M
~ O D
v0 ~ O o0
O I~ V1
~M
O ~i ~~
~p M M M
--~ V~ O
~ O O
00 O ~O I
O O
M M M
M
N cn
M
N ~ N
d"
00
vp o0 ~O M ~D O M I~ ~ M ~ p ~ N
~
N V7 M 00 M V7 .~ N pp N yp ~ M
.-~ ~ N I~ j l~ O M M M yp
N ~ Ov ~ N N ~ ~; N fV
,~ ~ ~D ~ ~
'
~ , ~ V ( M N M I
7 I ~ (V~ ~ ~ ~ 00
~ ~ ~ y~ ..-, ~ ,
N ~ t
M (~ pp N ~ 0 CL cd
Cr ~ ~ O
, ', ~"'-.J~ ~, v~ ,wn j, v~ y, v~ .-, ,Wn
O ~ ~ O pp m ~ ,~ ~ j,
O d ~
d
~
~
C7
~a..~C7w_ _ . ~' ~ C7 ~x~o
~ wa ~ ~'~ U~ dr~..,d
0.'C7 a.~ C70.. ~
0.'C7 ~~
d,~
'x~
0
0
00 0o 0 O O O 0o00 O O
y y O O O O O o000 O y
y y y O O O O y y y y y ~, y
y y
N O~ y ''' y ''''', ~' y y ~' V~ l~ O~ 00 I~ ''-'
O ~ " ~'' y ~p ~ 00 ~O M ~'
O ~'
t~-~
O mn O M O O w' ~n a\ ""' oo ~ r, l~ r. ~ ~
O M t~ M ~ ,n M ~n O N ~t oo
M ~ ~ M O
d' M l~
~ N
~
'~
~
~ N ~t I~ l ~ ~ N N N
~ N ~ ~ M M ~
N
N
~
~ ~
~
N ~
~
~
'
, , ~ ~ , , m-.,, _ _,
by _~ , , , ~ N , , cct
~ bU _~ , ~ ~ ~ ~
~ yn by ~ ,
~ , , ,
~ _,
~ ~ ~ O ~ >, ~ N ~ ~
~ ~
~
~ Q ~ C7 ~ E-~~ E-~C7 U ' d
C7 E-~ E-~ C7 ~ c1,~ d C7 ~ E-~ ,-~ C7 C7
,-~ E-~ ,-~ E-V v~ ~
O~ I~ o0 O ~ Ov N O
M
O O
N N N O
,-
, , , ~ -,
,
' r"~ ~ N N N
N N
M N .-~ .-
~ ~
V'1 M ~f' ~DI~ ~ 00 ~O
'
O O O O
M M N M O M
O
O ~ M M v0
M M M
0 0 0 o
Q d a
~ x x x x
a,
86
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~n o
~t
0
N O
N O
N ~O
O O
v7 I~
~O <t
M
N M
N M
M
i
.-
N
00
cV ~-! oWt y0 ~ -V N ~ O
gyp" O oo
,.N~ ~ ~ ,-~~ .-i M O\ ,-i O y 0 ~D ~ V7N O v0
~ N N N ~ '~ ~ M ~ ~ ~' -~
Ov
', m cd f~ M ~, I M ~ V7 ~ ~ erM V~ l~
~ ~ ~ ~ ~, ~ ~ ~ 00 00 O~
m ~O
~~c7~ ~ ~,~~7~a ~ ~,c7 ~ '~ ' '~~''dc7
c7 i~~ ~~ '~ ~ C ~
, ~U~ooo ~U~ ao C7U C7U 7 ~C7C7oo
0000oooo
y ,~ ~ ,., ~ ~ o y p o O o 0 o O o 0 0
~, ~ ~ ~' Y o ~' o O ~ ~'' au
y' O
M N ri ~ N ~ ~ ,~ .~ au au a.. a'au au
01 ~' ~' a.r ~ y., y c'~t~~O N vD
,~ M W p op ,~ ~ N y., N M M v~ O N
"'' M ~ M ~D I~ .-, ~ m v~
l~
d,
~ N N N N M v0 N M M M CVM ~ y0 ~
.~ ~-' M ~~ ~ I~ ,~
,~ ~p
W ~
C7 U Q E-~ d d E-~ C7 C7 ~lC7C7 d C7
E-~ C7 ~l E-~ ~ ~l C7 E-~ ~ E-~ E-~ E~ E-
v A...
M .-~ ~ vWO N I~00Ov
a\ ~ ~ ~ ~ ~ D\~
m t~ ~n v~~n tm n ~n~n
I~ l~ ~ ~ M I~ ~ ~ ~D
(~ ~f'~ ~ M o0
~ ~ ~
i i i i ~ i
N ~ o0
U I~ O ~ N 00 M ~
O ~O .., ,~,~ ~p
N M N N N M N N N
N N ~ ~n M t~
M
OMO O ~ ~ O W D ~
O
'~Ov D\ '~.~Ov
M N
O p o0I~
w w ~ ~ ~ ~ ~ d
~ a
A ~ ~ ~ ~ ~
x x x
x x x x x x
O~ O -rN M ~ v~
O~ O O O O O O
N N N N N N
g7
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ ~~ OM ~ ~O o00 ~ M v0 ~ ~ O N O ~ N
~O ~
o00
-, N O ~ ~ ~ .~ .-i ~ .~ N O vp ~D ~j ~ ~ ' ~' M
'-r N N N N ~ ~ .~ ~.,~ M M M
,~ M V1 M V1 I~ M O~ O~ ~ i
~ ~ 01 ' ~ ~ ' ~ ' ' ' O~ ' i i
~ ' ,
i l b4~ G 7,~ ,
7,N b4C ~ ~,~"~'...~'. j,y,~~ ,
~~ b-0~~ Gl.~~ ~_~'c~
tD
~
xa~ ~~~~d~xa~~~~~ ~~~~~~ ~~~HH
~~'~~
'n
0 0 0 0 ~ 8 ~ 0 0 o 0 o 0 0 0 0
0 g o 0 0 0 o
~ o ~ a.~ .w. ~ ~' M O
~ ~ ~' y' ar
~ ''' ' ar
' " Y
~
~
I 01 N M t ~ ~ ~ O M
V1 - ~~ N
00 ,~ I ~ M
~ ~ ~
~~~
~
~
~
~~NNN
,- ~ M
, ~ ~
~ 0 ~ ~ ~~~ ~'
o >, c~ ~ ~, ~ ~. dD bU Q.
o b~ >, w.
~
~
c~ ~ d0 s
~ ~ ~ ~ ~ ~ ~
>
~ ~ ~ v
~~ y ~a~7~ ~~~~7~>a
, 7
,
~
~,.
~
~~~~~
~d~
at H HH ~
7 ~H
H ~
H H
M ~ O
V~ V7 O
M
O
V1 M
i
i M 00
O
M M N
N
M
vD M
a oa
x
x x
O
N
8g
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
V'7 ~ ~ 00 ~ Os ,-i o0 ~'1 ~D ~ v'i Ov pp" Ov
I~ 0o M
M ,n I~ O~ ,~ v'7 ~--~ M ~ O N O ~ N y OW''~ ~n ~ Ov
O tip ~ ~ ~ N M ~ O
V) ~ vp ~O ~ y ~ ~ [~ ~ Ov M N ~ ~ ~ '~; M M M M M ~,
O~ Ov ~ ~ ~
~, ~ u;
, , _
?, ~ ~ ~ ~ ~ N ~, ~ ~ ~, ~ pp
~,' ~ j, ~ ~
~ d
>
~
E-.~H~E'_' _
t..addC7~dv~E-~~..a~,~ CSd
E-rHaddC7
dd
~C7v
Q N M N l~ O '''p O p O O ~
N O p p O M O ~ ~ ~ O O ~ O
O ~
' p
O
M N M ~
V1 ~ O
~O 00 M M ~O M ~ O ~ ~O ~ ~ ~n
~ V~ ~ l~ O N p~ O N ~. 00
O d' 00 l~ ~ N ~ ~ ~O o0
V~ V; V1 ~D ~ ~ [W~ ~ 00 p~ M V~7 ~p 00 ~~ '~ N M M M
~ ~ M ~,
~, ?s i-~ ~ ~ m C ~ s~. ~ ~ ~:, b0 GU GL >, y., ~ p
Q ~ Q i. ~ ~ p >, >, p
,~H~7e7v~ i ~-l~~av~~-~la:~-~10.~v~c7L7HvW~~~7ti >a;H~H~7C7d
M
N
M
M
O
N
d
x
89
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
00
N
M
O"
N
N
~ ~ ~ M ~ ~ p
~ N ~
~
vi ~ ~
~ N
~ O M
N ~ ~ O~ ~ i M M M M <t ~ ~ i '-; ~; N G~ ~,,~
~ ~ ~ V~7 ~ ~ N N N ~D 00
l"~~~ ~~
c~b-0bJOv~~~ ~~
af~ Na~
.S~',b-0~
_ , p 00
_ ~, ~ ~.
_ ~~~c~~~~~, ~,
~a~~x~~~~~~~
0 0 0 0 0 0 o O o 0 0 0 0 ~ 0 0 0 0 0 ~ ~
o O p
~ ,..~ ..yp O ~D 00 00 M O ~O O O ~ ~ O O O
O l~ V1 ~ O O
l~ O~ ~
p a'' O M ~ pp ~ M M
.r O~ ~ M 00 00
O M O~ ~ 01 ~ M V1 O N ~ ~1
00 O M
N v~ ~p ~ ~ ;' N M M M ~ ~ ~ ~' ~~ ~ .~ ,~N N ~p
~ ~ ~ ~ ~n -~ N N ~O M
"
>, ~ ~ on' ao a~ ~ .~ ,~
a. >, ~ o ~ ~ .~ '~'' ~ i o a ~
>,
H~~H~~~a ~a~~,~~~H ~ HH
~~~~~a~aa
~
l~N M ~ oov~
M 00~ l~O~ O~
M
, O ~ N oo O M
_,
~Dl~ M M M M
i i i i
t~~ O ~ N
~ N N N
N ~ oo OvO ~
N
N N
M N M N M N
O
N
N
O ovO M O ~n
..,~ N v~ v W
p
N ~ ~ U U ~
x ~ ~ ~ z
x x x x x x x x
00 a\O
O p O .~
N N N N N
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0 0 o r;
M o ~n t~
O o0 0o N
a
O
_
N
a\ O O O O
I~ O O v~ ~t
O o0 00 00
O t~ ~ ~ O
p ,~ . ~ ~t O
v0 N .-r .W O
O O O O N
O ~D O ~n O~
M o0 00 O
M
M N ~ ~ Q\
N ,~ ,~ ,-r ~
O v~ O O O ~n
O M O ~7 00 00
O1 00 00 00 tn [~
N ~ ~ ~ o0 O
O O O O O M
00 00 t~ 00 00 M
~O M .-r
O ~ ~ v~ O
M N M
N M
a' ,--y D
0o N M N ~ N Ov ~ 00 t~ t~ N 01 ~ 00
t~
Ov~' ,-i .~ p ~ j o0 ""' ~ N j op ,~ ~ N N
N N N CV N N N N
~
~ , ~';C~ ~
-, 'n 00 O~ ~ ~ ~! 00 Ov ~ ~
N M W ~ ' ~ .'~,, bD ~ '~ by
ran ~ ~ ~
~
~'~"d~ ~~aC7C7~~c7 ~"aC7C7
H ~ ~
dC7
C7d~p a.aad xC7 H o A. C7 ~' o
0 0. 0
o o
00 0 o Or 0
u~ O 0 0 0 o g 0 0 0 0 0 0 _
0 ~ ~ ~
O O ~
a.a. ~, au a, au V' M O ~ .~ ~ ~
~, M ..-~ 00 M M O ~
~ ~ ~ N ~
N N ~ N
~ N N
NN M N NN N ~ ~
~ ~ 0o . ~ ~ ~ ~
.., N N N
~ i
~ N ~ ~ ~ ~ ~ ~ NN N ~ ~ ~ >, N N ~ ra.,0 c~
~ ~ ~ ~ ~ ~
~
~ c~~a~a~a~a. ~~~Ha ~~H~~a~HC~
~aQH~
~o~oo Q.o o~~ o
NN M
~~ ~
M'~ M
N N.~ O~ Q\
''
M~D ~
_
00~N ~~ N~
N M~ ~w0 v~l~
N NN NN I~N I~
N NN NN MN M
~O00 O~ M~ 00
O
Nov00 ~ OM O
h
~ ~ n ~
o d' o~ o
o o o
D
x x xx xx x
x
N M~ ~n~D l~
N NN NN N
91
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o ~n
0 0~
N O
l~ O
N ~D
O
O
O v~
o0
N O
-i
l~ O
O
N
~D
O O
~
00 O
l~
v0
M
O N
M M
O
N N
~O
O ~ O
O
I~ Ov o0
O
~O O o0
l~
~O N ~O
v~ O l~
I~
N ~O
v7 ~ O
O
00 M O
O
00 N ~n
0o O ~t
N
t~ O
M
N
a' N ,-i
M ,-, N
M N --~ i
'
M N
M ~
N
V7 M
~ M
N ~ ~ M ~ 00 O ~
' ~ ~ ~ ~
~
~ I~ l~ d' V7 O~ '
~ ~ I~ ~ ~
i i i ~ ~
~ ~ i
i
~ ~, , i ~ i p i n
~ ,....~ p W i i i _
p c~ n ~-.~ ~, n s..
~ ~~ y ~
~ ~
~ ~''
~ C7
~''
~ ~ ~ N ~"C7 , ,
~ . . a ~ a E-~ ~ ,
,~ E-' ,~ E-' , U E-~
C7 E-~ ~ U E-' E-' E-~
c~ p o p
p p p O O p O 0 o O O
a~ p O ~ ~ O O O ~ ~ O O
O .~ O O ~ M
N '-' ~ r' y n I~ .-, o0 t~ ,~
~ ~ ~' ~ N ~ l~ O o0
~n ~ ~
N N ~ , r ~ . M M v~ oo .~ M v~
~ ,~ -, ~ , ,~ ,~ N 00
~ ~
~
,~
O O ~A''~ ~~''~Ta'~ ~ j >
O ~'> ~'>
~ '~ N
~ >
7 d C7 C7 ~ C7 , ,
= ~ ~ ,. ,
,. C7
C7 E
E
d
w as C ~ ~ H -'
.. a a. a a a
.~ as -
NM -~N ~ ~n M W O l~00~ vW O O
~p~p,~ ,~ ~p ~p ,-~.~,~,~ ~D ~ON
~ ~D ~ 00 N '~~t~ QW ~ 00
W ~ M N ~ ~ M N
n
' N ~ ,~ ~ ~O M v~~
M ~ N N
M
0oOvt~0oO ~ a\ O N M ~ v~ ~ N ~D
NN (~l~M M (~ 00 M M M M 00 00M
NN M M N N M M N N N N M M N
~n'~~ O ~1 '~ 00 M O ~O~nN ~ ~ N
~ ~
M~ ~ N M ~ 00~ O~ ~ ~tI
N M ~ N ~ O
00~ Ov~ oo ~ l~ l ~ M OvW o0 ~
~t N ~ ~O ~D ~OM ~-v,N
00~OOv ~ ~O O ~t00 ~ 00M
~ ~ ~O N ~ ~D M 00
00 0000M 00 ~ M
W W W N U U U ~ ~ a '~
z z z
A~ ~ ~ ~ w w w w ~ w u~ u~ w w
a
00Ov O ~ N M W v0
.-i,-, N N N N N N N
NN N N N N N N N
92
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o ~ o00
N .-~
OWE
~O ~ N M
O
M O ~D ~
d'
t~ O O ~n
O~
-.a M .-r
.-i
O O
V'1
O N ~ M
o0
O ~ N ~
M
O ~O ~
O
O O M
00
M ~ ~
.-1
N l~ O O
O ~ O~
M v0 ~ O
~n .~
O o0 N v7
~O
M
~O O ~ ~O V7
O~
V1
M O .~ O -~
l~
~
M M ~ ~~
~--~
N
O t~ O O
~n V~
O
~i ~ M
N O oo N ~w0
O
-r O -n ~ ~
Owt
M O O O ~
l
M M
O vD N ~
N ~ v7
O
O ~ O l~ t~
V~ ~ t~
M O N l~ N
\O ~O
O
l~ O ~ N l~
~ Ov
~
O O O O O
O l~
O~
~O M M
M
~-' N M
M M .-i
N N
O" N ~"
--v
x
M ~p v0
n ~; NN O O
' d'
~ N N
DM o0 00 vp ~ ~t vp ~~ ~ ~
' ~' ; p
d N <t 00 M GL M ~ ~ i i iii
~ ~ y", ~ ~ i'~
~ N b
~ ~
_~v~~ yn y4 A ~~ ' ~,L"
r_i~ ~ ,~ ~ . y.,
~ ~ ~ ~
,~~ r~ r~ V~ C/~ C/~
O ~j ~
OO O O O ~ O ~ O O O OO O O O ~ O
~ ~ ~ O
y~ Y ~ ~ ~ ~ ~ L
~ ~ ~
00M N ~-v Qv O~ Q1 ~ ~ I~l~,~ O~O w'M
N M ~ 00 p~
O
O~M N ~ l~ ~ N ~ N v~ MM ~ OvOv~ ;'
,~ ~' cV o0 l~
~
O~ O O O O ~.. s. D ~ ~~ v~ v m ~ N
:i t- ~ ~.. v W t.. ~~ a a ~ ~ ~c:7
~7 v 7~7v
;v vW
wa
;
a~ a ~ a ,,.
~
,a
N M ~ lmn ooG~~OI~ ooO ~ O~ O N ~ N
NN N N ~ N ~O~DN N NI~I~N M I~M M
~D~ ~O ~ I~~G l~l~~ ~O ~l~(~~D ~Ol~~D~D
I~ v~O OM M ~ ~,~00N O~ ~ ~ 00l~
V7 ~ ~ M 00M N O ~ O\V7
~M ~ N (~oo v~M N v~ NN ~ M
~ i
O 00 ~~ O M ~O V7~ i ~ 00
,~,~
y 0 M .~ ~ l~M O l~00 N N
~ ~ ~ ~
M V7.~ ~ ,--i~ ~ .-..i.~ M d'
N
(~00O~ O M ~ ~h~ N M e1'~Ol~~!1 ~D00l~00
MM M ~ 00'~ 0000~ ~ ~0000~ ~ 00d'd'
NN N N M N MM N N NM M N N M N N
M ~O ~'00Q\V7 ~l~V~M ~ d'00V~
00..r No0l~N ~,~,,00N 00 ~ M ~ l~
~ ~O01 OO v l~ ~ ~ O ~ OvN
O00l O~ ~OOv V'7007 (~ ~, ~ O l~M
t~~ V1 ~ O M ~
~M ~D ~ ~D~ O~G1~DM O~OV~M ,_,~OO O~
~ 0 0000 ~C O00I~~O ~.,~V ~O00
00D ~O 0 N O~ ~ ~ ,~7
~p N N ~ MM
V~ C (~ oo
'1w l /~7~ ~ 00 w a a ~
a v ~~
w ~caa
t~00~ O ~~ N M ~ v7 ~D I~00
NN N M M M M M M M M M
NN N N N N N N N N N N
93
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0 0
0 0
I~ N
~O M
M M
N
O O
O
~D O
I~ M
O
~O O
I~ N
r,
O O
O
I~ N
O O
v~
vDN Vlt~
N w '7
O O~
N O
~ O
.-a N
O O
N
,
M
.-,
O M
M
N ~7.,
~ ~
v'i o0 O gyp" ~ oO l~ ~ ~
N M
0o O ~ i M ~ _
o~O
O N N N O ~ ~ o
~
v~ ,- ~ d o
N ~ ,
~n -,
~
~ M ~p ~ n ~ Q' ~ ~ on
~ ~
O
E-, E.., ~,O p ~ ~
~ ~ O O p ~ O ~
U' O
O O O p
p
O
~
p O Y O ~ ~ O
~ ,n ~D N ~ O N ~
oo M O N ,~ ~ Q
M V~,-, M l~ I~~ '
pp ~ M
~p ~p ~ ~-r l~ O~ O ~ ~ ~ M ~O
I~ O
~ ~ _
~O _
00 ~ N
~
~ ~
~
O O
,
Q" ~ ~, cC N
~ ~ ; w v H v
C7 H ~
v vW x d c7 C7 d
a ~ v~ d a
~ 0.
a
G ~ ~
~ ,.
.
s
..
M M d'W O ~'~ (~ 00 ~ Q1
I~ M M M M (~I~M M l~M
O
~ N N
v N ~ o ~ 00
1 O
, , , , , ,
~ ~ ,
'-'M N N N ~
c M ~n
~1
O~ a\O ~ N O ~ M ~ N ~
0o W n ~m n a\o w ~n own
M N N N N M M N N M N
00 00N O ~OO~~n~D N l~N
M o0O O N o0l~O o0 l~O
N ~ N ~ O o0~n M Ov~
d' 0000~ 00M M U
M M M l~ M M O~01 '~ ~ V'
00 00~DV'10000l~I~ 00
M ~
~ ~n ~D~O~O0
0
O U W ~ d ~ ~ U U W
OvO ~ N M ~ ~n
M ~ ~h
N N N N N N N
94
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0
0
0
0
0
00
N
O
00
N
O
d
M
.-r
N
M
M
Q'
W O O V~ ~t
v7
V~ ~ O~ V7 _..
~ ~ ~ 00
~ N
~ M ~ ~
i ~ ,~ ,-, ,~
j N N N CV M
~ ~ ~ ~
c ~ ~, .~ ~ i ~, ,~ ~ ~ ~
~ o ~ ~ o
, ~ C
d > ,~ C7 E~
x p;
0 7 ~ a
0 ~-r~>v~E-'a.w>~
Q
0 ~ ~ O O O Q O O O O p
o p O O O
o
M ,., ~ O~ a, ~ aW' y
~D p~
d' WO I~ I~ " ~ O Gv ~ V~ v~ ~- ,.
00 ~ 00 Wit' a\
op O~ [~ O M ~ ~p [~
00 O
~, ,~ r, ,_, M pp .~ r, ~.-i in o0
~ N cy N N M .~ ~;
a~dHaa~~a, aa..,~7t7c7d~7a.a.~c7H~v~a
l~ooO ~ N
N ~N ~ O
l~~'~O v0
N
~~ ' a\
V1,~l~M M
v0 N M
M ~'~Ol~ 00
M MN N N
O Ml~N o0
00I~N ~ ~O
v~v~~ N ~n
l~O~~O O
O I~O~oo ~O
Ov00(~00
.-r~M V'1 00
x N
H
x
N N N
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
N
M ~ v0 " ~i ~_D
r~
i ~ 'i
n i
n M M i '-'~
i
O
~
c 00 Iy0 s0 v~ v
r ~ ~t c~
vi wi ~t ~ c r
N ~ N ~ O M Owe N ~
~ M O N
N N N -.
~ M O ~ O a ~ O
~
M
N
~
, ~ ~ ~ ~ M M O ~O
M ~ ~ I~ 01 "~
O ~ O
n
-,
a O ~ ~ O x.
N
N O
M ~ N N ~ N N N N
x M .~ N
N ~ N N N M N M
N
M N ~ ~ ~'. v7 N O
x
V1 V1 ~ ~ M M M m M N N N ~ O QO (~ ~O ~ V7 ~
~ O ,~ d' ~1 ~ ~ M M
t Ov ~ ~ --i oo ~t ~ O O x t~ M t~ O M o0 ~O .~
O ~ ~n O ao I~ M M
~ v0 M ~
x
x
_ ~ N N N ~ N N ~
N N N O N N N N ~ N N ON rrj ~ N N O
~
Ov x
N ~p ~O ~D N
v~ v~ ~t ~ ~ cn cn cri cn N N oo I~ ~D ~D v1 vi
N N O ~ O r-.7 ~ ~ ~ ~t M M ~rj
oo o
~ 00
O i
s
~
N o0 Ov ~ oo O 0
C~ ~ ~ Ov
~n M ~D OW ~ N ~n p~
p x ~ O
N N N N ~ N N O ~n O_w
N N N ~ N ~ a f
Z ~ ~ ~ N N ~ ~ ~
O N N
N ,~
~; N
N N
~ M l~ r'~4 ~ tn O ~ ~ ~ x
s0 V1 ~ ~ V. M M M M N N N N ~ 00 t~ t~ ~D ~
O a 000 p r"' O V7 ~ V M c~i ~t
Wn N M t~ O M OW ~ O x ~ O ~. ~D ,..-i ~O N ~
~ Os ~ O ~ O t~ O n
V
~ c ~ M oo ~O I~ OW
U n vD M O O O
W N vD t~ t~ ~ M Ov W O ,-, .~
~ N ~ r.7 ~ ~ r~i ~
~ N ~ ~ N O N N N N N N N ~ N ,-~ ~p N ~ N N N N O
b ~-' ~ ~' N N N o0
O ~ oo ~ N t~ 000 ,-ml
O
V n M M v
U M ~
O W O
1
c O
N N N N ~l ~ O I
sD v1 ~ ~ V I
N ~ V
x ~n ~ ~ ~ M
it ~~O~oMON~o~OO~O~T~MN~a ~'o~o~oMO~~~~M~l~~
~ ~x'~~i
CC O ~ N ~ N N ~ ~ N ~ O N N ~ ~.j ~; O N -~ N M N
L, ~,", .. r.; ~ -~ O N
' Ov N Ov
0
M
d
=" v0 Ov l~ I~ vD v7 W
M ~n ~ ~ M ~~
vD v7 ~ d: ~ M M M M N N N N
~ ~ O ~ O Ul
x
~ ~
Ci ~ ~ ~ V7 M ~ VO v0 00
O M C~ ~ tn M 00 N V
~O ~O ~O tn ~D ~ N O 00 I~ tn 't
~r N~; ~ ~ N o~~O ~ M O O N N O _
~ ~ ~M M~y ~; N ~: "" Ov ~' ~ N ON M O OM
~ ~~~~~~~~~~~~~a~ ~ N ~ N N
o
~ ~o~
E ~D v~ ~ ~ ~t M M M cn N N N N M ~ 00 Iy0 ~ ~ 0
~ ~ ~ x a x O t~ Ov O N
~ oo ..yp ~i N M O I~ N ~ l~ oo O m
~
~j v
~
~ . _
1 I ~
~ p O N
~ O Ov M I~ d' 00 M M 01 ~ ~D N ~
N N ,-i '-' ,~ ~
y M N N N N ~ N ~ N O ~ N N N ~,~ _,
~ ,
N N
O
V7 O N p
W O v1 ~ ~ ~t M cn cn ri N N N N O~ a0 I~ ~D V1
N Os x ~ a a x' ~ V1 ~h ~t M N
H O O M ~ N ~ ao vD v0 M O 00 M Ov M Ov v1 f~
O ~ ,~ ~! ~ '~ I~ ~ O ~O O
00 ~ Ov O I~ N I~ Ov o0 v0 Ov y0 N ~n OW ~ M ~
~ ~t ..-r N .. M ~j t~ O v1
N M ~ N N N ~ N N N N N N ~ O ~~ N N -~ N N N
~t N M ~ -~ M N N
O ~O N "~ O~ ~p
~
O
O O O p
x
x~
~x N Os oo (W O ~D
~ ~!1 ~!p ~ ~ tYi
l~ vi ~ ~t ~ M cn cn cn N N N N
N ~ ~
~ ~p
~ N W O v~ N o0 v0
N M N O _~ M Ov M N M O ~ Ov W M ~t o0 vD
N ~j "' ~ n
Iw0 "v0 N O M ~ ~ N N ~ ~ ~ ~
~
~D
~
Ov ~ Ul
O O
x~
r v~ yi ~ ~ M ci cn ci N N N O Ov oo ty0 v0 ~1
N ~ ~ ~ x~ ~ ~ '~ Vi ~t ~t M N
; ~ ~
N N ~; ,-" -~ N
00 v
00
.- Qv
~ vO V1 ~O N N ~ t
~ ~n N o0 ~ Ov O V7 ~ ~ ~ 00
i ~' ~ M ~ N
~ M V~ ~ ~ ~O O~ '~ 00 O ~ --~ ~ ~
~ 00 O
O 00 ~O O
~
O
~ ~
D O
_ _
_ _
_
_
_
_
~O ~ V) ~
xaxax.a
0o vi ~n ~ ~ m cn cn ri ri N N Oi o0 f~ ~O v0
N N ~; ri N -~ -~ ~' ,-i ~i ~n ~t ~t M N
N O O~ M vG v1 t~ ~ V O~ s0 t~ n ~ ~O oo N Ov M
~O Ow O M N d' O
00 t~ M l~ O O~ I~ O 00 M O~ M I~ O~ 00 ,~ 01
O~ ~ l~ ~ 00 O ~ ~ d' v7 (~ O M O~ l0
N O N N N ~ N -- N O N N ~ ~ N N ~ N M N O N
~ ~, ~ ~p ~ N N N N
O O O O O O
~ N
~ ,-i .-~
d N
M ~D~
M N
U
~
o
o
'Lr'M M ~
_
ooU
~ U U ~
d
A x x x
O
z .-~ N
96
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o v " r;
rr M " ~ N .-~-~ ~ "
"vd N ~ ~
00 ~ M ~ ~ ~, ~ oho op" ~ v-i ri N ~ ~ ~ M N N --~ ,-i ~ o°o O N ~ ~ ~
n i!'i v1 ~
M O O l~ V1 M a0 N ~ ,~ ~O ~ 01 ~ ~ WO v1 I~ M ~ Ov O O~ ~ O O I~ v7 M Vi O
x a ~ N N ~ ~ N N ~ N N N x M °N ,-~~ ~~~n N N o0 a ,-~ x ~_~ '~": ,~ ~
~-~ ON N
~" V' ~ ~. ~~ ~ ,~ cn N N op ~
00 ~ M ~ i,.j ~" ~ ~ O v1 ,~ " . O v0 p N ~ O
~ t~ VO ,_, .-, ~, ,-, ".~, 00 vD ~ V N a ~ ~ M N N ~~~~ ~~, ~~ ~ M o0 O N ~
l~ Vl V7 V
O O Ov . oo ~ ~ N ~ ~ ~ ,~ .~ c.j O t~ '~ O t~
EO-. '~ O ~ ~ oho ~ ~ 'n t~ O ~t N N a -~~ N o~_o n_ oho WO oo '.'a ~ a v? p a
o t~
~MNNN ~ M~_O M~~~ ~ NNMN
N~
N O ~ O ~ N O N oo y0 ~n ~ N ''~ 00o x '~~' M N N ~-! ,-i .-i p 0 ~ ~ ~ ~ t~
~O W v~
~ N ,-, r~ ,~ M l~ O M o0 N O ~O t~ ~~ O s0 ~ oo Ov a O O x ,..~ O v0 O oo M
O W ~ v~ ~ d' I~ 00 ~D ,...; a C N l~ V Ov OWO Ov
N N ~ ~ ~ " ~ N N O N N ~ ~. ~ '~ ~ ,-i ~ ~ N N N
'~ O oo yO vi ~t N M N N ,-, .-, ,-i O O t~ O ,n ~ t~ ~O v'i v1
.-i ~ O W N O N v0 M ~ ~ ~O r? x ~ ~ Qv Ov N N l~ ~O a x a x a a ~ N o0 O
~O O~0 N .~ ~ ,~ p~ ~ O~ ~D ~~ ~ " M ~ ~ V ~ ~~ O~ V ,~ .~ O op 00 ~O
~ ,~ N ..., ~jj M N N,,,,~~ N O N ~ ,~ ~ N N N N N N ~ N N ~; N ~ N O
~O~~N~N~N~~~ aM~°O ~~M~~
"O
O ~.7 'O N M oo t~ v1 ~ N ~ p O N d: cn N .-~ .-..~ ,~ '~,' O O x a O t~ ~D vi
v1
Wn " ~ v1 O ~ N ~ x ~ ~n M t~ oo O oo ~n ~ ,..] " ~l oo f~ N M
N ~ ~ v~ N O ~ ~ M ~ N ~ . - O ~ ~ w0 l~ l~ ~ ,_; ~ . 0v O t~ O~
-i ~ .~ p~ N -~ ~~ ~ N N N N N M ,~ ~ N N N O ~ N ~ N ~.j . . ~ ~ .-~ .-r N N
N
v~ Ov ~ N ~ M
O ~ ~ N N ~ ~ ~ O lWn .. O '~ I~ p O O
O x O M ~ ~ ~ N oo t~ ~i ~ M oo a O ~ et M N N ~ ~ x O O ~-~, "~ ~ oo ~O v1 v~
O oW O c~ oo "~ ~ ~~; so 00 os O os ~ x ''~ " ~ " ~~i O v~ ov
-, ,.; ~ O~ O~ ~ l~ ~~ ~ " .-i N V1 00 M O~ l~ 00 .~ .. ,~ ~O 00 O~ M
~D .. ~ cn v'i M O ,-, .-, N ,~ N ~ ~' O ~ N N N N I~ N N v~ ,-~ ~.-, N N
~ O n N ~ ~ ~ O ~ ~ ~ ''a ~ ~ ~ ~ ~ O O
O
x x ~ ~ N N -~ N o_o op" t~ ,n ~t cn ,~ x a ~ ~ cri N N ,~ ,~ x x x x a x oo
v0 wi v1
.. ~ ~ ~ M M v0 M Ov N - ~ v1 ~ M M v1 f~ ~ ~ ~~ " I~ ~ N v1
M ~ N ~n t~ Oy-i ~' N M oo ~n M o_o v1 ' N N '.'r ~:~j ~'
v~ O O ~ W _p M_ O O N N N ~' '-' O v0 ~ ~ ~ ~ ~ O ~ O ~ O O
O O O O vp ~ <t N ~ ~ ~ ~ ~ ~ N ~ " O O
xxa~~NvO~DOvpp"yDd:M~~(O/~~l~~tYiNN-~~-!"~''SO,~'a~'xV7 oO~O~nv1
O o0 (~ 00 N ~ ,~ ~O M ~D M ~ ~ M N -i ,.~ ~ N N_
M N "' ~ O ~ ~ N N ~ vi O N N N ~ N ~ ~ n N v~ ~ vp °~ ~ N N N
~D O ~ O ~ ~ M O O ~p I~
W O ~ ~ ~ ~ M O ~ ~ ~ O N °~ O O O
x O N .~ ,~ ..-i ..r
_ O
M .~-y0 ~ ~ l~ ~O ~ M .-i ~ x ~ d: M N N ~ ~ a V1 ~ x x " ~ 00 ~D V7 V7
n O N ~n l~ ~ M ~ N N ~ c,i M v0~1 ~ ~ N ~
N ~ " ~ N N M ~ N l~ M ~ O OM N ~~ ~' N I~ 00 N I~ ~
N N N N N ~ ~ N N N M N ~ ~ ~ ~_O pv O ~ ~ N O
O O ~ ~ ~ O O ~ ~ ~ v1 ~°D O O O O b
°x~M~~~~° x
a ...; .~ oo ~ ov ~ i~ oo °° W o ~i r; .~ 'r' x o ~ r~ c~i chi
,~ ,~ ~ vW x ~ x ~ os .ri ~i ~i
N .. N r, O ~p ~ op ~ O M O N M ~ '-' ~ Ov N N v1 v0 O M N ~ '-' N ~
~ M M N ~ N o_o v0 O ~ o_o N O op M O Ov o_o v_0 oo m I~ I~ v~ s0 °~ O
p Owp ~ Gv
p O O ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ y..-~ ra ~ x x C0~7 ~ N
~ ,~ M ,~ ..r ~ ,~ p~ l~ vp V7 M N ,~ ,-i '~ ~ M N N ~~ ~: ~ M N ~~" ~' ,~ .w
OWO V1 V1
~n N O -w0 t~ N Own oo ~ ~ " .~-~ M oo OW O O ~n .-, N O~ M o0
n V1 00 ~ O~ 00 O M M O M ~O ,~ O ~ WO ~ ~O 00 O O~ ~ ~ V~ ~ N 00 O~ ~ 00 ~ I~
~p O N N N N N N N N N ~ N ~ M N N ~ N N M N ~ ~ ~ ,~ ~. ~ ~ N O N
O O O O O O O v~ O O O O
M ~ ~ V1
N
N ~ l~ ~O
~ O,
M O~ M ~D
00 l~ V'1
p~ ~ ~ N
xa
U ~ C7
M ~ V7
97
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N N
M Vl 01 ~ .~ 00
~' Ov ~ N O
0 ~ O ~
O
~ V M M N _ M ~j r.i Ov o0 Iw0 v0
N ~ ..~ .-i v1 ~ cri
O ~ ri N N N ~ ,-i
,.
00 ~_--~ ~ M .~ ~ N_ 00 Ov w0 M '~ ~ ~ o0 O v0 I~
v7 N M O n nj O vp _ O '"'~ Ov M M O
nj ~ ~~
T
NN~NO~~ ~N~MN~NN~a~,j ' C NNNN~NNN
~ ~ ~ NN
'
~ ~ ~
O ~ O ~ '-' ~ p ~i
~p
~O . ~ ,--n
x "'
x
ri ri N N M ~ M M N N N ~ N ~~ ~ ~ ~ ~ ~ ~ ~D
~ ~ ,. ~~ O v~ ~ ri
~ ~
M_ ~D O_W y0 t~ O Ov Ov ~ t~ t_~ t~ op ~ O --~ Ov
_ v0 Ov N O ~ 'C M O N O o0 v~ M
N ~NO ~ 00 O ~ M 00 ~
N~O N~NN~'~'a ~ NN~a O 00 00 .~
N
NN N N .~~,~ NNNN~N
N
M C~
~t ~ cn cn M ~ M ri N N N ,-i N ~ ~ nj p ~ oo l~
N N ~ ~ ~ ~ ~ ~ ~ ~D y0 v1 ~t
' tri
OW O Owl ~ ~ ~ 00 .-~ p ~ I~ ~n '.". "~ l~ (~
O O~ N ~ ~O '~' O ~ 00 ~ 00
O Ov ~ N ? O p O O et
N N ~ O N N oo O Ov N ~ ~ ~ ~ ~ N O vp N
,."I,' ~l ~i "~ N O
~
~
CO/1 c!i ~~~ ~ M
0~ N
_
,
cn cn N N ,~ N ~ ~ ~ ~ ~ ~ ~D ~n
r,-; ~ ~t M M N N N ~ O t~ ~ M
0 M t~ O M N ri W Gv M O ~t t~
' c N f~ M ~ oo N ~t x O W O
t O t~ ~ ~
_ ~
0 ~ ~ ~ r-~ N ~
~ ~ a V'7 ~ O tn O
, ~O 00 O I~ ~O W O O M O
; ~ O ~ ~ M 0O N
l~ M N O "
l~ M
N ~ N N M ~ N N ~ N N N _ _
N p ~ ~ _ _
r~ ~ ~ ".~ vd' _ '~ N
~ v~'1 O N
ri cn N N 1 ~ ~ ~ ~ oo t~ ~
~ .-i ~ ~t cn tn N N N N -y ~O v7 d: cn
--~ oo p ~ p .-i
O ~
M I~ I~ ('~1~ V~ O~ ~O ~ 00 t~ ~ I~ VO O~ C~ ~ O~
00 ~_ M 00 C/~ a ~ O~ ~ M O~
~ N ~...~ ~ ~ N N ~ N O
N ~ ~ N ~ O O
N ~ ~ ~
~ ~ ~ ~
N ~ M ,-i ~'
N -
N -n
~ ~ ~'
~l C/l ~ ~ ~ ~ ~ ~ ~
~ te
O r
~ d~ M M ., O ~ ~ Ov o0 f~
N N ~ ~t cn ri N N N ,~ .-. .-~ v0 y0 ~!i ~t
C .~ O O O ~t ci
~ ~ ~ ~ ~ N ~ ~
~ x O
~
00 .~ oo O M t~ OW 'i mn l~ O v0 t~ ~ ~t ~n ~
Ov ~ M v0 '' Ov ~ v~ N N
'~ " ''~ '
M M O ~O ~ ~ ~ ~ ~t ~O ~O N O~
M 00 ~ ~ O O~ ~ N N ~O l~ N ~' OW ~ N
~~ ~ ~ ~ ~''~ O
N '-' ~
N N O N N N N N N N
N N M .--~ M N ~ N N N N N
N N N
~N
V ~ ri ri ~ ~ ri ri N N N ~ N ~-! '-' N Oy oo I~
N N -- ~ ~ a a a ~ ~l ~O ~D W ~ ri
~
t~ ~ O t~ 00 0o v0 ~n Vi -~ O r' ~ ~ ~ N oo ~n
Ov oo ,--i v~ 00 ~ ~ ~O ~ ~n v~ vW O
~ ~ ~ O v0 Ov ~n ~ 00 t~ l~ ~ Own ~ oo
v0 ,~ M ~t Ov N N ~ ~" ~D N Q,
M v1 Ov ~'
~
N M N N O N M .--i N N ~ ~ ~ ~ ~ ~ ~ ~ ~-~ N N
N ~ Ov N N N ~ M
~
O N
M M M N ~ ~ V M M N N N ~~ M ~ ~ O
~ ~~ ~ ~ ~ ~ ~-a ~ N ~ 00 00 ~D
~O In ~ M
v0 O ~ O O v0 M oo O_v ~ WO M M ~ N f~ OWO ~ ~
~ O t~ .--~ "~ ,-i N ,~ N_ N
N ~ ~ ~ ~ ~ N N ~ ~ N ~ N ~ ~ ~ ~ N O N
~ O N
N
O N N N O N N ~O N ~ p ~n N
N N N
,,,,~~
O opo M
,-, O O
p0 ~~
ri cn M N ~ ~ cn ri N N N .~ ~ ~ ~ Oy o0 0o
--~ ~ ,-i ~r ~ "'~ wj .-; v0 ~D ~!1
.~ ~
'~
t~ ~ I~ Ov O O l~ ~n M M M oo ~ ~ M ~ ~ cW G ~n c~
N ~ O N '-' '~ " ~' N N O ~n
~ N N ~ N ~ N N N N O ~ ~ N ~ ~ O ~ ~ ~ '-' ~_
~ ~ ~ ~ M O
M c~i N ~' Q~ V cn ri N N N ci N ~ ~ Qs o0 00
,-i ~ ~ ~ ~ w~ p t~ ~O v7 d:
O N ~ N ~ N ~D Ov M N . 00 vD M M --~
~ '~ N ~ O~ t~ f~ M
~
W v~ t Ov M I n ~~N~~NON~ON
v1 N NNNN~NNN~oOM NN~~~
NNONON~~
~~~~~~~x ~~~~~~~~~axx ~~~ax ~~~~~~~~~a~
~t ~ ~ cn ~~ ~ M M N N N ~~ v~ N ,~ .~ p~ Ov o0
cn N ~ .-i ~-! ~j ,~ ,-i --~ ty0
~ ~
v7 OW O ~O Ov N V ~ M ~ N O ~ -W O T O ~D I~ N
W O ~ pp o0 ' p O OW O M -r v)
M 00 ~ 00 00 00 l~ ~O V1 M ~ I~ QW O I~ M M ~O
l~ M ~O I~ ~ ~O M ~ N '~ O~ ~ O ~ ~n
M ~
N N M N N O N N ~ O N N N -~ N N N ~ N N N N N N
N N O ~ ~ ~ ~ ~ N M O
O O ~O O O
N'~'
~_
N
N M
M
O M
~N
98
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
M
N ~ O~ O
~
s0 N .-i ~ _
"~ O Ov
..N~ can pN ~ .-M-~ ~ ~ ~ a O
N ~' ~ ~ O ~ ~? M CV N N N
~, V'
p O ~ N ~ x
~ O ~ ~ ~ N
~ ~ ~ M ~ O ~ CW M V O~ ~O M I~ N ~O
n ~ ~ ~ M N O O
~ 0 o0
O N -i o v
M O
-~ ~ v
x
j M a x V7 ,-. t~ t~ ~ _ _
N M N O ~
yD ~ "~
a 0o
~'! y.. l0 v0 O ~
..
N M-rV O ~ ~ rte., ,-M.a ~ ~!'1 ~ M M N N N N
M M ~ ~ ~ ~O N ~ ~ N ..-i N ~
. ~~.,~,~~~~o~~ ~~M~'NONM.~~x~
apxOa
M Qv N N v0 v~ ~
N M ~ N "~_'~N N N N O M ~' ~' N N N N M N O ~-~
,-; "~ r' N ~ ~p ~ vj
N
O ~ O oho
o0 p
M a ~ ~ ""' ~n cn N ,WO ~!1 ~ cn M N N N N
O ~ x M - ~ N ~ N O a
'
0o ~~ O O -d N ,~ ,-r ,~ .-r ~ ~--~ M Ov o0 00 O
Ov r~ a x Oy ,~ oo I~ '-' v0 O ~ 00 ',I,' ~n
.. .. . b O
'
G
,n ow ~ t~ av o0 00 0. oo
M 00 x ~ a V~ t~ I~ v1 ~ ~n o. ~ .-.
~ ~ ~ M O v
,~ o vD ~ N t .-~ ..~ ~ O N ~
o ~ 00 0o N N t~ O N N N
,~ ~ ca ~ .-i '~ N
_ _
~
O O N ~O
O~ ~p
N ~
x Op M M
~O
p ~~ O v0
,~
~ ~ a O ~ N ~D ~ N ~ O p~ N N I~ oo ~ ~ N cn
N ~ O ~ M '~ ~ Ov O x O
C~ -~ 'w~
~
~
~
~
.~p~ . ~ONOVOO~NI~oO~-~ ~OVO.-~
N ~ ~t~~N ~
N p ~rj N , ~ N ~ ~ N N N ~
~ ~-' ~ , N N ~
,
N.
-~ N N ~
"~
~ ~ ~D '-: _
~t '.~ O ~ M M ~ oo O 'n
~; cn M N N N N ~ ~ ~ ~ O
N M O 'W ~ ~
O ~n ~O ~
00 M M I~
[v
~
ri ~ ~ a p ~ ~ ~ '~ cn N ,-i ~!1 ~ ~t ci N N N
N CO/J O ~ ~ N N N N ,~ ~ O ~ N
~ N ~' ~ M ~ 00 IW O V'1
~t O ~D O ~ ~ ~
"I~
I x ~ a ( O~ " vW
t~ /~ v-i t~ ~ N ~ O , O
O ~ ~' .~ p Oy ~n ~D N ~ N v0 O~ ~ O
~D t~ O ,...,
N ~ C~1 ~' ~' ~; ~: ~ N
.-n~! ~' N ~' .~ .~ ~ .--n .-n N N N N N N ~
,~ ,~ r.; N N N ,~ N
00 vp ~ ~ O~ ~ M ~ ~ ~ ~ ~ ~ ~ ~ N Ov
N '-' ~ ~ ~ x
~
0
0~ MNNNN~ _~ _~_~O V1 _
OO~Oo ~ x x
x a V1 W
V
7 D ~O v1 y0 ~ ~ t~ Ov M o0 O
~ ~ O OWD !~
N ~_t "..' ~ 00 O ,~ ~D ,~ Q_v O~ ~O ~ M ~
,~ ~' p y0 I_~ ~_ M_ ~_' I~ M 00 T ~r . I~
'~ .- O_ O N N N N N N O .~ ,-, N I~
' ,~ ,~
~ ,~
O N
N
N O r oo Ov Ov Ov O M v0 ~
N O ~ ~ ~ ~ " t~
~ ~
0o O ~ ~ O ~
M ~ N N O OM O N pp" ~ ,n ~ M M N N N M
N N M a ~ d_ N ,~ ~ ~ E-i ~ N
~
a a M .~ <h N 00 v0 .~ M ~n Vn v1
N ~ ~' . O V1 V7 ~ ,~ ~ 00
~ m
,~ .-, .-~ t~ t~ O v0 v0 ~D t~ ~n W oo N
N .~ ~ N N N ~ v0 0o t~ M ,~ O
N ~ ~ " ~ t~ o0 ~ M ~ O ~ ~ N N O O ~ ~ o0
N " " N .~ ,~ rr .~ .-n N O
~W O WO
vD O~
~., ~ M
..., N
v0 l~
O O O O
O ~ 000 0~0 ~ ~~ n i
~ M a x 0 0 N
' M
N
x a
ri a a 0 c r
N O O ~t N w v1 d
.. x N N N ~--~ N N N N N
~
~ ~ ~ O ~ M O ~. N. O I~ O ~ ~W
MM N ~D Ov o0 .-i _~ O
N ~ ~ ~ ~ ~ ~ t~
~ p ~ ~ N N ~ N N N
~ N N O N
~ O~
O
N ~ M pp
N l~ ~ p
'
m N in ~ N ~ ~'~ -M
O ~ ~
.-a .~ x
~
, O O
0
p
M ~ ~ ~ N ~ ~O ~n <t M M N N M
N ,. ~ N N ~--~ x a N
~ ~ ~ ~ i ~-~
"~ ""~ ~
~
M
N N N N ~ p n M dW V -i M ~ f~
~ ~ ~~ ~ p .-i O
pp Ice, v~ t~ M ~
p
p
~ N ~ N N N Ov
M Vi ~t
N~ ~~" N~O~N ~~~~" ~~NNNN _
ON~NNNO~ooO~NO~~
rj N x M p~ 00 ~ ri ~ O ~ ~ O O
x O O ~ ~ ~ '
N ~ a a N .~ .-~ .m ,~ ~ , ~
~ .~ ~ ~, ,~
ri ~,~ ~ N ~ ,~ oo <t N ~ ~O y ~ M M N N N cn
N ~ ~ ~ N N ~ . ~ N
~
O 0o U N ~ n M O v'1 0o Ov w0 v7 Ov N t~ N
O N O ~ N V1 ~ ~O ~ ~ c ~D Ov M '-: '-' t~
~n ~ O~ O N M O N N N ~O ~ 00
t~ ~ O a0 O ~ ~ O OW O 00 ~
I ~
~ 00 ~O M O ~
_ _
N ~ ~ O N ~ ~ ~ _ _
~ O p O
,;-: M O
xaxxx ~~ ~aa
~ ~ ~ ~ ~ ~
cn N M t~ ~n ~ M cn N N ~t
N nj N ,-i Oy1 N ~ ~'~ N N ~ N ~ N
0 r" ~; oo ~n o0 n oo N N OwD t~ OW--~
' .. o0 v oo O 00
N cn N
~ ~
O t~ ~n O c O
o ~ ~ ~ ~''~ ~ N Ov N O ~ ~ Ov 0o N
vp ~ O ~ t M v1 O ~ N v0
.~ v~ -~ Ov 00 M oo ~ N N N N M
v0 dw0 00 ~ ~ N M N M N
N N
~ N
O N O N ~ O M N ~ N N N .
~ ~ ~ - ~ ~
O O O O G O O
M
N N
Ov O N N
N
M
N
I~M
00~p
N N
O
99
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
_~ -i ~ ~ _ r; N .. ~ ri
.. N ~ .--~ ,~ ~ .-i ~ .
~ .~ ~, ~ ~' O ~ ~ .--i .-;
N ~n ~
~ n N O
i '~
,-, c ~ W ~ O O O
N N ,- M M M N ~
.-, oo d
, O '-' ~ ~ ~n ~ ~ ,~ '
~ oo
-
O ~n :
,~ . ~
. W O M O O O
N .. O ~ W0 O V N M p ~
N ~p O E-~
7
h
-i 'T' O x '~ O ~1 ~"r' ~ x O r-
x x x O O
N N ~ o ~ O N ~ x O x
n O o
O
N M N N M N ~
~ ~i
~
. ~ ,..
,-..~ , ~
N ~
O
N N M ~ N v'1
oo ~ M ,~ ~ 00
N N ~ ~ oo
O ,n N ~ ~ O ~ M O N ~ p 0 p ~ M M M N ~ ~ ~ N
~ ~ ~ O O ~ ~n
xxxx ~NN~ ~,~~M~~~
xxoxxxx aa~xxa0
ax~
~ _
_
O ~
p ~rj N _ ~ p~ N r,
~ ~ ~O ~ ~
N ~ ~O Ov "
~ O ~ _ M
~ O N M N ~O O ~ " ~ ~ ~ O O ~ ~,
~ O O ~
O O x N N t~ Ow0 ~ oo ~t ~-7
O N ,-i . O ~ x x O
M twD ~ p O O N O O (O/~
x O O O
xx ~_~~~~xx~~x ~~~,~~.~.~ x
~x x r-7
~ -.
~x
_ _ ~ ~ M pp 00
_
_
,n M N ~ N -~~- ~ ~ v1
O-' wj
N
O O '-' N ~' ~ ~l O ~ O W M M y ~ V M M N ~-' O vp
O O M ~n ~ . O '~' x
O O .- m
x
x~x~ ~~~~xxxa~xxxax~lN oMO~MVI~~N
'-' ax~~x
N ,~ .~ ~ N ~ r.; ~' ,-, O N N N N N M ~'
00 M ,.~ .-i ,-i N ~ ~
-
N
~ ~
~
~ ~ ~
O O ~ O, ~ p o0
- 0
, l~ h ~ N
j
0 O o0
O ~ N ~.i .-i x ~ O ~ 0 ~ p
p ~ a p O O ~ 0
v'i yt ~ ri ci N N
a ~ x x x p p
f/1 ~ O v7 Oyp V7 V1 ~ ~-7 ~ ~ t~ V1 Ov oo ~ cV
x ~ ~l "x, ~l c~ ~O 00 M \O 00 M M
0 \O O
~
~ ~~
,_, ~ 00 0 _
~ w N
,.N ~
~ ., ~ ~
O O ~ ~ ~ ~ 0 ~ ~ O O N
O Ov V1 ~ Ov ~ V7
~
O O x .- ~
O '~ r vi ~ ~t M M N N ~l
N ~ ~ '~ O O O O O O x O ~ x x O O
x O O O O
xx~x ~atl~~.7x ~
~ .~.--mt~a~'~~.lxH ;MN~.--,OvOrj~
~
~ .-a _ _
.-n _ N O ~ N N N ON O N
N ~ N M ~ N N N ~ ~ "~ p T ~t ~ ~i
,~ ,~ .-~
O ~ ~ N ~ O ~ ,-~~ M
O t~ ~ ~ oo ~ ~ O ~ ~ O
~ ~ ~
_ O
~ ~ ,~ t~ ,~ O ~ O O O ~ ~ O
O O O O O Vj x x
M
x x
,~ x x x ~ x M N N ~
~ ,~ ~ v ~O d: ~t
C/7 ~ ,~ ,~ ~
~ x x
~! ,~ ~ oo ,
~ , Ov N v0 ..~ N s0 Ov
-, .-r ~ c~ ~O ~ . ,-, ,~ ~ ~ oo Ov oo Ov O Ov N
~ ~ N ~j M O
O v0 N ~ ~ cn N ~.j ~--~
.-, ,~ ~; ~ ,~
v0 O a '~ M
vp ~ ~ ~ N O O vp Ov O Ov W O
~ ~ ~ N ,-..~ ~ ~O ,~ ~ W O O N ~ O
O N V'7 O l~ O O O ~ 00
axxax O ~~~MMNN'~axxxxa
N-.~~,,~aaax~xx~ax~
cn N N ~" v_0 ,~ ~,j N ,_; O Ov M o0 00 00 Ov
~ r" ,-i r-! ~ ,~ r; ~-.i ~ N
,-i .-i ,~ Ov ~'
N O
~
O Ov N ~ N ~ pv Ov ~ ~ ~ N ~ ~
M ~' "" ~ ~O ~p ~ N N O ~
--i ~ a yn p ~ ~ O ~ ~ ~ ~ N N N N N
p ~n ~ N ~ ~ O ~ O O O ~ 000
~
~axxa M~~~:axaax~axxx~ axxxxa
M M M N
j
~ N '-' .--i ~D ~O ~ ~ cn N ~.j I~ v1 ~t
,-i .-i r'; ~' ~' ,-i r.: V
,-i .-i ~-: O ~ 00 M ~ ~n M ~p
(V ~! .-i ,-, ~ ,-i
N N t~ Ov ~ ~ .-WO ~j .. v0 f~ ~ ~--~ M -~ t~
~ O v0 : ~ ~ in f~ V
C~ N N .~ ,-, t~ O v1 N O ~D O N N N M N v1 N o0
O I~ ~, ~p ~,~ O v1 ~ ~ Ov Ov ~' Ov
M a r ~ ~ ~ ~ ~ ~ O ~ ~ O ~ '~ dwn
~ ~ ~
~~~ ~~~~
~~x
xxxx
x
~ ~~x ~
aax~ ~, a
-1v oaa
-l~xxxv
~
., M .-~ .~ .~ ~ ~ ~ ~ .. I~ V1 ~ M M M N 01
~ N ~' " ~ N M M ~O N ,-, ,-i
.~ .-n ~ N ~ ~ ~ cvj N C~j ,~ ,~ ~ ,-i
,-, ~ ..r ,~ ~ ~; ~~ ~ \
O M M
N N M ~ M O ~ ~ ~ "'' _
~ ~ ~ O M ~ _
O N ~ ~ M O
~ M N M N N
N
ooooo ~~~aoo~ooo~oooo'o ~;
p;
~~a'~~~~~a'xooooo
xaxx~ ,~axa~~xaxa~x .xxxx~,a
r.; ,.y M N ~ ~ ~ c,~ ~.j N ,-i ~ V~ ~ M m M N ,= N
,-. ~.i .-i ,~ ,-; ~-i ,-i ,-i .-i .-i ~; -i
,-i
p Owt ~ M "'" ~n Ov Os 00 p ~ ~ .-N, 0~0 vp ~ M
~,j ,~ M ~' .-~ ~ O N vp ~ ~n O vD M op '~t
v0 ~ N N M N O O N ~
~ ~
M
~
N N ~
O O O " V7 O
O O ~ ~ O O O O O O O
M ,~ M
O ~ ~O ~ p
O O O O O O O O O O O
O
M
N N N
v~ O --~
~p M O~
V'1 M N
O N O~
0000
00
.~-,N
M
1
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~; °' r;
" v7 ~ .~ ' ~ N N
O~ N I~ ~ '-a y!j O p o0 ~ N '~ ~ " N .-i
O ~ ~ M O ~n N ~ 0 it ~t cn M cn N N N ''~ ~ yn ~ ~ cn N ,
O O '~ ~ O O ~ N ~ oo vi N t~ M_ O N Os N_ ~ O O ~ O t~ ' t~ N ~O vD N
x ~ x x a N a ~ ~ N N N ~ N N N ~ C~ ~ p~, "T" a N N ~ N Ov Ov p O
-i ,~ r., a ,~ ~ ~ ~ ~ N N ~
cn "N oo ~p r' ~ O O M v~ "'~ O
N '' v'7 ~l v0 ~
,~ M ~ M p m ~ O yt eh ri M M N N N M l~ ~ ~ p x ri N ~-i ,~ .-. ~ d'
o V;xo'°°°x"'o-'~o~oci,:-
~oo.~~oni~v°Woa°°ow~ov~~o~
op O V7 x O ~,] ~ N I~ ,-, r oo N O~ O ~ d~ ~ O Iw0 v~ Ov
~ ,-i ~ N M ~ N N N N M .~ x ,_; ~ ~ ~ .-w rr N N ~ C/~
CC~ O~O ~f1 V~ ~ ~ M N
t~ °~ O ~n r O O O ~ ~ ~ ~~ ~ ~ M M cri N N N ~j O O ~ O n 'n <,'? N N
~ ~~ ~ v
O ~' ~l O O V1 x ~ O O O o0 0o Ov O~ ~ OW 'i f~ Oyp ',C, ~l x O O ~-~ M N ~t
O~ O O
ov ~ ,~ ~ ~ ,~ ~ "~ x ,wo vo M ov o0 00 ov ov ,n x " ,~ '-a ~ oo ~ .-..
,~ r., N N N N O ~ N ~ ~ ~.j N ~~ " ~ ~ ~ ~ N N
N ~' M 00
~!i ~j N ~O V7 M ~ pp ~ ~ ~-
x N N cV N c~~1 ..
~ ~ O O x ~ ~ O ~ ~ d; M M M N N N o0 O O N O ~ ~ cn N N .-, .-~
ono ~ a a x x O a O ~ ,w0 N oo ~O t~ ~ M ~ x x O x O y0 O ~n N ~ O O
" ..i a ~ N ~ ~D o0 M OWE I~ O Ov ~ " a Cv o0 I~ I~ ~D ~l x
ri .-i ,.-~ " ,..; M ~ N N ~ N N f~ N N " '-' " '.; O --~ N N N "
00 M ~ M N O N ~ ~ v0 ~ Ov
O oo ~' ~ ~ p p vi ~ ~ uj a N ~ ~ O O ~ " ~ vp
N p ~ O O x 0 O O v0 ~ ~ ri M M N N N .~ O x O ~O/1 O O cn N N ~-; ~'
a o~~",~axx~a~,yOMO00tn,-,vOvo'~tUx Cn .,_,a~oOtrlO~N,~a
~ N v~ N M two 00 00 Ov ~~ " ~ ~ ~w0 O v0 ~-~
N cfi N ~ ~ ~' ,~ O N N ~ O N N N N M N .--n ,_; ,-i ~~ N ~ M .-~ N
O ~ N p O ~ 0~0 ~ ~ ~ ~ ~ ~ oo v7 ~ ~ ~ d'
~t 00 op ~ M ~ O ~p O V'1 ~O " p O ~ O ~ O " O
CO/~ .-~ N O O O O x O x O M .~ ~ cn cn cn N N N ~ ~, a O ''~' O a c~i N N ~ ~-
~
~a,~xx _a "a_.~~~MM~:~~,~~ x "a ~~,~~:~M~~
-i O " ~' _" ,~ ~ N t_~ M M Ov o_o v0 ~n l~ .~ N " ~' - .mn N v0 ~O N _"
M ~ N o0 vp N v0 vD ~ ~ ~~ op
Ov ,-, ~O O N O N V1
b O O O p O ~ x O O O ~ .~ .d: M M M N N N ~ C/j a O x O ,~ ~ N N .~ .-n O
~ r.~ ~ ~ x a ~ 00 ~ M ~D ~O ~ ~ d' O ~,,~ N ~ ~~ a ,-; M ~O V1 M N x
M N N ,--n .. ,-, ~ ,--n ~ [~ M V' M .-n N O~ M ~D ~ ...1 .-a 00 ~ O~ l~ ~ M
'~r
~ N N N M N N N O ~ ~'~ N ~~ O N M ~ ~ M
,~ O ~ O ~ ~Y °o _W n ~O O_ '~ ~ ~ ~ ~ 0 O M O ~ p
~ t~ p ~ ~ ~
~ ~ o 0 0 o x o 0 o so o x o a ~
Vj M N '~' ~ ""~ "~ ~ ~-.7 x a ~j ~ ~t ~ c~i cn N N N ~-~ x ''~ V1 " ,...a ~ ~
N N ~ ~ a CO/~
~ ~ ,y0 N Ov t~ ~ OWn M O~ M ~rj N ~; ~ ,~ ~ N O N V7 ~n
N ~ ,~ oo N ~D t~ t~ ~n N M oo .. M .. ~ .. p oo ~ ~t oo ~ <"? .-i
00 ~ ~ t~ O ~ O vD ~ N N -~ ~ N N O N ~_ ...., O oo N N N ~ N
M ~ ~ ~ ~ l' M M O 00 M ~ N ~p ~ ~ C N
00 ~t O O ao M ~ ~ ~ N O ~ O ~ O
M ~ a a ~ ,.~., O O O " O O
O O O O O
" "°a~~~~~~M~.;MNa.;~~x~xax,r;cici,-,,-;av~
~" r.; M O d: C~j N ~; ~' ,-i .--~ ,yp O ~ M O ~-n N l~ ~ M M N ~' ~' ,~ '-' O
WO ~ Ov ~ N
l~ ~D oo Ov Ov M oo O Ov M V p p~ p O ~O M v0 ao
m ~ ~n ~ ~~ ,~ ,-, .-~ N ~-~ N N ~ ~ O <''~ O v0 O Ov O O ~ N N ~ O
~~x°axxa°x~~~d~~~~d~~~~xxx°ax~~~~~aa
Ov O " " " " " Ov '!~ ~ ~t cn cn cn N N ~~ m N ,-i ,-i ,-i .-i ~? cn N ~ ,~
,., ~ ~ ,(j ~j N ,-r ~~ ,--n ~ ~-! O ~D v1 t~ ~ M ao v0 t~ N " U (~ OW1 00
0o N N t~ N ~ ~ t~ N ~ ~ M t_~ N ~ oo t_~ a_o -~ N t_~ ~' n O O N W O ~~ Ov O
~O O I~
M~OOOOpOO ~~~ ~~~''°~''"°~',0~,,~0,~,.~~p, ~NNNN
x° t~Ma~xxaaxao
V1 N N .-i ~a ~--~ ,~ ~--i '~ V'f ef d' M M M N N ~ M N ,~ -i ,~
.. ~ ~ .. .. cn s0 O oo t~ t~ O v~ N Ov .-~ " .--~ Gv cn ~n cn O ~ N
N O O M N v~ ~ ~~ 00 N ,n Ov ~ O M m O ~-~ N ~D ~ ~ ~ M oo ~. v0 OW v0 O
N ~ M ~ ~ ~ p ~ ~ ~ N O N M N N M N N ~ p ~ ~ ~ ~ ~ O M ~~ ~~ N
O O O M M O O O M O O O O M O O O O
N N N N
M V~ O
N ~ t~
N I~ (~
t~ ~O ~ ('
N M
z
lol
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~i
"
r; o '."
v c~i ~ ~o ~ os oo ~o ~ ~ r; ~ o
..-v ~ ~ ~ N N r! .~ ~ .-r .--i ,~ .~ ..-n ~ VJ O~
N oo ~.j Os oo tW O v~ v1 v'i ~t M N ~ ~;,~ ,~ Iw0 WO O ~D O
O l~ N 00 O~ I~ ~ M M ~ ~-n O O O l~ .-~ 00 00 O~ ~ I~ l~ 01 ~O M I~ N O
~-.~ O N N ~ O_v °~ ~O oo ao ~n oo M O N N ,..., ,~ N M N ~ ~ N N ~_ ~
Ov N N ~ oo v0
00 y0 t/O V7 v1 ~ c~i M
O ~ 00 M N_ 00 ."r VWO Q_v ~ N ~_D O ~ N_ V~ 00 v1 N ~ N ~'? O
NON'-'~N~'~NNOON N~NN~NN~Nn~~N
p M Vi N .~ O oo Iy0 vi y vi d: cn ri ~p .-i O oo v0 W ~ cn N O ~ ~ rj O
~-1 O ~-! ,~ ,~ ."., pp M Os O N ~O M M O N N N ~ ~ ,-r .-.r ~
N .-mD O (_W0 I~ 00 00 M l~ --r O t~ O~ 00 ~ l~ ~D o0 f~ .-~
vD f~ ~-~ M et ~"~ O M N I~ O\ ~D M N ~ ~ ~ ~'
~ N N N N M N N ~ N N N N .. O op
~ ~ ~ ,~ Cv
O ~ 00 fy0 ~D v7 ~ ~ M cn oO ~ x
~D M ~-~ O N 00 l~ M M N O O~ O~ ~ '~ O 00 ~O ~ ~ M N ~ ~ .--y'
..-n ~ .~ ~ ~ l~ I~ y~ ~ 00 O~ M O~ N N N .--~ .~ ,~ ".H ~ .-r .r [v M
M O v~ r. N ~' "~ O ~' N O N o0 V~ M Ov ~ Ov M O ~ 00 N
N O ~ Ov w0 M (w0 ~ M -~ ~ N ~ O
xp ~~~.~~;~~MM~ N~~x
.v~ ~; b:o~.oooo.o~o~nc~i~ ~~~~n
I~ M O 00 O 00 ~ M ~ ~O 00 M (~ ~O N O 00 l~ V'1 ~ M N ~~
.-r ,~ ~ .~ ,-, M .~ N N N Or,~ ~ N ~ N N N ~ ,~ ,--s ~ ~ r.-n ~ N O
vp0 ~dN'N~_~~ ~~~x O~~~'~~o~OVV110_~~'~n
x o Os ~ v0 so vi Vi ~ ~ cn .~ N oo ~!i
~~~~~~~~~~~~~x.:
M ~ O N Ov OW O ~-, Ov N
~ v1 O~ v~ 00 t~ W G N O ~ ~ OWD
~' t_~r_iN_O_NN,~NO~NONN ~NO~_r_'_~~_~_'~N_~_ O
M
~D ~ O ~ ~ ~ Ov ~ ~ O Ov N ~--~ t~ O ~ T
N l~ \O 00 O~ OO M ~O O V) M p
O vp N N ~ l\ y0N vi Vi ~ ~ ri ,-, ~~ N ~ ,~ ,.-~ N N N N N ap~ vp (~ C
f~ M ,~ v1 l~ t~ ~O ~ ~ ~ N p ~! ,-..i
.-r " ,~ 00 V7 O~ I~ t~ ~O M V1 V1
~p ~ ~ M ~ N N N -~ N N N ~ N N O~
op Ov M N O O~ N O OWE ~ ~ M M ~ O N
-; M ~ OWE ~D I~ M O~ O V7 M N O o0 N O O
N ~ N ~ ~ ~ ~ ~ ~ ~ ~. M N O N ~ N N N O N N N N
~~ " N d' ~ N ~ I~ Ov dW0 N ~ v1 N ~'i .-i
~O l~ ~ 00 O O V1 00 ~ ~ ~ p M
O ~ N N N N N ~ N O N N N p t~
.b ~ ,~ N ~ ~ ~ N N ~ ~ IWO ~ M M ,-i p
N in ~t ~O p~ oo tW O ~n v1 ~ ~ M N °~ ~n M ~n Ov ri ~t v0 N oo
Oyp" ~ "
'-' .-i ~~ ~ N N ~ ~O O O ~t oo cn ~O ~ ~D N N ~ N ~ N ON N N N ~ O v0 ~ "
~NNNNON~NN ~~~ ~~~NNO~M
~ ,-N, .~"r ~ ~ N N N ~ 00 v0 ~ M M ~ O
-i ' " .~ 00 V7 ,--i Ov 00 l~ ~D V~ ~ ~ d: M N M M OWO 00 V~ ~O ~ ~--~ M ~ ~
(~ ~
,~ ~_p v_0 O_v N ~ M v) ~ ~-~ ~ ~ .-i ao o_o t_~ N o0 v_0 o_o N N t_~ Ov -~ O
M M
00 ~ONNNNONNMN ~ NN
~
N ~ N .--~ ~D ~ .~ O~ 00 v0 ~ ~ M ~ p " N
-; N .~ ~.r ~-.-~ p~ 00 l~ ~O ~ ~!1 V7 d' M N d: N N ~ ~.-i .~ .-r ,~ ~ ~ O~
I~ C~j ...-i
vp W O ~ oo N W W o0 O two M M M v0 ~ N OW v0 M O N O N M
M ~ ~ O~ M I~ ~ 00 ~r l~ O ~D ~O l~ ~ ~ 00 .-.~ ~ ~O ~D 00 00 M O~ ~O ~ V7 l~
~
N ~ N ~ N N N N N N M M N M ~-~ ~--~ N ~ N N ~ O N N ~ N
O O O O O x
N N N O N
v0 00 ~ O
M M ~ O
N ~ ~ Ov M
N M M M 00
t~ 00 ~O ~O M
M M
H
0
N
102
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ .~ os
00 W ~ m N ~~ O O ~p M ~ N ~-i ~-i ~ 0 ...; ~; .-~ ~ cn
O ~O W M O ,~ pv O ~ ~ 01
N N ~~ ,~ ~j <t' d ~D v0 ~-~ O tn ~ 00 t~ ~D v0 ~ y!1 ~D ,~ M ~ O ~D ~ ~ ~ ~i
~ 'ct
d' O~ O o0 V v1 ~ ~O o0 00 ~ ~ ~' ~O M ~1 ~ V O O ~ ~ 0 O E" ~ 'n p op Vj O a
N N N M ~--~ ~--i N N N N N ~ N ~ 0",~0. x x ~ V1 ,~7.'~, ~ ,-i ~O.] '0,I,' ~
O ~G
~~~x ~~~~~~~~~~~~~~~~~N~~~o~~~
cy chi ~ ~ °° ~ ~ ~ ~ ; ° ° os o0 0o so .o ~ x ~ ~
~ ~ ~ N o ~ N
r m ,:.; p ~ c'.i c.i .~ O v0 ~ v~ ~ v~ N N ~ O ~!~? O ~-~° N o ~
.°~, x ~ ~ O .D Sri ~ o
Ov O N ~ O oo ~ Ov Ov N OM N N N N ON N N ~ a a xN x .-. '-' ''~ x a o ~: E"'
a
O ,_, ~, N '.''. ~' y0 ,~ ~; ~ ~ O ~ vD
a ~n ~ M ~ 0 N ~ ~ 00 M C/7 01 N
N N ~ -~ oo W ~ M N N ~ O ~ 00 00 vD vO ~ ~ ~ O ~ O l~ O '~' ~ N p N O O
O ~0v ~ oho p v1 I~ M ~-~ N O N O ~ Ov M v0 ~ ~ ''~ x a H x '~'" ,-i a a "'~ ~
~ r~' C~
N N O vp pp ~ M ~ M tn ~ N M N N N ~ "" ~ _~ "
O
'~i ~. O ~ ° 00 NO O ~ ~ ~ ~ N
~O ~D ~ O O O W O
~_ ~ ~_ O ~ ,-~-~ ..~.n .-.-Mi ~ .N-r .-~-~ ~ i j ~-~, N N ~ v~'7 ~ a x, a x ~
a x a ~ a
_ oo ,~ oho V r oN_o ~ ~ O M N N ,-
N N ,~ ,~ Ov o0 0o fy0 wi ~ O N due' ~
~ °oo~xooa
~ o°~o ~ ~ Own ~ M N N ~ o ~ ~ ~ °' ~ N ~ a x ~ . ~ ~? a
.~ N M M ~ ~ ,~ ~--n .~ ,~ ,~ .~ .-r N N ~~ N N ~ M N C~j ~ ~H ~ p\ "'~ rr ~
V~ M
~O Ov I~ N M .-s 00 ~' O ~ l~ M M ~D ~ M ~n
Ov O_v ~ ~n V ~ O_v o_0 ~ a v0 N v0 N N N O ~ l~ ,~ ..r o_0 ~ N
I~ t~ ~ ~ V7 O
M N ~ .-, Oy o0 00 Iy0 V'1 ~ a ,~0, a ~p ~ y-~T.', a a (M/~ ~ ~ a '"~
00 ~ .--i I~ ~ V_'1 ~ ~ N N ~ _~ .~ ~ "
OWD ~ ~ ~ ~ ,-~, ~ N N ~ N ~ '~ O pp ~ ~ 0 cn ~ cri N M
~O~O~O~O V1M~~~ ~00~OM~~O~OO~O N~NpO
N ~ N N N N N N x a a ~ '~'" ~ a a " x x
~ t~ N oo ~ N ~ ~ vM1 O O N x N ~j N '-' '~ ~ "' ~ x O ~ ~ ri
N ~ N ~ O t_~ ~_t c_n N_ N_ ~_ O N N N O N M N ~n ~ ~ ~ 00 N ~ N ~; ~ p y0 ~
oMo
00 v0 Ov O ~ 00 d' O ~ ~ ~ ~ ~ ~ p Q ~ ~p ~O ~ ~,Ox ~O ~ p ~x0 ~D O O O
cn N N ~ ~ ~ N N ~ ~ N ~ Os o0 00 t~ ~O v1 N x ,."L", a a ~ x _" x a x ~ ~,
°M x x
N ~ Ov ~ M ~ oo ~ oho O ~D M N N N "~ ~' ~ ~! ,~ -~ ~ ~ in M
N ~ N N O N N N N N ~ N oo N oo °~ O ~ M ijj ~ M o0
N~~~.-M,.-N~~~ ~~~O~OOOOOOp00 ~~00
cn N N ,~ p ~ WO O ~n ~-~ ~ O~ Oy Oy o0 ty0 ~n ri x ~ a a x x x x a '" x O Ov
t~ Ov o0 ,~ ~n W O N . . ~ " ,~ ~ ~ ~ ~, . ~ M
v0 N f~ ~ ~ N ~ ~ M O N N N v0 M I~ f_~ t~ O ~_ M N N N ~' --, _ .~ .~ .~ N O
p M
t~ ,~ ~ N o0
N N ~ O ~ ~ N N N N N ~ M ~°p ",~ ~ ~ O ~ 00 ~ ~ ~ ~ M ao
I~ v1 ~ M N O
N ~ ~ a a is ~i a x V] is x C~ Om0 M x xi
c~i N N ~ Ov Ov o0 y0 v1 cn . ~ " .. ~ ~
Ov oo Ov o0 O O cn ~ ~'? N N N ~ ~ '.': ,-, r.; ~~ ,~ M ~ vj
M ~O 00 ~ ~ ~ 00 M ~~~~ ~D O l~ ~ M ~ N N M ~' N l~ . . . ~ 00 O~ M
__ _ "''oo,~N~ NN~'O
.w0 v0 M v7 O N N N M N M N ~O ~O ~ Ov ~ ~ O M M y0 v7 O
N N N N ~ ~ ~ ~ ~ ~ p O O O O O O O O O
~
N I~ V7 ~ M N ~ O ~, a ~ ~., ~ x, (/~ ,~ ,~i Vj ~ N ,~ VJ
C N N -~ r.; N --~ .~ .~ ,~ ,~ ,~ r-, Ov Os 00 I~ vp vp ~ M N N N ,~ ~ ,~ ,~
,_.; .~ .-, Ov ~h ,ri M
n oo ~D N op v0 Ov o0 V v1 cn t~ O N ~ ao t~ O ~ N .--i ' 00 v0 O ~ O m
~ M Ov o0 N O»D ~-~ Iw0 I~ ~D O Ov O N N M oo ~n ~p oo Ov ~ N ~ M Ov O l' t~ O
~' v0
N N O ~~ M ~ N N ~ ~ N N N ~ N N N N N N ~p M ~ ~p N ~ N ~ ~ ~p N ~ M M
O O O O O p O O O O O O O O
N ~M
M M N M
Ov ~ N
N ~N
M ~M
O, ~
N M
N N N
103
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ r;
N ~ ~" d' -i ~ vp 'b
~~ ~ ~ '~ ~ ~ ~ ~ ~ O
~ .-~ M ~D ~ ~~ p 0
op N
.
N
N
~
~' ~
M l!7 V'1 V: ~ M M ~ 0
~ ~D M M N ,~ f~ vD
O N ~ OWO O~ N t~
O v1
~
Ov M O O O
~
~ N v1 Ov ~ ~ l~ OW ~
O n l~ Ov ~ O N N ON N N
M ~ oo M ~ N ~ ~ oo --~ M
a O ''O v1 I
' ~
l ~ x a O x O ~ O
v I
~ _
~ _
~ a _
_
N N ~ ~ f~
N O ~D ~ ~ O ..
I~ ~ O ~ N ~ O ~ O (W O N ~ O O
~ ~ M O N .--~ .-, ,~
00 ~ O O O ~1 ~i V V ~ ri M .~ ,--~ .-r Os
~ ~D ~ cn N ~ o0 I~ s0
~ N O N I~ O ~ M o0
O ~ O O x x M ~ O t~ 00 I~ 00 ~_ ~ ~' M
~ O ~ Ov O o0 00 ~ ~ O Ov ~-~
"T. 0 O n
Ov O o N N N
~ ~
O
"'~ m N .
~ N
N -~ ~
N
N ~ ,--n .. ~
crj ~~ ~ ~w ,_,
~
M l0
~'i
~ M O O ~ ~ ~ ~ ~!7 v~ ~t ~ V O o0 v0 N ~ ~
p M M M N ~ O O~ oo tyD
ov~xO'OO oWc6,.ncWnv,ovovi c~,~.~,~.~,~.~~crioov-,
~
xxx~~~?~x~ ~~,~N.~~,~~,~,~M ,~
N ~ N N N ~ N N O~ M ~ O N O ~
N ~ N N N
d
.~ ~ 00 O vU1
~ ~ 0~0 ~j
_ M M ~
p O O I~ y0
O t~ ~ V7 V1 ~ ~ ~ M ~ ~ O\ 00 l
a N N I
0
O
VJ O ~t - V1 ~ ,--i V7 ~' 00 ~D M N ~
x x x ,., -r M ~ M O ~O ~ O ~
~ O r M V7 ~ M ~ N N .~ .-i '-r .-,
T, ~ ~D t~ t .-.a ~ p o
ra ~ O O M o
, o
r. _ _
~ _ _
s0 O
vp ~ due' ~ ~ t~ ~ ~ 00 ..-W ~ ~ oo
~: OWE v0 O
N M ,~ O N
CO/1 O O O x x p vi Vi ~ ~ ~t ri ~ ~ O~ oo (~ t~
~ O O O M M N N
'
a
"~' M 00 l~ ~O v7 ~ ~ ~ V1 N M
x ~ . N I~ ~ --~ N o0 ~O M N -w
a x a ~ Ov N ~n ~ O ~ O O t~ ~ 00
N ~ . ,~ ... ~ oo M v0 ,--~
~ ~ -'
~ ~
'
'
N
"-' ""i ~ ~' N N N N N N N ' '-; '
D O N '
vp N '-' ~ O ~ ~
~
~
N N N
_ ~ ~ N vp oo ~ ~ M
M O ~ O~ ~ o~0
00 N O O ~ ap ~ N - N M N O N
vD l~
O
~ ~ v1 v1 ~ ~ ~ M ov o0 r r
x O a ~ x x a cri cri ~i N ~
O O p
'-~
l x
a
," vM1 0~0 .-Nr ~ ~ ~ Ov N N
~ 00 oo ~D M N
~ .--i ,~ '-i o ado Ov ~ oho ~ O
~ ~
N
'-'
N _ N
~ ~j ~ ~' O -~ M N N N N ~
N ,~ N N N
N
~
OO~pOOOn~ N no
~ c
OVD~
p N~DV'i~t~t~criricnMNNNNON~~p~oot~t
x~xxxx~-.~~a,~
Ov O oo O M o0 00 ~ Ov ~ l~ ~O
~ ~ .-r .-i ,~ N O ~ oo O oo N
~ ~ ,_; ~ O O ,n ~ oo M
.~ t~ M t~
M o0 M ~j M M N N ~ N N N ~ N N N N
N ~ ~' vp N ~ M o0 ~D M N ~
' O
O O~ N
~ ' M
N v0 I~ oo ~D i-
O
p
O O O
O O y , I~ ~D 00 M W N
~ ~ M .-- M~D~~~~MMMMN N~M~M~NO~OOOOI~
x~~~xxxaaC~~p
-, ,-i ~ ~ -i tWD O ~ oo t~ M ~O ~ ~O
~ N ~7 O ~ 00 ~O M
Ov M u1 l~ ~O ~O
O O N ~ ~
N ~ ~ ~ ~ ~ N N N N N N N N ~ N N
Q' ~' N -~
t~ ~ O N N ~ N
h x ~ N
O O O O ~ ~ O
'b
O
~ ~ M Ov N l~ M M o0
C/] H x x x ~ N
a a x ~
V1 v) ~t ~ M M M ~p ,-.n ~ 'r v~
M N Q~ V) ~ O~ 00
t~
N N ~ ~~ ~' ~' w0 0o I~ Ov N O ~ N N N O ~ N
'~ .-i ~i ~' ~ t t~ N o0 O
~: ~ v1 ~O
~ N ~ ~ O p ~ _ ~ ~ ~ ~ N N N
~n ~n ~n N .~ ~ O ~ N N ~ N N
N oo N M ~ N N ~
~p ~n t~ M wt ~
N ~O ~
O
O O O
O p O O O ..~ ,~ .-r
O ~:~~N o
xxxxxxx~a~x r, M ,~ ,-, ,-
~
N .~ .-r ,~ ~~ (vj ~ ~ V~ ~ ~ M ~. M ~O Ov V~
~ .~ ~~ ~ M M M N O ~ ~ O~ 00 l
' ~
N
~
O pp N O 00 M O M V ~ 00
O ~ ~ ~O M 1 ~ ~O M Ov ~~ ~D ~ O ~ 00
~_ O~ V7 ~_O M
N N N ~ N
~ ~
~ oo d' oo O O N N ~ ~ ~ ~ ~ O N
O ~ ~ ~ O
in oo v7 O d' N
~' 00 00 ~ N
~
xaaxHaxaaxx
O ~O ~ N ~ O
M N N ~ ,~ ~ ,~ ~ ~O V1 ~ ~ ~ M M N ~ ,~ ,~ ,~
,_; r.; .~ ,~ M M M N ~ ,--n O~ O~ 00
l~
r; ~ ~ M N v0 M N ~O N ~ N ~t ~ ~n
0~0 ~ N N N ~ M M v0 ~ N ~ f~ Gv
~ ~ ~O O l~ ~O ~ M -~ N ~O. v0 O Ov
N o0 V~ ~n ~ OW ~ ~ N ~' M
N ~ ~ ~p ~ ~ N ~ N M N N N N N ~--~ --, ~
~ ~ N N N ~ N N M N N N
O O O O O O O
p p O O O
N N M M
~
_
N
O O ,n M
00
N
V7
N N
104
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
O vi M N ~ O ~ N
0 ~ O
0 ~ ~ ,~ .~ .~
n ~
v0 ~ 0 op
~n y0 v t~ ~O
C vW n ~ ~t ~ c n
N ,~
h O y p h V1 0o O ~ ~ tW ~ ~ ~ ~ Qs oNO o~0
O O OW O ~; ~ oMO
~ 00
0
v1 h O o0 h 00 ,~ N .~ N ~
01 0 M V7 ~ ~ N ~ N N N N N
t .~ ~ ~ ~ ~ ~ ~ N M
N ~~ N ~ N N N O
N ~.,~
xi
v0 ~ 00 y0 ~D vi vi ~ ~ N ~~ O o0 tW ..~ N
vi ~ ~ ~ M N O ~n ~ ~' ,-i O
~ N .r .~ .~ ,~ .-r .-r
.-,
O N ~ N oo M N v1 ~ Ov p~ ~ ~ nj ~ Ov N v'7
~ M M O oo ~ M ~ ~ M tn
~ 00 N h ~O 00 ~O 00 O~ M vD M ~ O '~ ~O D ~O
~O ~y O M M .~ ~D ~--n --W ~
N ~ N ~ ~ ~-~ N ~ ~ N O~ ~ ~ N
O N N M N N N N N M M N N ,...,
~~~ ~' N N M ~~
a~
~x
dx ~~
d
i v o0 v0 ~D wi v1 ~ v'i M ,-i M
v0 1 ~t d~ ri N N ~ 00 IW O ~ ,~
1 ! vp ~ N ~, O O
~ Q n
00 '-' v1 N N Os O o0 ,~ ,--n ~ ~-r ~ ~t
0o O ~n h d' vi ~ p~ --i ,-: o0 v0 N
O ~-j Ov ao .~ O .~ c~i h O
00 O h Iw0 O W D cW O Ov O ~ Ov v0
~t M Iw0 ~D N
~
N ~ r., ~ N M M N M N p~ M N v0 h O N N
N N N N O N O ~ N ~
,~, O N N N N p ~ ~ ~ N
v0 ~ oo v0 ~O ~n vi ~ N N
v-i cn M ,~ ~ 00 00 ~O vi ~n ~
N cn
~ v~ ~ ~ t~ wi N ~ O O Ov ~
0o O Ov oo O Ov ~ M o0 ~ N O h
Ov Ov ~ h vD N v
N
~j
Ov "" 00 .~ ~n ~ O_ ~~ -, .~ r, ,~ O 0 ~'
o0 O~ ~O Cv h N ~ Ov M O v1 h_ w v1 ~"
~ N ~ .~ .-i N N
O
N O
~
~
v0 y0 v0 v1 V1 V) ~ 00 00 s0 V7 v) c'n N
V'1 ~ M M ~ ~
V1
~
O ~ N O v0 O ~i M h M ~ Vi oo ~ O v~ ~ ~ ~
h O O~ -~ h V7 M ~ O O p~ Ov 00
O Ov p ~ h ~ 00 h -~ h O~ O V'1 M ~ Ov .-r
M ~ ~O 00 l0 ~' ~' ~' ~ O\ ~'
h -' ~' ' ~'
'
N ~ N ~ ~ ~ N ~ N N O N ~ ~ N N M N
N ' : N
~ -
N ~ N O N
N N
~O O~ h ~ ~ V~ V~ ~ ~ ~ ~ ~
V'1 ~ M M "~
V'7
.-i
M V~ O~ O~ M ~O h
O O~ N h ~~ ~ ~ O N vO N ~
v M h N O ~ -~ 00 ~ ~
00 ~O ~ \O .-1 O~ ~D h ~ M N O O N N h
~ O\ ~O 00 M M N N N 00
1n O ~ N N M N O ~ N
.~ N N
N N
v0
~
r~r N p
! X
~
~O
~D m N Oy v0 wi V~ ~ ~t O N
Wi d: cn M N _O~ ,~
~ n h ~n O~ O M OWt 01 0~0
N ~ O h ~' N N '~ ~~ Ov h
O t~ 00 h v~ Vi ~ ~
oo ~ -mo ~ O h ~D
~"
~D N d1 ~ ~O O N Ov M o0 ~ OW--i '-r Wp
~ V'1 -r Ov N
~
N N ~ N N ~ ~ M O -~ ~ N N N ~ N N N
N N N -~ N O N
~ x
cn ~ ~D M ~ M
~D M Oy~ ~D W o v~ ~ ~ ~D o0 0o N O ~ N ~
Vi ~ ri cn N oo (y0 vi ~ ~ 00
~n M
M
0~~ ~~n~~o~oo~0~~c~nN ~ N~
~ ~~~
~N
Q ~
- N O N N ~ ~ ~ N N N NNN
N N N ..h~ .-~r ..m-v ~ .-i
N -~-i ,-N-n ~ ~ ~
'.".a
vD . ~ ~ ~ ao ~ ~ Ov N
V'7 . o0 h s0 Vi ~ ~
V1 ~ ~ y0 ~D vi v1 ~ ~-~
M ~ M M N pp
OWn N M ~ .-. M v0 ao ~ N N ~ N M h oo oo N
oo Ov N ~n oo v1 ~ ~n ~n O N .~ N
O v7
N N ~ N ~ ~ ~ ~ N N ~ ~ ~ ~ ~ ~ ~ N N ~
~ N O O ~ O N N M
~D ,~ Os t~ ~O v0 v1 OWD ~ ~ oo Iy0 wi c~i
Vi v1 ~ <Y cri cn N et .-~
vi 'y 0 y0 ~
ci
M ~ . 01 00 M O~ h O (~ V~ ~1
m ~ M ~ ~O ~O M N h ~ <h V) N ~ \O ~~
~O 00 M ~ O~ '-: d'
W OW N ~_O h ~_O - f_~ ~-, O N ~ ~ N O_v ~ N
_~ ~ ~n ~O M M M M o_o h ~ M O ~ N
o_o O N
OV1MN-VO .. MN
~D N Oy o0 ~O y0 V'1 M ~ ,--a ~ .--n 0 N
N V7 ~ ~ M M N ,_; ,~ p1 00 Iy0 V~ ~
~ y ~
~t'
O~ ~O M ~ ~O ~ ~O ~ M M 00 00 N ~O ~~ ~O M
M ~ O~ M 00 V~ h M .~ l!1 ~ N ~
M ~ O~
~O
v0 ~ N N OW O M Ov O ~ h h v7 ~, W O s0 W
M o0 v7 O~ M o0 M U N t~ .~ O
h N N N ~ ~ N N ~ N M ~ ~ N M N N O 00 N
~n ~ N N N ~ N N
N N ~ M
N O
N
,
O
'~~D h o0 Ov
N M M M M
N ~ N O h ~O
~ N Ov ~ O~
h O~M ~ h O
-aN O 0o ~D
M N M
O~00~ ~O V7 ~D
h_
~i~ U
x
N N
N N
105
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
°' o
~ M; ~;
ri ~, O .~ N ,~ ~n ,-r
O~ 00 I~ two v7 v'1 <t ~ N o0 M ,~-, O ~ ~ 00 v0 vO W Wn v1 ~t ~ M ~ ~ ~D ~.,~
v1 ~ ~D
~O h h ~_ 00 M .~ ~_D ~_n h ~ O O ~ ~ ~D O~ N_ oo M O ~ M ~n ~O ~ O h p h p
N ~ N ON M N N N N N ,~ ~ ~ "~' ''~ x ~ N ~ N N ON ~ ~~ N N N ~ '~' a x x x x
a
OW D ~ O ~ ~Y N .~ ~ ~ ~ N
Ov oo t~ tyO vW n V N ~ ~ ~ p ~ ~'~ oo t~ s0 v0 ~i ~n vi ~ ~ M ~ ~ N N O W O
O M r o_O ~n ~~ M O ~ O O O O ~ op y~ M ~ .~ .~ pv M O_ W O ~ O ~ O O O
N N N N ~ O N ~ a a x~ x a x ~ N N N N ~ N ~ N N O p
~ ,:~ O ~t ~
0o h ty0 v0 U1 ~t N ~ v~ ~ v~ v0 ~ oo ty0 v0 ~n ~!1 v1 ~ ~ M Oy h M h ~t O O M
~ ~ M Ov ~ O a '~' ~ a O N ~ Ov d' Ov Os V M M N ~ O O O O x ,.
p N ~ ON N N ~ O N ~ x ~ . ~ ~ ~ h Ow0 M oo M v0 v0 00 ~O M a ,..a h-1 t/7 _
N N ~--~ N N O N N N O
O~ 00 l~ tyD y0 v1 ~ M h p O Np M ~ ~Q oo I~ ~O v0 v1 m w yt ~ M ~ ~ v0 t~ M O
p
O op p~ ~ ~ O N ~ Ov O O ~ x x a a M .--m0 M O~ O ~ O t~ l~ N ,~ O a ~ x x ,~
h oo ,~ h O oo vo M vo ~ . . os o0 0o v M oo ~O ~ h M N ~n .. x .. .,
N N N M N N O N ~ N -~ ,-; ~;! ~; ~,j ~ ~--n N N O O N ~ N N N M N N ,~ ~! ~
.r
N d' e~ ~ ~ l~ M N .-~ 00 00 M O
v~ ~O M O ~ ~ ~ O ~ ~ ~ ~ O~ h
Ov o0 f~ f~ ~D v0 v~ ~ M ~ O O O ~ ~p oo t~ ~D v0 ~i ~n ~n ~ ~ ri N O ~ p O O
O can
~ ~ ~D N Qv N oo ~ a a x x a x N t~ N o, mn ~ v. wo 0o E" x ~l ~ x x a
O OWE M OWD o0 N V7 V1 ~j ~ ~ r, .. O ~O 'ch 00 M M O ~~ h ~ 00 .~ .. - . ..
~' N ~-~ N N N O N N O ~ _.. .. .~ "' ~ N N N N N N ~ M N N M N
~t N ~ N ~ ~p h ~ v1 ~D h N h
N ~ ~ ~ ~ O ~ N N N ~ ~ v~ ~ 0
os o0 0o r~ yo yi ~ ri r0 ,.°..~ ~ ~ .a x ~~I" °° t~ so
~o ~i Vi ~!i ~ ~t ri c~i ~ o ,°~ x x x a
0o v-; O c'~i cn Ov h Ov ~ ~--~ O oo ~ c~; OW O ~n ~r vi O ~
M V7 h h M M W O ~ ~ N "~ ~ ~~ yO O N O N N ~ Ov OW o ~O c'1 nj ,-; ,-i r;
ONNN~ONN~N ,~ ~~ ..~j ,. O~NNNNNMNN~-~N ~~N_
~ ~O ~ N O O h ~ O ~ ~n v~ W
O ~ h N M N ~
os oo ao t' vo ~o V; ~ M a ~ ~ ~ v? ~ ~ oo t' ~o ~ v~ ~i v; v v ~t N x ~ ~-
°a ~~.., x x a
V'f ~~~ h 00 h ~ ~O ~O ~ ~.j .. ~ V7 ~f ~D ~ 00 00 ~O M O O M
h ~_ ~ O o0 00 00 N O_ ~ ~ ~ ,-, M ~n ~ ~ tW O O ~ ~ O M oo M ~j N
N N N ~ ~ M N M M N N
O OO p,WO~ ~~OmpOOOON
00 00 l~ h ~O tn ~ M i...~ x x x x ,~ ~ °' oo t~ ~ ~ ~n v-s v, ~ ~ ~ N
~ v~ x w x v~ x
oMOONOOv~~O~~r~NNr''pp"'"~ ~~Mr~~ONOQo0~0~~~NN~-i,..;,
r, ,~ .-~ M N N ~ N ~ ~ ~ ~ ~ ~ x M ~~ N ~ N N ~ N ~-~ ~--~ N N W D o0 N_ p~
N M O ~"
M O ~ 'L1 ,r ~ ~ ~ O O O O O O M
os o0 0o t~ t~ ~ vi ~ ~ ''4 x a ~ x a ~ '~ 00 0o vo ~ vi yi yi ~ ~ ~ c~i ''~ x
x ~ x ~ a
V1 ~fJ ~ N_ M W O M t~ ~ N N ~~ ~ ~ ~' ~ Ov M o0 ,~ I_~ ~~ I~ N_ h v0 00 ~ M N
~, M ~ ~ 00 00
~ N M N N O N N ~ .-.-Mr r M ~O ~ N ~ N ~ ~ N N O N M N N N
M O l\ t~ .-, N M ~
O O O O O O
o~~~~~a~~~~axa~x°ax~ x,~,~~~~x
Ov o0 00 l~ h v0 v1 ~ ~ ~ ~ .. .. ~ Ov 00 vD sD v~ v7 v7 ~ ~ ~ M ,~ . ,_;
N W oo W h M VW O ao O ~ N N ,--. .. '~ ~! O~ ~D v0 O t~ t~ vi V l~ N O ~O ~ M
N .~ ~'
N V o_o N ~D .~ G~ ,~ W_ O ~ M CW p ~' Sri ~n -w_0 t_~ l~ t_~ ~O ~ l~ ~ M O_v
OWD ~y M ~ p ~ h
(~ M ~
~~~~~~~~~~~x°a°xaa~~~~~~~~~d~~~ax~°ax~xH
O~ O~ 00 h l~ ~O ~ V~ ~ ~ M N .~ ~~ .-~ .-i ~," Ov 00 ~O ~D V~ V) V1 V'7 ~ ~ M
~j M N
N ~ ~ Ov o0 ,~ N ~D r1' N ~j ~, ,:.:, M N M o0 N ~~ ~ M ,-i Ov N t~ ...-i v0 .-
, N l~
~O 00 O o0 N M Ov M ~ M tn v1 M ~ °~ ~n l~ M o0 v0 h O\ h N v1 N OWE h
~ O t~ ~ 00 h o0
N~NN~NNNOOOMOOOOp~~~~~NONN~NOOOOOMOO
O
N
M
N
h
~O
M
W
U
x
O
M
106
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
~' ~ -~ N ~ N .-i ~--i ,-;
.-i ~-, ~ N .-i ~.,; '~ ~ r;
N M vD ~
.-i : ;
~ ~ v7 Op ~ ~ ~
, ~ ~
M rte., ~ pp" V1 'ct ~ ~ M M N , ~
.-. N N O pp ~ ~p O ,
~ p
N
O C/J ~ v0 v0 ~ V~ l~ Ov O~O C/J vp U M ~." O M
O ~ ~ x ~ C/~ "' O O O ~ p p
,-, x
x
O O ~D ~ N ,_, ,-, N ~ N N x ' a
N N N O x ~ a x
N -r N
O ~ '~ ~ '-'. ~ y0 d' ~ t~ 00 ~O
pp uj
O
t M cV .~ .-i O ~'
t M N o0 00 ~7
ri M N N N O N v0 ~ a
~
~O v~ ~ O . .. a O vp v~
O ~ ~ M O
M ~
00 . .. .. . ,,~ oo O
t~
O"~'~ ~~~~~~Mrn~c~NOxO xx aax
U7 ~ NON~x'~'x~
~~ N N N O N ~ N N ~ j p
~ ~, _
N " 0
~ ~ ~ ~ " "
'W :
~
~
~
O n ,j ,
~O ~D .
-, ~n N i
M O ~ O~
O
~ ...
~O ~ ui ~ ~ ~t cn cn ri N O "
~ N x O 0 ~ v~ t
N O N .~ ,-i a ~ ~
N ~ O
I~ O
p Cn N ~D ~D O M M N d ~ -~ ~ x O O
p O x O O ~' N I~ ~~ O O
o Ov O .--~ N O O
~ o C~ v0 0o d' a x x
o O a a " a x
~ a
~ t
W
N
~ ~ ~ ~
_
_
_
_
_
M
v0 ~ O ~ N cn N O ~ N
~ '-' N ,~
cn ~
~ O -i x O ~j ~D O
i N O ~
M M M N N ~ ~ N N
~
O ~
v ~
O x V '~' _ O p O O x O
O ~t ~ O O
c O x a x x _ a
~ x T ~
N M M O OW 1 O O ~O t~ '"
~j O x O
~
a ~ o I ~j x
a ~ O O~ O ~n OwD ~ x ~ ~ M
a ~
~'? N o .~
_ __ _
N ~ _ O _
~ N N ~ ~ ~ O N vN7 ~O ~ ~ ~ ~ O ~ ~ ~ ~
v0 ~- ~ ~ '-i N
M ~ ~ d' N
N a
M M _ O
'~'
O
O M N N C~ N N ~!
~ p p p O .~.
~ O . . O O
~ 'n ~n V ~ ~ ~
.. .. x
a
~ a
a N O N O ~ ~ ~~ O M ~ M ~ '
r; 0 ~ x '~ ~ ''
~ ~ N N ~ N M N N N ~ N ~-i
.-~ ,~ '' ''.~
Ov ~ <h o0 O
,~ r., N .~ ~ N N
o .-i ~' ~ ~,! r.;
O
N ~ ~ N O Ot~ ~ p ~ O~ ~ O O t~ 00
~ O O~ M
M O
O ,--~ ,-
I ~ .l
a O ~ ~ O o ~
~ x OOOO
O N
~ o
yOvytd;MMMNN O '-".;
~O ~a N
- x~
:o ,a
a '~av~x
~oo~ a
i~os' o~o
"~
oo
:
. N ~
, ~
. ~
"~
~
.
a
-
-i _ ~~ N N N p ~ N '.'
y0 .~~ N N ~ N N N N N '-' ~ p
~ N ~
~ ~' v~1
~D~N , O~ ~
~~
0
7
~
~
0
b
. 0 ~~OOO000
r x ~
v
1
0o
0
a x p~ N f~ wi ~ ~ M cn ri ~ N N ~~ \O x a C/1
~ N N ri x x a c~a a x ''
~ ~'~ yn o0 00 .-r N t~-~n N '" a CO/~
" O O~ M ~: ~ ~ ~ O ~ O ~ "
-, ~ N o0 O I~ M M N ~
. ~ N v0 lW0 -~ O~ v'1 00 ri ~ -i
....a M .~ ~j ,-n
'~
,j~ N r., .~ ~ M ~ N N N ~ ~ '-' N '-' ~ oo
N W ~ t~ ~n p~ M ~ Ov
~ ~ Q '~ ~ O ~ r, ~
OO' ~ ~ ,~
O ~ ~n T~O~
NO~ M p
0 0
~ 00
~0
Q O r 0
O O -~ O
ax~ O p 0
~ ~o~~;~~~MMNN~t/)xaa as 0
NN~~a",h'aV1'~'ia,~
.-i ~ ~ ~O O~ ~ M O~ ~i 00 M M V~ N ~ M r-i
,-~ ~D -~ ~ ~ ,_; ~ C~j ,-, ~' ,-, ,_;
'-r ~O ~O v0 0o Ov ~ N ,~ W ~n N ~ . . N
- v0 ~ N . . 00 . . . . " .
t~ ~ .
O
-s ~p o0 ~j N ~ op ~p
o0 W v1 N N ,~ ,~ .~ (y ~~ 00 O N N O ~" ~ O
,~ N N ~ ,W
N ' O ~ y0 '/~ ~ M ~O N ~O M
. a N
M O
p O ~ ~ a ~j O O 4 O O O
O p O O O O O
O O
is N ~ I ya (vj C~j -.; -Wa
x tn ep V ~ M M N N ~ a x a C/1 x W a a
x x a ''~
~
-i ~ ~ ~ N O ~ M N ""'
~ ~ N ~_ m!1 N -~ O ~O I~ N .-i '-i '-" ..;
.~ CWT N ~ r-i '-' "' ~
~' O ~ !~ ~ ~
N N N N N ~ ~ t~ N ~ OW ~ O~
N ~ N ~ t Ov
N N N N ~ ~ ~ ~ dW
O O ''~ O O p O a
p a O ~ ~ O O
p
ax~x ~~ x~ xax~xaa
axa~?
~ ~; ~N~~
.-i v7 N .~ ~n ~ ~t ~t cri ,~ ~ " .-, .-i
-..i M N N " ~ ,~ Ov N ~ I~ v1 M N ~
.-i O o0 t~ v1 WO ~ 00 ~ oo N ~ .-i
.-i cn o0 N ~' '-' O ~ M
~
M ~ ~ N ~ ~ l_~ O_~ o_o ~D M O_W ~ ~ ~ ~ 00
~ o0 M OW 1 O O O~ O M .-,
N ~ O ~i~i
000~0~ OOO ~ O ~ ~n ~O O O ~
O ~O
OO
~~O a0 O
O N x x ~ aOOOO
O
O
aa~x ~; aHa a aaxaxxa
-i N t~ oo ~ ~ ~ ~t cn cn ~ _~
-.i N N ~~ N .-i ,-i ~ ~j v? N '-' .--~ cn
-~ ,~ ~j
,-i
vp O ~ '-' ~ O ~ M ~n o0 ~ ~~ Ov N ~ M ~ ~
O v0 N vp ~ n O o0 ~-. ~:,~ ,jj ,--y0
~ ~O -~ N N OW ~ v1 O~ O ~ N v0 00 ,-, r,
N o0 v0 ~ ~
Q
O M N ~ ~ O N M N N N O N N ~-~ ~ O o
.~ O ~ ~p M 0 .-
v7 -~ ~ ~O
O O O O O O x O O O O M O O O
O O
O O
N ,~ N M M
N ~ ~ N
~ ~ 00
~ N_
p1M O
~O~ DD 00M
'~W ~ w z
U
x x x x x
N M
M M M
1~7
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
c%i
~n
h
-i (y
~'
M . a
cn cn N N cn N N ,~ ~rj ~j ,~ M N N N ..-i
N ~ ~ ,-: .-i .-, ~ M p -~ ~ .~ ,-i
"
M h ~ M Q\ ~ O M ~ ~ vD M O M I~ ~ 00 ~O ,--n
h V) ~_O O ~ l_~ ~O .~
D\ N ~ N N ~ ~ O N ~ C
N ~ ~ N ~ ~
~ N ~ N ~ N N
,.aN N ,~ ' N
' ~ ,
0
M ~ cn N N N M N N ,-i cn N ~ ~ v~ ~ N N N
~ .~ oo -, ,-i ~ ~ ~ ~ O
p v1 ~ O h N M N M M v1 m vD 00 V'1 N h N
00 M ~ N - ~ O p ~ ~ h ~ v1
Q ~
N N N O ~ ~ N N O N N N ~ '-~ N ~ ~ ~
~ N ~ ~ ~ ' M N '."
a
~O ~ ~ ~ ~ O M ~ ~
~p
M N N N -~ M N N .~ tri N .~ ,~ ~ N N N N
,~ "~ .~ ,-i ppp M opo -~ .-~ -~
c . x
i p p '-"' i oo
~ -
~ Ov N oo r ~D ~t ~ h M .~ ~t O
M o0 N ~.; v0 h ~_t O M_ , I~
~ N ~ N ~ ~t t O -
N ~ O N ~ ~ ~ N ~
~ h N a N N ~:
p~ N N N M
~~~ ~~~ N
,_; ~
x ~ o ~
0 ~ M N N N M N N ~ ~v ~ N N N N
~ ~ ~ ~-v ~ ~ ~ ~ a
M N .--~ .-~
O p ~ ~
~ O Own O ~D N N h h v1 cn Ov ~~ M o_0 ~
Ov oo ,~ ~n N a C~ ,~ ~ oo m Ov 00
_~
N ~ N ~ M N N N ~ O ~ ~j ~ N N N
~ ~ N --! ri .~: O ~ ~p
~ ~~~ ~~ ~ 0
r~,
~
O ~t M N N N M N N N M N N ~ p ~ M N N N
-~ ~ N ~ ~ Q O a ~ ~ E"
w O N O vmn M h ~n N cW O cn Ow-7 M N vi v0 ~D
vD N ~t ~t "~'' a . ~t ~ ,-i t~
d' O ~ ~ Ov ,~ .~ oo ~ Ov o0 00 N ~ ~ M
M M ~n ,-, ~D r.; r,; ~~! N O h
N M M N N N ~ O N N N
N M N N N ..
N N N
O
rr~~!! -- r,~
rr~,!! ~ ~~~0
r,~ ~
Oc ~
M N N N ~ M N N N n t M N N N
~ -~ ~ ~ ~ N ~ ''~''
M N N -~ -
x a ''
'
x ~ x ~ :
~ ~ ~ ;
i'i o0 N
N
M ~ wO M O ~ M N N h ~ . Ow
_; N O O W h O ~ h ~ OW
~ V1 h ~O ~D V1 h M ,~ h ~D ~O 00 00 O
h O~ N M h W D ,~ .~ ~' ~D h M
N
, M N ~ ~ ~ ~ O ~ N N M N O N ~~ O ~ ~ N
N N N N O -- " p N N ,n N
~ N ~ ~ ~ O
W n M N N N c!1 N N M N N ~ Q ~ <''~ N N
-~ -~ ~ N --! ~ x ,.p..~ N N ~-!
x x
~"
~ O v~ oo ~ ~ O o0 ~ O ao ~ " v0 ~D h I~
d' h ~D N 00 .-y ~ ~; v0 ~D ~ I~
O~ h ~D M ~O O O ~O .. N O~
O M 00 \O N O~ ~ O M N wj ~O h h M V7
N 01 M ~
~ N ~ N N ~ ~ M N .. M~
N N N N N N N N N ~
~ ~
~ ~ ~ O
b O ,.a
C .~ ,-i .-i cn N N N ~ M N ~ Q d~ M N N N
v7 M N N N ~ ~ ~' ~ ~ x N ~
~
.. .. ..
0o h v0 h N o0 h ~ ~ ~n O O ~ N
~ ~ Own v~ t~ OW 1 N Ov
D ~ M N Ov M ~j ~ r,
O _ _ N N,,..~~ O QM N N
N ~ ~ N N M ~ N N N ~,,..~~ N O N
N ~ N M,,,,~~ ~ N ~ ~
N,,yy ~'
00 ~~~ ~~~'T' ~~~~~p00
D M n N i N ~ a x ~ ri N N M
~ ~ ~ ~ ~ x x N ~ cn
--~ V
~ c r OW ~ M ~ N
N N N N N v h Ov ~ Gv
~D M ~ ~ h oo O
~n cn o0 Ov oo v c~i N '~ "''
OW O W O~ M
O W O~
_ _ _
Q ~ N ~ ~ ~ _ _
O N N N ~ O N ~ N ~ ~ N
~ ~ ~ M N N ~ ~ ~ O O
x ~ a a x
y
D M N N N ~ N N N ~ M N ~ v7 M N N M
N ~ ~ ~ --~ ~ v0 ~ cn N N ~ ~ O
v~ -~ ~ ~O O O ~ N ~ '-' O t~ d' O
oo O ~ 00 ~D
~ W O ~1
O v O --m0 ~ t ~ N ~ O o
M ~ O ~ O M Q o0 o0 ~ O
O O M M O~ ~O t h
N OW
O oo ~ M
W oo Iw
O ~D w
_ _ _ _ _
_ h h _
O O O
O
x a
axa
00 M N N N ~ N N N ~ M N ~ ~ ~n M N N ~t
N ~ -~ ~ ~ ~ N r.; "~ N ~ ~ ~--~
'
M ~O 00 ~ ~ N N M ~_ ~f ~ 00 ~ M N_ V7 V)
O~ M ~ M h G~ I~ ~ ~ ,~ ~ N O d M
Q ~ ~ ~O~ N
Q ~ ~
NN NNNNN NN N
NO~N~N N N~~ NN
h
O O O O O
O
N N
O N o0 ,~ h o0M
Ov
M ~ ~N
' vp
V'~ V7 ~O ~ ~ 0000
O 0~0 ~ h h h
C~ ~ f~CA
~
x x U U ~
x x x x
y vo h o0
M M M M M
1
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~b
o c -
N ~ 00
~ ~~
, . ~ O - . . O v'i
M N c~j ' ' ~ cn N N ..-, ,-,
t~ v1 wi d ~ cn ri -, -- ~ ,~ ~ t~ ,-~
N N N x ~ N .-r N
~ O
MI~~v10t~00s ~n~D--~N~ ~nwn~O~vlO~
O~O.~ ~0~~'T'O Op~c~~
_ N ~ ~ N ~ N _
pN N ~ N ~ N ~ N N ~ '-' a N ~ O N N OM
N C/~ N a
O ~ ~ ~ ~ ~ ~ ~ c
x ~n j v?
V' ~
tWn vi ~ ~ M M N N N N ~ N ~ ~ M N N ~ ~ ~ ~
N ~ ~ ~ O ~ p ~ can
'"" ~i '~, Y
O O
M N O I~ I~ N IW O ~D N -, c_rj p~ t
~_ N_ ~n t~ a i vG ri ~ O_
O Do
h ~
~ ~
~ ~ ~
N N M M o O N N ~ M ~: N N
o N O N N
N ~ N N ~ O ~O
_
O
M ri N ~ .
r wi ~n ~t ~ M cn -~ ~ N -~ ~~ M N N
cn N N N ~ ~ p
~D M ~ Ov Ov oo ~ M .-i ~O oo O_ N_ v0 I~ N
~ v0 0o O v0 00 O ., ~O ~ O ~ O
a O ,~ p
~~NN~N~ON~'~ ~ ~NN~~ MMN~NN
NNN Na
~ O ~ ~ :-:
O
0o W v1 ~ ~ ri ri M N ~ cn N -~ ~
cn N N ~j ~ ~ ~,'I,' cn N N
O
.--W D ~ M l~ O~ 00 cn v0 N OWn I~ O N w0 d'
OW O ~ r-7 t~ 00 ~ "~ Ov p
~D M ~ ~D O~ ~ M ~ 00 N ~O ~O O I~ I~ t~ 00
a0 O~ -m0 O l~ V1
. N N N y,~ N N ~ N ~ N N
N N N N N N N N N ~ ~ N ~-~
~ .~ ~.j
~~~x o~ r.p
M ri N ri N ~ cn N N N .-i
a0 Vi y ~ ~t cn ri --~ ~', a .
ri N N d: O ~
O ~W D O ~ f~ oo t~ N cn O l~ ~n ,--~ N v0 ~n
ci s0 ''~ O~ ~W "_; .. oo O ~D O
OO~NNNNNNOc~-: NOON NNN~O~ NN~~~NpN~
N
O ~
00 v cn N m N ~ ~'
wi d ~ - x ri N N N ~
n cn M N N w~ a a
d
0 r.
; c
:
N N ~ O ~ Own O~ ~Wii cn ~ -r O ~ ~'~ -~ Ov oo
po0 M . O O N ,-i ~D ~ M t~ E-~
~ -r .~ ~O ~O O\ ~ O~ 00 M 01
~ ~D 00 O M 00 ~O w ~O O~
~ M O
N O
. O
~ N ~ N -~ N ~ M N N O
~O t ~ O
( ~~~o
N O ~ M N O N M N
o
n M M N M N N
~ a ~ ~
~ x ~
O x
~~oo v0 v1 d: ~ c - -~ ~ N
N N ~ ~ " N
V
U
M
M~D O I~ N ~ -~ l~ O ~ ~ O M O Ov ~ O -~ ~D
W ~ N ~; N N ~ f~ t~
~D I~ 00 00 I~ ~D l~ 00 V1 ~ l~ ~ 00 'd C~ O~
C~ O~ 00 l~ O~ l~ ~O U ~ M ~ <t
' ~ O
N,--~ .~ ,~ N N O N ~ ~ ~ N ~ ~n N N N ~ N N N
xN N ~ ~ ~f ~ ~~~ao~ ~~~~~~~v
~~~~~~~~~~~o ~~~~ "~o
00 v0 v1 ~ ~ M cn ~ N ~ M N ~ y
cn N N ~ 'T'' ~ N "~'~ ~ N N N ~
nj
~nW oo CW ~ ~W O ~ Ov N c_n O Os cn v_~ N t~ M -
M O_ oo ,-i ~t ~_ ~~ ~ ao ~ N
~
N~ ~ O N ~ M N M N N O ~ N N N O N N N
~ ~ N N ~ M O ~ O O p N
0
~ ,
~, ~
.-,OwD v1 dwt M M M N V N -~ ri N ~ ~ N N N ~
N ~ -~ ~ . ~
~Oo0 ~ oo ~ N ~_D N N ~ N oo l~ ~ oo ~Y Ov OW
cn O o_0 .--1 -~ M ~ OW_: n t~ O o0
N ~~ '-' ~N
O ~~ N
NNNNNMNNNNN NN ~M~ NN
~ N ONN~~
"i ~~a ~~~ ~
~
r
r ~~x
r
~
OW O v1 ~ ~ M cn cn s0 N M N ~ v~ cn N N ~
N N ~ ~,~ N ~ -~ ~
~ ~
IWO M M O o0 O M m ~--~ N M .-~ Vi M Ov N M N M O N ~
~~ v1 oo l~ Os O 00 00 O~ O~
O~ O M O~ 00 OWE 00 ~ ~ l~ - --v O~ ~ tn 00 Vl
N l~ M ~ ~ O O O~
~ lW
N~ N N ~ N N ~ ~ N -~ N N N M -~ - ~ N N ~
N N ~ N N N ~ ~ M I~ ~ I
,~
~''~
ax
.-iOy~ yi ~ ~ M cfi M ~O N ~ N -~ ~n c'i N N ~
N N N ri _; N ~ ~ r;
,~ r;
etOWE v7 N ~ Ov Ov N ~ Ov M tWn ~ Ov M N N ~D
M M M ~p s0 00 M p~ Ov
~ ~ ~j N ~ N
vDoo Gv O o0 v0 I~ Ov N O ~ N ~ O O~ N t~ N v1
M ~ N ~ N Cv 00 0o
O ~ N ~ N ~ ~ N M N M N N N N w~ N N O N O
N N ..~., ~ N ~ w~ ~ ~
~
O p O O O O O O
v
7
N M
00~ O
O~ N O N o0
~Ot~ O I~
O ~ ~n O
ov ovoo ~n t~
O O
H
a ~
a ~ v
x x x x x
O, O ~ N
M
109
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
_~ .-i N r
(V O
(V
M ~
-
N .. N N N -- p~ o0 l~
O 7 ~t cn cri cn x Iy0 v1
.--i ~D N N N ~ p
:
:
00 ~ '-' ~ r., ~
d' ~ a r ,~ .--y
p ~' p wt ~ ~ O O ~D ~ Ov N ~t ~_~ Ov o
~ ~ ~ O --~ t~ ~ N -~ N ~ o r ~' M
"'~x'"1"' ONNNNNNNN ~~ v~ t~ ~_D
O ~'N~ONN
1
0
''I''x~'O~O
~
~ MN M
- p~
l
/7
C
ri N .--i .~ ~~ ~
~ a .-i
N r ~ O ~
r ~ ~ M ~O ~l pmp vi ~ M M M N N N N ~ ~ ~ 00 I~
M N N ~ x (yD V7
C r ~' M 00 O O~ ~00 ~ r N ~ ~ ONO
x 00 M 00 00 O~O
x x ~ O ~ O
/~ C~J ~ N N ~ M ~ N O N ~ ~ N r, N N
x N N ~ ~ N N
N N N .. .. .. ~ ~ ~ ~
r3 .~ ~ .~
O
O M_ r v~
M ~ O ~ r ~ ~ O x ~ M M M N N N M N N ~ .j p oo
~ ~ O ~ ~ r r ~O
v1
O O O O ~ ,.~ -~~- ~ ~ N M O M iii " ~' ~' ~
O ~ O OWO M Os N r O ~7
x Mr~GWOCnOvM~ O N ~n
xx NOooOoo ~rr~M
x O ~~ M N O ~ N M N M rN
x N N N ~ ~ ,~ ~ -~
~ "a ~~ N .~ N
~ .-, ,~ ~
"
~
~
M
V~ 00 ~ 00 ~ ~ ~
V'7 ~ !~'
O i M i N N ~ o
O ~ i ~
~ N ~
0
i
~ ~ p ~ p ~ d: r r o
O c! ~~ v
p ~ N ~ M O~ M t
x O O ~ N r t
C~ x ~ O x O Ov o0 ~t w0 N s
O v0 v0 M O Ov O
M ~ O
~ oorrowrow00 err.-.v~~ r-!~ooOM~M
xxa _ . ~,~ ~.7
cn N r.; ,.~ ~ ~ O ~ N --, M ~ ~ ~-~ N M p~ O N
~' " ~; ~ N N N N ~ N N N
O r Ov
N ,~ ~--i
N N .. ~ ~ ~,j ,-,
N .. '
~
~
~
N
O M "
r ~ ~ ri M M N M N N ~ 00 r (y0
~ N N r- d.~ v'i
~ O O
O N
p 0 O O O O ~ ~ O
~
O N M vD --w0 M - Ov ~ ~ Ov W O
'~"' Vl x ~l '~' r O O ~O ~ o0 .-~
x '~' '~ " ~l x ~O ~O N M O r
~ O~ O~ O O~
~ ~O V7 O~ ~ M .~ N N r
M N N N '-: '.".' M M 01 r ,~ N ,~ -~ '..,
-~ p\ ,~ ,~ ,~ .~ O .~ M N N .~ N M
.. N .~ ,-, N
.. ~t r
p r yn ' m
''~
~
~ ~
r
O ~ .~ M N N ~ Ov r r ~O
O M M O O t~ ~ M M cn N 00 V1
O N N
a x x O O
O O O sd
x
~ax.~
axx
x O~O N~nooMVO vGMOVOO,~
~ - ~NNOV v0 N O ~ ~ M V7
~O oo vp 00 00 M
~ ~ ~D ~ M O
oo O O
N N N N N N M N r N O N
'' ~ 00 N ~ M N M ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ O~O
M ~ ~ a
rvoNON,~ov,~
p O O ~ ~ ~ N O O ~ " .-, ~O N
W O O
I~ ~t cri cn ~ N N ~ '-' N Os
~ cn N N N ~ ~ ~ oo IyO
M N O O M V~i M v0 N VO
W 00 O 00 ~O ~ M r N
00 00
N ~j ~j ~~ '-' -~ vO o0 <t O o0 ~ O~ ~ M oo Ov
.-i .~ ,-i 0o r v0 vD r ~ ~ oo vD
~j N p~ O " " " ~~ N N M .~ N M O N ~ N ~ N ~
op N N N M O N
,~ ~ ~ ~ O_
~~n~~~
~~
_ b
~ a f/~ x "~ x x ~ ~ M M m M N ~' N N ~ ~ Ov o0
,~ f-7 ~ N N ~ ~ ~ ~ t~ ~D ~D
N ~.j N ~ '~ ~ '~ ~ Ov ~ ~n O oo ~O cn ,--iM N M ~n
'-; .-i ,-i ~i1 ao ~i~i Ow1 - O
' ~ v0 v0 N ~ N O~ O
W O Ov r oo r v~ ~ r N N
~ v1 N Ov x
~
_ N .~ ,-, N N ~ N N,y ~ O
N M ~~ O y0 N ~ ~ N ~' ~ ~
~ ~ ~Q ~ ~ -,
~ ~r ~ O
~" oo ~D v0 ~ N ~
M v0 r
O
O
. x .
O O O O ,
O
a a ~ N -i .-i Ov oo I~
a ~ 00 ~ M M M M " s0 v0
~ ~ x x x x ~? N N N ~ N N "
~rj N ~j nj r; "' M ~ ~ I~ ~ r
,-i ~: .-i ,-i ,-i Vj M c_V V ~ 00 N ','' ,-.v ..i
O r Q_v N I_~ ~ N N N p o0 ~O
~' oo p~ '-' .~-~ ~ N ~ ~ Ov
O ~ "' '-' r O ~ N N N ~ ~ N ~ ~ N N
~ N ~ O N
O ~ ~ ~ ~ ~ x ~ ~ ~ O
~
O M O b ~O ~--i
O O O O O
O o
xaxaa~x~xaa~~
00 ~ M cn ri ~ N N ~ ty0 v0
M ri N N N ~' '-' cn N N N -~ ~ ~ ~ N Ov o
,~ ~ ,~ ~ ~ 00 ~ cW
cn ~
N
M_ v0 00 O _
N ~~ N r ~ O ~n v0 v0 ~D
~ ~t N r ~NN~N~ D
W ~~NNNN~NONN h ~O
~' ~" ~~N~NN
~
v~
Ov N N
O o0
~n
r ~1 r v1 N ~D O
N r v0
O O O O O O O O O
O vr1
"~, ,-~ x r~ ~l ~ " . N -n
x C/~ x ra ~l ~ ~ ~n ~ cn M M ~ N N ~ N ~ ~ oo
V1 N N N - ~ ri c~ W O
M ri N N N '-' ~-~
~: '-' ~~ ~' '-'
,.~
r; ~ ,:"; ~ M O ~ o, r ~ O M O r M ~ ov N
~ O oo Ov r N N ~ oo M r v N ov r .-.
..~ oo Cn Ov oo Ov ~ w0 OW t
OW p M ~ N N M ~ ~D oo v0
p
h ~ ~ O M O ~ O M M '-' N '-' N -~ ~ N M -~ N N
~ ~ ~ N N N N N N N N
O O O O O O M O O
O ~n O O O
M
N
r
M Ov
V7 M M
N
r
Q
x x
M
1l
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~O M M pp ~ ~~ 00
v1 ~t .N ~ M m N N ~
~ ri - ~ ~ I~ ~O v-i M N N ~D ~
,-; N ~ --~ ~ ~
~ ch
M ~? ~ pp ..r ~ ~ ~-~ ~ N ~ '~ O ~ ~ ~ N
O ~ t~ ~ I~ V ~ O QW~
N N O O~ O v1 o I~ O v0 O
~~ O Ov ,r O
~ 00 O
a
p~ _ M N N M N M
_
,~ M ~
. ~-.
~t ri N ~ p~ t~ s0 vpn N N N M M N N ~
,-i N .-i .-i ',..C v~
~ CW 1 v7 O M ~ ~O N M O I~ ~ ~l ~ N l/1 M
~ O a0 (~ M ~ O M .-~ ~
O M N ~~ ~ oo O~ ~O O M t~ ~ O N oo .-. N
~-~ y M .. rte, t~ O
o
N N M p N N N -~ M N
~ p p~ .-, ~
N N ~., M .--~ N N O
N N N N O ~
O
M
V1 ~t .-i ~ O WO ~ d: N N N N M M N N ~
d' M ,-i ..~ x, M
N
cW D v0 ~'? ~' l~ N ~ ~ oo v7 W O M O ~D M
O ~ ~ Ov oo N ,. I~ O
~ ~ O
~
N N N ~ ~ ~ N N
~ O N N ~ N N ~ N ~ ri N N N
N N N ~ ~ ~ ~ ~ O ~ '~
~ ' Ov
WO ~
~ .. op
v7 ~ d' oo v0 v'i d' N N N ,-i ~ ~!? M N N
cn N ...i ~
O
M ~ ~ N ~' O O OWE Ov cn \O ~ ~ ~t o0 M O
O~ ~n M O v0 N rte, N ~ O
r O 00 M ,-n -r ~ ~ O~ 1n (~ l~ N ~ V1 'r
..-n l~ M OWO N ~ o0
V'
1 ~ij pp p~ N N ~ N ~-n
N N N ~ O ~--~ N ~ ~'
N N
ONOM ~~M
~ ri N ~ oo v0 v-i ~ ri N N ~ M cn N N
~i ~ ~ ~j 0 - ~
0o O I~ '~' .-~ QW ~ a0
N Ov OW ~ O oo ~ N o0 I~ oo O Ov
~ a
00 v0 ~. ~ ~'
v0 ~n ~ ,"
~D N M v0 O lwD O O~ N O~ vD o0 00 O
00 v1 N ~ ~, ~ 01 ~
N O N M '-' ~'' ~,~,~/..~ ~ N ~ N M N
N ~ p M N N N N N N ~ .. ~
p ~
a
O
0 0 N
0 0
NM
'
vi ~ ~t y0 v0 d: ti N N ~ ~-~ N ~ M N N ~
c'i N ~ ~l ~ O
~
v~ ,~ .~ W cn OwD ~ N O~ oo v0 ~D N I~
oo O ~ --~ oo ~-.7 M
N W~ OWE 00 M O l~ 00 ~O
OWE ~D N .~ '~
~D M "
r..
N N ~ ~ ~_ 0 N ~ N O N ~ -~ ~ N M N O ~ ~D
N ~ ~ ~ O
N O v1 ~ ~ ~ ~ ~ ''~ ~
~
O ~ ~t ~ O O N
M O N N pyp" v0 ~ ri N vG N
W v'i N N ~ ~ ~l ~ ~ M M N ~
~ M M cn -~ ~
C~ M O ~
M ~ M W O ~D
Ov N ~ I
. ,.~ Ov Ov
N ~ N v0 OWD vD o0 00 O o0 OWD v0 I~ d'
N ~ ,-, N o0 .. M ,~
N ~ N ,~ N ~ -~ O N N N N N 'N
N N M N O '
~ ~
O ~ O
~ ~ ~ p ~
~p ~,; vp ~ O
00 O
O N N ~ ~ ~ ~ M N N N vi M cn N N
-~ ~ ~
00 f~ ~ ,_,
O f~ oo ~n N ~ v_~ V'i ~ O .-r N oo .~
-n .-i l~ t~ ~' N O _~
~ ~ N ~ ~ ~ O N N N
N N N N N O
-..i N
.~ N ~
,~ N
O ~ ~ ~ O ,-i '~-' Op
W V'i ~ ~, 000 Oy v0 ~ M N ~ ~n cn M N ~_'
~t M N N ~ ~ x M N .-i f/~
cn a
O~ t~ N N ~ Ov M ~ <t - N ~D N -~ N ~ O N
c0 O N -n ~ . ~ O_ ~ --i
M ~~~ON~~NNNN-~~NM,O~, ~NN~NMN"
OONNNNO
x 0
0
N ~ v'1 M M N N
i vi ~ N .-i .~ ~ ~
M M Oy v0 ~t M N N N
~ M ~ n ~ . . _~ ~D
o~O~N~n~ .. r. ~~~~~0~o~p N
NN~~~~~O~o~OUN~"'o0
~
N N N M N ~ ~ N N N ~ N M N N N N O N
N ~~ 00 ,~
M O
N v0 cn . . ~ 00 . ~ W O
V~ v) I~ N r"~ Oy~ ~O ~ M N ~~ v~ M M N 00
~ M M N N ~ ~~ r; ,_, N ~ N ,~"~
,...;
~ Qv ~ Ov ~ O <t' N ~ --~ N M O ~ V7 l~ d'
N ~1' ~O Ov O O N ~O Ov I~
t~ --~ ~ v~ ~ t~ ~W O o0 O oo M ~ ~n O ~
-~ t~ N I~ O v0 0~p ~ Ow0 ~ ~
O ..Mr
N N N N N M N ~ ~ N ~ ~ N N O N N N N O N
-, O ~ ~ N ~ M
O O O O O
~p I~ 00
N ~ N ~ N N
N
M 00
l~ M
O
N ~ ~ N N N ~'
C~N N M M M
vp [~ 00
d' ~h
111
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~
0 rj N - '-' ~' ~
v0 M N O
W ~ v'1 a0 v0 tr1 Ov N
o ~~ ~ p~ Oy o0 I~ t~ t~ ~O vD V~
<t ~ M N N N N ~ et M o0 ~
--~ tV ~ ~ O ~ i~ ~ O
v~ 00 O~ O~ N M M I~ -
O t~ v1 ~D .
N ,-~ Ov Gv o0 00 Ov ~ t~ .. . .. ..
O~ O oo ~ O N ~t Ov .~ v~ c%7 ~n Qv O N ~D ,~
oo v1 ~ ~ ~ M ~, a ~ ~p
~
N N N -~ N - ~ N N n o_o v1 C/1 ,.~ ~ ,~ O
O ~ O N ,w_p ~' W_ _O v0 O t~ _o M
'._'
-'
N
~ N
':
a M
v1 ~ ~O OwD M O oo N O ~ v~ d p
v0 ri N oo ~ Oy o0 0o f~ t~ s0 v0 Vi ~ cn N
~
~
yt M N N N N .- ,--~ .- p
, V1 ~D ~ M ~ ~' ~ O M M 0O N ~O 00
--~ r~ p~ N p O O p V1 I~
V'7 M O~ M M M O ~ x x x x ,~
I~ V1 O 00 p ~ ~D v1 0o Ov
~ ~O N N
~
~
Ov ~ O I~ ~O ~ ao ~D ~
M oo v0 N ,~
.-~ M M ~ N N ~ N N I
N N N ~ f
O ~ .-r t
N N M N N N ~ N N N N N
N ~
~ ~ O~
N
n
D
0
o
00 N v0 OwD M O oo s0 v1 ~ c
~ ~ N O ~ 0
M N N N N ~ -, ,-, t~ l~ ~
.-r ,~ cn O O ~ 0
N N O' O O
.-, .~ .~ ~
p O
~
N v~ ~ oo t~ oo Ov M
OW n O
x
O x ~
t v0 t/W ~ ~
~ ~O ~ ~~ O ~D M O "
_
_
n o0 N ~
l
~
~
x
~ ~ - ~
N N t N M
~n f~ ~ ~ ~-~ O O v~ N
O M M N ~ ~D w0 ~''~ N N ~ N N
N ~ N M N N M N N N N N -~ ~ ~ ~ M ~ ~ ~ ~ r-! '.'.'
N N ~
p 00 I~ ~ M ~O
O O x O
" ~ 00 00 f~ y0 v0 vi ~ ri ri O
O N ~D O v0 cn O o0 p
v0 ~ N O O a
' M O p
~'~ O Ov N M ~ I~ Ov I~ v1 l~ a
~
x
x
M M N N N -, ~.r ,~ "
,~ ~ .-~ ,-,
N d ",
x ~~~~-,0~~~~,M
.~ N ~D _~ ~ ~n ~n sC v~ oo ~' N N N N N N O N N N
O~ ~n N t~ ~n _" N ~ "' .-~ ""' _" ~.;
M ~ M ~ ~ N N N N pN ON N ~ ~ ~ N ~ p~ Ov ;~ O~ Ov
N ~
Oy o0 0o t~ tW0 v0 v'i ~ M M O O
O O O O
O
p . .. .. ,~xxx
M
.-: ri t~ o t~ ~ o ri o o ~ ~ ~
0o t~ wi c~i o ~ ~ n x "
~ n v ~ c
v7~MCnNNN~~-~r-!~,.~ _
OW ~ ~ s0 N o0 O ~ ~~~~~-~NNNNN ONNON~rj~~~~'~,
-~ O -~ 00 t~ M ~ W O is
~ ~
O ~
~ ~ ~
~O M ~ D N
~O O~ ~O M O~ O~ O~ O
~O M t ,
~ N .~ .~ N N N N O V 01 N M
N O a N N N
O v0 M
O
' " O M O
' O
~ ~ a x '"~, V~ x
-
~ ~ ~
,. d' 00 .
! W O d~ O Ov N ~ Ov
, I~ l~ ~O ~ 00 O 00 M M V) M N ,-,
N M t~ N t~ ~' O ~_ ~ ~ "'~ " r.;
t_~ V7 M_ O_ .-i ~' M O O_ ,~ .., .~ .~ N ,-, ~ O N
N N ~ " " '-'
00 Ov ~ M Ov M 00 v0 ~ d' N ~
N ~ 00 vD M ~ ~ ~ ~ ~
~ O O O ~
,
~D M W o 00 00 00 O~ l
~O O V~ O~ M M
O N N ~ N N N N ~ N d' O O O O
~ O a M N N ~ pp" pp" ~ ~ ~ gyp" ~j ~
~" ~rj a x x x x ~
~~~~~~~~~~d~~x~
,
N
~ ~ "
~~d~N~N~o~o~~~ ~
r
.-r
M ~ t~ N t~ ~ N OWE ~t O O N N N M N M -~ O N O ~
~ M O ~ ~' ,-, ,~ .~ ~ N ~ ~D
M M N N N .-~ .~ ,~
,~ ,~ ~ N
N M ~D N O v1 t~ 00 'O ~n O O O p O O a O O
.-. N O~ t~ O p p~ M t~
t~ v1 OWO v~ t~ W O a x
v0 0o N N O ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ M a x x x x
x
N O O -~ N N N N N "
~ N N ~ ~ N ~-v
~
Q
N N N N O
p
O
'~
M
M
uj ~n v1
N
~
j oo O
~
cn ~t t~ N oo W N OW v~ ~ O ~ ~n ~p O v
~ v7 ri ,-i ~ ~ 1 p
M N N N ~ ~ ~
~ ~ ~ ~ ~ O
O
~ O O ~ O ~r O O
v1 <t M
~~~~~;~o~~~;~;~~x ~MO~;~~~~~.~~;~~Max~ x "ax
~--~ O N ~D ~ O d' ~ M ~ ~ ~ ~
~ ~ ~ M ~ " O v1 -~ Ov N N N ~ Ov O ~ N N '.'
N M N ~ N N ~ --~ N ~ O M w
N N r; .~
0o N _
.-r V~ ~ ~ ~ N N N ~ N N ~ O N N N ~
M ~ 1n M
O
O M
~ ~ ~ ~ ~ ~ O O O
M ~ O M oo v1 N OW x
~ ~n M ~ O O O
~ ~ ~a O
M N N N ~ ~ .-~ ~ .~ ,~ ,-~ ,~ ~ ~
1 ~ x x
d
~ ,
v N N ~ ~ ~ ~ I~ t~ Iy0 ~ ~i ~ M .
: ~ ~ ~
~ O N oo N ao cn t~ ~ Ow0 O o0 00
M Ov ~ O o0 O ~ 00 l~ ~
N v0 t~ ~t ~ "
~ "'' '
'
'
~
~ ~
~ ~
'
n ~ Ov 'ch l~ 00 00 M O~ ~ M N
. O
. p~
0o t Ov
o_o O_v OW _
I_
d
~
~ ~
~ ~
N N ~ ~ -~ N -~ N N N v1 ~ M ~ ~
~O O
~~
g
a axax
v1 ~n O V7 00 ~D N xaa
O~ l~ ~D M -r Ov N O "
M N N N ~ ,~ ,--~ ~ ,~ ,~ r, pv Oy o0 l~ (~ I~ WO v'i
~ N ~ V M ~ M N .-i .-i ~' .
N O ~ cn O ~ OW ~ cn .~ v'1 ~ N M W O t~ I~ O Ov ~ ~
.~ M M W jj
.--W~ ~O ~O ~D 00 ,-i 00 QW O (~ ~D 00 l~ ~ 00 O~ O~ ~
I~ 01 00 M M ~ O M ~ ~ I~ O~ 00 O O ~
N ~ .-r -~ O ~ N N N ~ N ~ ~ ~ ~ N N N N N N N ~ ~
N ~ O N ~ ~ ~ ~ Q rM.,
O O O O O O O O O O
O
O
O
M
r~
U
a~
112
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
~' .-r " C
'~
~O M [~
M cO
I~ V1 ,_,
N .-i ~D ~ ~n v7 ~ ~ ~ d: M N N N .-! -i
O 0 cn cn tri N . d
x - a
N vi
O
v0 ~ ~ N ~ .-,
x N ~t ~ ~ N ~n N ~ M v0
t~ 00 cn oo . ~
~ " in N CWO .-, O ~ N
~ V1 ~ 00 Ov -~ f~ Ov oo I~
00 ~ N r.~ O
N .. N N N ~ M N N M ~ N ~ N N N N N
.~ ~' N N N p ~
~M ~~
O
N t~ ~D Vi vi 0 wi
N ~ O M M ri N M N N N ~ ~ ~ a
O O t d' ~ ,N
ooxxx ~ ~
~
~;~~;~~;o~.M~~:o
--~ l~ O ~ O~ oo ~O o0 N M O v~ Ov M f~
O ,~ ~ 00 0o v0 l~ v'7 N .. O
"O M NN-~.-r.-,N ~N NNMNNN~NN,..;
M.-n
~' G
.p~ ~ O ~ ~ ~ ~ O vN'1
M
~
' N
., l~ s0 yi ~n ~t ~ ~ M N N N .-i ri in
N ~ CO/7~ cn ri cn N .-i ''~ ~ ~
O ~
x
~ [v 00 I~ ~~ 00 l~ ~O l0 M 00 \O M M O M
~ 01 O~ M O O M M x O
'~
I~ f~ ~O Iw0 M ~ -~ C~ o0 00 W ~--mD O ~D
r; Ov Ov O O M M
oo ~ N N N N ~ N N N ~ N N ~ N N N
~ N M ~ ~i
~
O N N ~ O
~
~ ~
~
p <V
~p a
~j ,-i t~ ~D ~n ~ ~ ~ ~ '~ M N N N .-i ,-i
xi x cn t'~i M M ~~ M x
~
""' ~ M v0 I~ ~ ~ ~t O
--ioho ~ t~ N M v0 ~~ O N N ~O Ov N ~D
~ -.i ,~ p~ t~ ,~ O M O
v7 O O~ o0 O N N Ov N o0 v0 Wn N
N ~'
00~ N ~ M .-~ .-~ N N N N N ~ ~ N O N N
" - ~ N ~ N N ~ "
~~~ ~~~
x
ri .-i v'i cn N N N N ~
x x IWO N ~ ~ ~ ~t M ~ ~.rj x ~
~ M cn ci N
N t~ M t1 M ~D M o0 N Ov ~ N o0 ~ V1 ~ M
M I~N " ~O ~O ~ N ~n 00 W D
a O N ~n Ov o0 t~ D OW O W D O N N
~ ~ -W ~ oo Ov M M ~W ~ ,-i "'
O N ~ N N N O -~ ~ N N ~ N N N O N N ~p
~j '..; N N O ~
~ ~ ~ ~
~ ~ ~
,~,~ ~ O x ~ 0
N M 0
O
M D ~i v'i ~ ~ i cn N N N N ~ ~ v0
-i x cn cn c'i M N ~t x p
x p f
, ~ v
y ~
~
.-, p~ y0 N ~n O ~ W O ~O m s0 W
N ~ Own ~ oo ~n O ., a
V7 M V I
~ ~ N N Ov N ~O ~t o0 N Ov ~ l~ ~n v1 ~O
,~ M M ~D o0 M N 00 O~ O .~
N N N N ~ N ~ N -~ N N N N N ~ O N ~ ~
~ N ~ N N oo " ~'
M M .. ~~ ~~aNN
x ~~~ON
p
x
M ~ ~j ao v0 wi ~n ~ ~ wi ~ M N N N -~ ~O
~ ~ ri M M M N -~ ~ x a
V1N o0 ~t M v1 00 O ~ M N v) O ~O V7 t~
~ ~ V7 U Os O O ~O l~ l~
~ 0 ~D I~ 00 v0 Ov vW O v0 Ov V1 t~
~t t~ d' 00 N M O~ ~D O M f~ N ,.;
~ .-m
N~~~y~~ N~N--~O~NNNNNN N-,NNNNNN~~
O ~ ~ ~ ~ ~
~ ~
x C/~ p O
a N O o0 VO V wi ~t ~ vi ~t c'n N N N 0
c'i ,-i M M Ci m N ~ ~ ~ xi y
ri 'T'"
''~'
.~ ~ tij N ~t 01 --~ ~O O l~ Ov l~ M I~
N v1 00 O I~ d' l~ M ~h l~ ~O Ov ~ O
N ~j M ~O Iw0 v0 00 ~ ~
~! ., ~ o
W ~ I~ ~ M Ov M 0 00 N ~'
D -~ ~-n t~ O
''"!''~ ~ x _ _
O oNO _ ~ 00
~ ~
x M " " O O
N M N ~ OWD ~n ~n ~n ~ ~ ~D ~ M N N N ~ ~ ~O
" a <t M M cn N -~ "~ a
~-a N NOWn~:.~t~~N-~OwtOOvMNt~M ~tOf~~n'Noo~~MN,.; m
0000 O O ~_O f~ N oo t~ o_0 .-, ~ N ~_O N
v0 ,~ t_~ 00 f_w0 vD t_~ M M ~ ,~
.. ~n
~ ~ ~ ~ ~ O O
O O ct
~ O
N ~ ~D W p
x '~ vi ~t ~ ~ cn ri t cn N N N ~ ,~
ri N ,-i a "
OWD
N ~ v ~ O
v1~t p Ov ~ ~ 00 M N ~n
~ OW N ~n o0 00 ~ Ov O M N '".
D '-' O ~ t~ l~ 00 rr
0o v1d' M O~ V O ~~ ~O M l~ 00 ~ 00 O~ ~D ~ l~
N N v7 00 M ~O ~O 01 O I~ O~ .~
M
O N O W ~ N M N -~ O N N N N N N N M N N
O p N N N O ~ W p
ON ~~~'"O~'y-1
~a~~xa
..-i N ~n N OW D vyn v~ V' ~t o0 ~ cn N N N -,
~ .-i d: M M M N ,-i .-i N .-i ,-i
,_;
O oo ~ ~n N t~ -mn ~O O 0o f~ N o0 ~ M ~ N
~D~~ ~ cn ~t o0 two N ~ ~ N ~O n
vD Ov ~ t~ OWE f~ ~ ,~ O v~ 00 00 v0 ~n
N N ,~ O Ov N ~W I~ M OW
O N ~ N ~ -- ~ ~ ~ M N N N N N N ~ ~ N ~ N
~ ~ N ~ N N ~ ~ ~
O O O O O O
N ~ ~D
N
0~0ONOOMO ~ N ~ 0~0
O ~ ~Ov7 ~O M ~nV~
0~000~ I~ d' 00 ~O~D
E N O y OM O
a a o ~ x
N M
113
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M
" ..,
o "'
0 00 ~- nj ,-~ t~ ~ ~ ~-~ v;
M M N N N N N ~ -~ M y0 ~i ~ ~ ~ M ri N N N O N ~ ~ p a ~ ~ ~' ~'
t~ ~ mn s0 I~ O~ ~ oo ~ op ,-, N Omn N oo O ~ ~ ~D ~ a ~~ ~ " v0 .-~ M
.~ O ~ t~ Wn M N v0 Ov ,~ oo t~ oo ~ oo O O w0 l~ O O x x .~ N ~ 0~0 v0
N M N N N N N N N N ~ ~-~ ~ N ~ ~ N N ~ ~!? C/~ ~ " ,~~ ~ ~ a x
~~x
ri cn N N N N N ~ ~-~ ~ y0 VW t ~ ~ cn ri N N ~--~ O ~D o0 0 p r7 ~ p N '~ ri
M N t~ 00 00 O M M O~ I~ ~ ,~ O~ O Ov .-, W Ov ~ M oo d~ a N O x x " O O I~ ~D
op
O N N ~ ~ O N N O N N ~ N N N N ~ ~ N N ~ M M ~ a ~ " ~ V7 ~ N ~
00 ~ ~ Ov N oho N ~ ~ V7
~ cn cn N N N N N ~ ~ ~j ~ ~D v1 ~ ~ ~t M M N N ~' x ~ N O O "~ v~ ~ N ~
O Omn M ~~ ~O M M M 00 "'~ ~ l~ M M ~ ~n ~n ~ N O~ ~D O O '~' x ,.; O O N N N
~ 00 O ~ l~ O~ 00 l~ 00 t!7 0 ~ lp ~O M O ~ V1 ,~ ,~-~ M M M a Cn . a a 00 ~O
~ M
N O N N ~ N ~ ~~ N N ~ N N N N N N N M O N ~,~ _., ,.~ ~~ ~ ~ ~ N ~ ~ N
N o0 ~ v'7 ~a o~0 '-' O Ov ~ ~ ~ x x
~ cn cn N N N N N ~ ~ yD ~n ~ yt V cn cn N N ~-~ x o0o c~ M O a pOp p ~.j ~-;
r. 'O
N N o0 n ~n O O ~ t~ I~ ~'~ ,~ oo ,~ v1 N N ri ~ ~-~ ~n O O O ~l ~ ~~ O ,..a
oo ~
~-r ~O ~ l~ ~ l~ OWE M ~' ~ l~ N o0 M ~O ~ OWE ~ ~O ~ a x ~ ,~ 'Z' ~ ~ ~O ~O
N M ~~ N ~ M N N ~-~ N p~ ~--~ N N N N M N N N N N _
N~ omON~~~r~'Y~roNO~
~t c~i M M N N N N ~! r-! ~ ~O W ~ ~ ~ ~ cn N N ~ a p ~ O x ~ ~ O N ~~
v0 ~n .~ ,~ ,~ ~ N vo M .~ ,--~ t~ p f~ p ~n Ov M .~ oo M ~ f/~ x x ,..a "Wo m
~O M N O l~ O ~O 00 O~ M ~ ~ I~ O~ M d' l~ O~ d' N ~ ~~ ,_; ~ " " ,~ O~ M ,~
N N N N ~ N ~~ N "'' ~ ~-V N N N N N N N N M N w ~' ,-, . . N N
000
~ M cri M N N N N ~~ ~ ~ ~ t~ V7 <t <t V d' cn cn N ~ O O a x ~ O a r; N --~ --
n x
~W _O ~ ~D s0 ~D ~W _O ~ N .WO t~ oo ~ t~ ~ M m ~n N ~ x Cn " ~ ~ a ~n N Ov ~
NNN~~O~M~N ~~~NNNN~ONONpN~~.'?N~~~~~ ~ON~O~
000
y m cn cn N N N N N ~ N ~ l~ ~n ~t ~ ~ ~ cn cn N N ~ ~ a x x x a V~ ~ N .~ .~
,'T'.,
00 N M ~-~ ~ M ~t o0 O o0 ~ N o0 M N I~ WO t~ tW O ~ ~ ,~ ~ " ~ ~ t~ ~n o0
O N ~~ 00 .~ M O M Ov N l~ oo Ov ao ~ oo ~ N t~ ~~ ,~ M ~j . . ~ ~ . . ~ . . -
~ O ~ M . .
M N M .-r N O N N ~ N ~ ~ N N ~ N N N N N N N ~ "~; ~ ~ N O ~ ~ ~ N ~-n N O
'-: ~ Ov ~ ~ ~ p O ~ O N
vi cn M cri N N N N N ~-~ ~ N ~ l~ ~n ~ ~ ~ ~ M M N N s0 ra a x x ~ a x C~ N ~-
-~ ~ x
N N O OWM l~ N ~O ,--~ O ,~ O~ OWE \O V7 vD ~O M I~ ~ 00 ~.fj ,-; ,~ .-i ~ ,~
,_; ,--i ~ I~ .-i
t~ a0 Ov O O oo OwD ~O O ~ N oo ~n N Ov Ov Ov M ~ O ~ .. N .. ~ ~ " ~ N ~p
N N ~~ ~~ N N N ~ N O a ~ N ~ N N N ~ N O N N l~ N ~ O ~ ~ N N N
U ~~''4p~000~0 ~~~0
-i N ~ ~' t~ ~i V. ~t ~t ~ cn tai N N ~ x a x x '_n a x ~ c~; ,-; ~-; x
vi ri cn cn N N N N N ~ ~ _ _
v0 ~ ~ ~ ~ O ado ~ M M O ~ v7 Own O ~ O ~ Ov N N O M ~ 00 ~ ~ O t~ WO oho
.-r .~ N N N N ~ N N N ~ N N M N M M N N N p M ~ M .-~ Ov O N vp N ~~ N
x ~ ~ ~ a N p O O O ~ O O O
oa,~xxx°xx "a
M M N N N N N ~~ ~ ~ ~ I~ ~O ~ ~ ~ ~ M M N N ~~ " ~ ~ " ~ ~ M ~--~
v7 M l~ ~ ~ O ~O Ov ~ O I~ ~ 00 W O ~O ~D O t~ O Ov Ov ~ ~~ c''~ N ~ ~' .. ~jj
,mjj ..
0_v O_v O_W ~ f_~ O oo ~O o0 Ov N N ~ M ~ M 00 '.., O_v O ~ v1 v1 N ~ ~ O~ ~n
°~ N M in M f~ o0
~~~~~~~~~~~~~~~~~~~~~~~x°aaaxxaax~~~dx
V1 ~ M M N N N N N ~ ~~ -~ ~ I~ v0 v'i ~ ~ ~t M M N N ,.~ M N ~ ~-'~ '-' ~-~ '-
' ~ ~ ~ ~ N
N I~ 00 00 W O_ O\ V'1 N O I~ ~ V1 00 ~_ p~ .~ M O -_-~ ~ ,_; .--s ~D 00 ~ N
~..~
N ~ ~ ~ ~ N N N N ~ N N ~ ~ N M O N N O O N ~ ~ ~ ~ 0 ~ ~ ~ ~ N M
N N N N
O O O O O O O O O O
O
M M
00
M M
O
O o0
N O
114
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N cn
O O
i ,-i ~ "
~ N N N ~ ~ ~ .N-~ ,-N~
N ~ ,-'-'~ ~ oo fs '~"
i
i
n
~ v
~
~
t~ ~D v~ y _~
r O ~' N I~ ~ ~ I~ ~D
c M ~t
~t ~
00
~
N N
o
M
M
'
~ M O O ~
O
v~ ~ ~ N ~ N N N ~ N N
0 ~ ~ M ~ I
ct
N
O
O M O (~ o0 I~ oo Ov ~ Ov
,~ N O x x O
_
N N ~ ~ N N N N N N pp x
M
~ "
O
~
ty0 v~ y ~t ~t V ~ cn N O~ ~ ~-~ Os t~ ~n ci
N ~ ~ M ~ ~ cV ~ O '"
~ v~ ~ Ov ~
N N N .~ ,~ ,~ ,-,
.
v0 N V' M ~O o0 N O ~ ~ M v1 M ~n v~ ~D O~
O N O O ~ O v1 M ~ ~1 ..
~ ~O N o0 ~
v ~ "'
v0
N x x O
M M N OW _O O N Ov M .~
0 o_o o_o
N _
N N N N ~ "x
M N N N N N N
~;
~~~~~
~~~~~
o,!
~
~
I~ ~D Vi ~!') ~ ~ ~t ~ M O ~ ~~ Ov o0 V7 M N
N N ~ O ~ ~ N
N ~ p ~
O N
Ov M OWE Ov ~ 01 ~' f~ 00 M N N --~ ,-n ,-r .-r
,-i N O .-, ,--. .-,
x '~' N O N
~ v
00 ~n O ~t N Q~ M M ,wp "' ~
,w0
, M ~
, M ~ W O ~
O O M N N N N N N ~ ~ ~ n M
.-i a N
" .-i .-, wD M v0 I~ N O
~~ I~ v~ N '-' W
~ N N ~ O ~ ~ N N ~ N
~ O
~ ~~
~~ x
~~~ ~~~~~~~~
d~ ~~
d
x~~~~
' a
D v
0 N
0 O vp o
~n ~ ~ ~ d~ ~t M N N i,,.j . " ~ O
~ D
I~ ~ 0
O n N
O
x ~ O ,~ O o
~n ~ M ,--~ v~ OW ~ oo v0 ~D c
,-i r, ~
; r-7 ~
v o M N N N ,~ .~ ~ ,~
o ~D O t~ M ~W ,~ ~ ~
O ~ t N O
~ ~ x
v
O O
_ _
,- O
_
_
_
_
N M'\N~ O
N N N N
cn N N vi ~ O ~ Ov oo v0
00 ~D ~
v1
'1
t
0 ,-i
!
~
~ ~
~
~n ~ N ~n Os M ~ M M O O ~ ~O oo O
~ ,~ x ~ ,~ cW D N O o0 v0 cn N
v0 !~ ~ Iw0 Ow1 M oo O~ ~ O p~ oo Ov
O v0 ~ .~ N
- N N ~ N N N O N ~ N t~ M N N N .~ .-~ --!
C~j - ~.; N .
O N ~n N M O chi ~ I~ V r
N ~ N N N N N N M
l~ O O et O\ 00 ~O
00 v0 V'1 V7 V1 ~ ~ d: M .. ..
M N ~ O O x Q 'b ~
O~ t~ N
M V1 I~ O ~ ~ O M I~ tn
N v0 a ~ " a ~
~p M N O W O l~ O ~D V N i.rj ~p~ N O o0 ~D
v~ N r.; ~~ ~ ,_, M N ~ O
N N M O N N N N N N ~ ~ M N N N .-r .~ .~ ,~
~ ,~ ,~ N
V ~ ~
~ N ~
O O
~ ~
0o vD wi W vi ~ ~ ~ M M 00 0
N ~ a ~ x a x 0
N V7 O~ M --~ V7 O~ M 00 O
00 O V7 ~ " ~~ N M ~ N N ~ N M
N
~D oo Ov ~ ~ 00 t~ oo ~ M Ow0
-w0 N N '-' '~ ,~ .-a
.-i N M M N ~ ~ N N N ~ ~ ~ N O o_0 v_0 M_
~ t~ ~ O ~ ~i O N N
~
~
~ N ~n o0 ~D O ~ O t~
O p O Ov
~
O N O~ O~ ~D 'ch O~ M
0o v0 vi ~n vi ~ ~ ~ ri M (~ ~D ~ 00 l~
ri N -yl ~ '~' ~l ~l N N N N N N N
~ ~ e--~
M ~ ~~ O ~O I~ 00 \O O ~ M ~O O~
O .-i .~ ~ " ~ ~ ~ N O
\O Ov O v0 ~ -~ Ov M v0
~ N t~ N .. . ,-, .-r
~ ~ O N M N N N N N ~ ~
~ ~ oo
p O O ~ ~ ~ N N ~ o0 vp ~
00 ~O V~ ~ ~ ~h ~ ~ M M M 00 N M V'7 ~ N I~
N ~~ a ~ x '~ "~ ~ 00
M t~ N I~ M v1 M v0 W O N ~ ~ O ~ N N N N N
~ V7 N ~ ~' .~ ,-i ~ ~W O
v1 t~ 00 M ~ Ov ~ Ov N ~ ~ ~ ~ N N
00 ~ ~ N ~ ~
N .-~ N N N N N O --~ ~
N
a O ~ t~ ~ N N ~ ~ ~ ~.-i
~
~ V
t M M N N ~ ~ '~ . ' N N N
00 I~ vi vi " Ov o0 Is 'n
1 ~ ~ 0 cW
Yi
v M .~ ..
c O v0 t
N ,~ ,-, ~ ,~ I~ OWE 0
O I~ ~ oo N ~O ~D l~ T N O O ~ 00 ~ M o0 00
-~ Ov - . Ov N ~ ~ W p
v0 O l~ I~ t~ M I~ 00 0o N M N N -~ N N N N
v7 Ov Ov O M ~-, .r ~O N v0 ~ O~ p
O N ~ ~ N N ~ N N N -~ ~
N ~ W O O
vD O
x x a
~ ~
'' t~ Ov V' ~ OWE v1 N
N -~ .. c~
Oy v0 vi vi ~ ~ ~ ri m N d: N N N ~ ,~ ,~ ,~
N N .-i .-i ~; .-i ,-.r .-r p~ oo t~
t~ N N o0 ~D v0 v0 O o0 ~ ~ ~ ~ N t~ N t~ O
l~ oO N ~ op .-; ~O oo t~ M
Ov O~ M O N V ~ 00 OW ~ ~V ""~ ~ ~ ~' Ov M
00 I~ ~ 00 l~ ~ N N o0 Ow0 v1 O
~ N M N N N ~~ ~ N ~ ~ N N M N N M N N N ~ ~
~ ,~ ~ ~ N N N
O O O O O O
N ~ NN N
~ M ~O~ l~
M
O
OO O
00~ OvOvI
~O00 000000M
z aa ~,~ c~x
m5
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
.o . ~''
o .-, '°
r ~ o~ ~ "
',',' ,~ ,~ ri o 00 ~ v ri N ~-~ o .:.~ o ,~ ~: ~ o0
M M N N N ~ ~-i .-i ""~ ~ O ~ M N N N ~ ,~ ~~ ,~ ,~ .~ ,~ ~p ~ ~ ,...., ,
~n N O ~n v_i ~ M ~ ~ ~ O ~ , h M W vo .~ N W cn ~ ri h r
N N N N N N N r., ~ ~; ~-Ol ~ ~ ~ N O~ O ~ h ~t M Ov N ~ ~ x ~D
h N N N N N N ~ N N N N ~ O O N
O N O ~ M ~ ~ ~ O ,-i .-, 00
x h WO O ~j t~ ri .~ 00 ~O vi ri N ~ O ~ a 'n oo .-
M M N N N N ~~ ~ ~ O ~ ~ M N N N ~~ ~~ ,~ ~-, ,-n ,~ ~'~ N C,1 v~ M r, ,...,
Owl O h o0 O~ M ~ ~ O x O 'b W o0 M ~t Ov ~ OW ~ O h oo N ~ .~ N
vD ~ h ~ 00 00 M M N ,~ " ~l ~ M Ov M O ~ h N o0 O ~ ~O yp x a v1
N N ~-~ N N ~~ N N v~ ~-~ " _ N .~ O ~ N -~ N N N N N vp N
pv O r., ,~
O\ v1 ~ ~ ~ M
cn N N N N ~ ~ ~ O O o0o Iyp" h ~ ,~ oo ~ ~i M N ~ O N °.
N ~ h o0 ~O O oo M ~ a x a a ~!? N N N ~ ~~ '~ ~' ~' ~' O O O ".
~D N ~n N v0 ~ M ~-~ ~ .-i ~n -~ ~n ~ v1 cn oo O cri O o0 ~ ~ ,'r, ~1
N N N N M N M h N r"~ ~ p~ h ~. op ~ ~ O O h h h h " . 0v
cn O ~ ~ N '-' O N M M .--~ N ~ ~ a ,~ ,-,
M N N N N ~ ~ ~O ~ O ~ h Wp ~ ~ M
x h
_ _ O O O ,-i oo t~ ,r7 M N ~ O N oo O O N ,.hi
.~ 00 vD d' O O~ h 'N.r ~ ~~.~ ~ a a M N N N ~ ~~~ .~ .~ .--n ,~ ~ ~ N C/~ ~
M N N N N -~ ~ M h ~j ~i ~ ~j ~p O h v~ O o0 h ~D ~ N N ~ ~; M
r.~ ~ ~ ~ ~ N ~ N ~ ~ O N N N N N ~ ~ O ~
M N N N N ~~ ~ ~ O x O O ~ ~ ~ N ~ O O
M o0 W O ~ O o0 ~ N a " rW-.~ _" " v0 C~ ~l ~'
\O vp v0 N N N ~-h~ N N N ~ "~ ~ ~ N N N ~ ~ ~ ~ ~ .-~.i ~ N ,-i -i ~!
v7 ~p h ~t N O_~ ~_ h C_1 v0 M M ~ O o0 ~ ~ ~ ~ M
M N N N N ~ .-~ ,~ O O O op O h pv
" x x ~ a ~ h vp O ~ 00
vD N Ov oho ~ oho M O oho ~" ,-i ,-i " " ~ C/yl
N N N O N N M O N ~ " O o0 vi r' O~ h v7 ~ N ~ O N ~; ~~ M
~ M d: N N N .~ ~ .~ .-m-a .--n ~ r..i c;1
~ M N V1 ~-~ O~ N Ov ~ O~ ~Y ~ h h
00 N~~~'~'~oo~00Mh ~h M .
' O N O ~ N N N N ~~ N M N ~n O O N
~_oM_OON_O~NvO~~~N
~-~ Oi v0 N Ov ~ ~ ~ ~ ~ ~ ~ h
N N N Oy h
O O O p~ ,~ N ,~ ,-, ~D v0 WO v0 h Ov h h ~ v1
~ M N N N N ~~ ~ ~ ~ x' ''~ '~' ~ ~ N N ~ ~ N N N O N ~ ~ a ''~ ~ ~_
O ~D ~~ ~ ~ ~ ~O M 00 ,~ .-i ,-i N N
00 ~O N O~ h ~D N O~ ~O N .. .. .. N p~ ~n O
N ~-~ ~ N N N N O N O u1
~n ~ N N
-i .-.i ,~ x ~ ~ N ~ O~ M ~O ~ h ~--~ ~D 00 h gyp' ,~ ra C ~ O
V'1 M M N N N .. ,~ h v0 00 O~ ~ O ~ ~ Ov V~ M ..
V'7 N h M O ~ 01 O l_~ M ,~; ~ ,~; N ~ N O ~ M N N N N N N ~ N ~' ,~ ~ M
N N N ~ N N ~ pN N ~ ~ O~ N ~ ~ N ~ ~,~
O O O O M O v0 N OW ~ ~O V cn ~ O O ~ O O h0
V'1 M M N N N .~ ,~ ,~ ~ x ~ x ~ M N N m-r ~ '.r 'r ,~ ~ ~ a ,~
h 00 ~ M vD ~ Ov ~ N d' M O ~ " " ~O O
~n ~--~ cn v0 N OWO cn O M '~ ~ O ~O v0 ~D M v0 Ov oo ~ h o0 0o O N '~ '-' h h
M h N ~ Ov M o0 ~ O ~-~ N O o0 N ~ ~ ~ N ~~ ~ N M N N ~ W p o0
a~x~ M~~MO~.~~~N~o
00 M M N N N ~~ ~ ~ ~." r; r; r.; V~ M N N N ~
Ov N ~O O~ m h --~ O ~ ~; op Vj ~ cn N ~-~ v0 0o O o0 0o O ~O O M M p h N
~O h ~ 00 V7 h 00 O~ ~D M N M 00 ~O ""~ N '~ ~--n d' 00 00 M h ~ ~ 00 N ,~ ~ h
00
-~ N N N ~ N O h h .~ ~p N N N N N N N -~ N ~ ~ M
p O O O O O p
N N ~ O N
vp h ~ 00
M M
~r ar ~r ~ ~r
Ov O
116
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
..-: v, chi .. ~;
0 o v; N " ~ o r' ,;; r
I~ ty0 vi ~ ~ dwn cn N N x O ~ ~ ~ ~ ~t ~ M M cn N N ~~ .~ ~ oho M ~~ ,~ ,~ ~
00
~ N M
t~ oo M ~ 00 Ow0 Ov O t~ ~t ~j O O oo Ov oo M ~~ ~~ Ov OW ~ O N O ~ O v0 v0 ~D
o0
N ~ O pN ~~ N N O N N N O x a ~ ~ N N N ~ O ~ N ~ ~ O x x x
O v0 ~D N ~ ~ ~ x O oo O ..
I~ ly0 ~ ~ ~ ~ M M N N "~' ~1 ~ V7 ~ ~ ~ M M M N N ~ ~ pp ~ ~ ~ ~ ~ ~ OO
v1 ~ ~n ~~ l~ 00 v0 OWO M Ov N O ~ 00 I_~ I~ ~n ~ ~ ~ ~ ~ ~ ~ a ~ O ..
~O O~ d' ~ V1 O o0 Ov ~ V7 .~r N t_~ ~ I~
N N N N M N N M N N ~ x "~ ~ N N N ~ N ~ M ~~ N ~ N ~ "~'" N N ~ ~ N
t~ Iy0 ~ ~ d: d' M M N N x ~ ~ V7 ~ t? ~ M M M N N ~-! ~ ~ ~ M ~ ,-i -i O" 00
0o N ~ ~t N M ~D O O ~ d' N x x V N ~ M O o0 OWO O v1 O~ ,~ O O ~ ~~ ~-~ ~ ~.1
00 ~O 00 O~ ~D O~ ~D vW O ~O O I~ ~ ~O ~ 00 ~ ~~ 00 N ~~ V'7 M C~J ~ .~ ~ ~ ~p
M
N ~ N ~ N O O ~ ~--~ ~ " ~ N ~ N ~-~ N N ~ N M O O N ~ " .-. N ~D Ov
~~~~~~~~~~~xMM °~~~~~~~~~~~~~~ ~~~~~
l~ Iy0 p y ~ ~ M cn N N 0 O ~ ~!~ ~ ~ ~ M cn ri N N -~ ~-~ O N N
.--i .~ ~ .~ ,~ I~ OWE ~ M O M x ~ ~D ~ M ~ o0 ,~ p v1 (V O V~ r'a O ,~ ~' ~
,~ ,~ O V1
N ~O Ov ,~ oo '~' O N O~ oo v0 O " OW D v0 v0 00 ~D t~ oo I~ ~-r O x " s0 ,-,
,~ ,~ ~.r op
N -~ N M ~ N M N N N N ~ r; '," ~ O ~-n N N N N N ~ ~~ N N N r"~ .~ ~ ~ ~rj
~,j ~jj N
N N O N
l~ ty0 ~n ~n ~ ~ cfi ri ri N ~ O a ~ vi ~ ~ ~ ri cn M N N -~ --~ a p O ~ ~ ~
Oy
OWE O ~i N N N ~ O OWD o0 H ., ~ N l~ V1 O O N N O N ~D x '~ cu ~ ~ t~
~O o0 o_0 v1 M O_v V M ~ N m v1 ~ ~ N oo ~n I~ ~D O ~n Ow0 ~ ~n N . ,-i ,~ '~
,~ ~-, O t~
N N -~ N N N M N N O N N O
O M_ l~ d' N ,~ ,~ M
t~ I~ v0 W vi ~ ~ cn cn cn N ~ ,0~, x ~ v1 v1 ~ ~ M M cn N N ~~ ~ VJ O a ~ ~
Oy
M v0 cri v0 0o N N two M OW 1 - oo v0 ~O O I~ c~i .--i cj ~, Cv ~ ~j ~ _., _
00
N O~ O~ V1 I~ M et M I~ V1 r.,i ~~ ~ ~p ~O O~ OWE M 00 M ~ ~O O ~ ~ .-..n .-r
,~ ,
N N N ~ ~ N N N N ~ O .. ~' N -~ N N N N ~ N M --~ .~ ~ N ' I~ ~'' ~' O N
l~ l~ vD Sri ~n ~ ~ M ri M N -~ O ~ N ~1 vi ~t ~t M M M N N N --~ x O ~l x N N
'~ N Oy
I~ M N oo N_ ~G W O M O s0 Ov x ,.~ ~ 00 ~O t~ I~ ~D Ov d' v~ M v0 d' N a r.;
~; ~n
N N N M ON N N N ON O N ~ ~ _~ N N N N N ~ ~ N ON ~ N °~ N oo N ~
N
M N
N ~ ~ ~ O ~ p p ~ O M
I~ t~ ~D V7 ~ <t ~ M M M N ~~ ',,~' ~ ~ V7 V7 ~ ~ cn M M N N N ~~ "W -.~ ~ "~
M ~ N ,~-, Oy
N ~t O o0 0o Ov M W d' v1 O N ~ ~' t~ Os N O_~ ~t M vD vi Ov o0 .~ N
N v0 t~ ~ M Ov O oo ~ t~ O v1 ~'
~NNNN~NM~O~NO~~
N ~ N N N ~ N ~~ M N M O ~p O
x " .xpx,~N~~~
0o tW O s0 v1 ~ ~t c~i M cn N ~ ~ .. ~ ~i ~n ~ V cn t~i c~i N N N ~ ''4 ~ ~
000 ~ ~ ~ Qs
I~ N ~D ~-~ ~ M_ ~ ~ oo O ~ o_O ~ '~ N ~~ M ~ Ov ~ N_ oo l~ M N v0 N N ~' ~ N
~~ ~~ N c_~
N pN ~ N N N N N ~ N N N ~ ~ ~ N ~ N N ~ M N N ~ N N ~ M can ~ ~ ~ ~ N
~ ~~~~~~~~~~~~~~~~~~xaxxN~~~~
0o ty0 v0 v1 d' ~ M cn cn N ~ ~ ,....; ~ N ~ v7 ~ ~ ~ M M N N N ~: ~ N ,-i ,-i
~ 0~0 ~ WO
W o0 M vW0 N N (~ M o0 00 ~O v0 V'1 cW0 M ~ 00 M M vG ~ N V'7
00 v0 ~ N 00 .~ vO M m N oo N ~ O O ~n --w0 Ov O ~ M oo Iw0 O~ ~ ~ ~ M N ~ N
N ~-r ,~ M N N N N O N N ~~ ~ N ,'~',
O
00 t~ v0 v0 vi ~ ~ ri ri M N N ~ x ~ ~ ~O ~n ~ ~ ~ M M N N N -~ cn N ~ ~ M ~M'
.-~r
N I~ ~D OW1 Ov O Ov M ~ ~p pp ,~ M I~ Ov N N Ov V' ~ ~ OW O ~~ tn N V'1 00 ~'
WO N N
~D 00 I~ O M ~ O 00 .~ M ~ O .-r N ,~ ~ O~ d' 00 ~ U 00 M M 00 ~O ~ ~ N (~ tn
o0 N O~ ~ O~
N N --, N N N N N N O M N ~ ~p O N N N N N ~~ N N N N N N N ~ ~ ~p N N ~ N N
O O O O O O O
N M
M V7
l~ M
N O
.~ M
00
M
N M
~D ~D
117
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ _ o
h Iy0 v0 v7 V'7 ~ ly0 ~!1 ~ ~ M M M M N M
M M ~ ~ ~i ~! p ~ ~ c~i
D 0 N
Ov -~ O~ ~ h ~ O v cn
M 0 v'7
O O~ ~ ~
~ 1 x y .
,~ v~ ~Na~
~ O ~t v
,:.;, O ~D h h
~~oo.-,ownh~~xoo o,ooovo.~v,ooo~nov.~
"~o
'
'
M N O N ~ N N O ~ T,
,~ ,..~ ~ O O -r M N N N N N
~~~x~-:~' N ~ ,
t~ ty0 v0 W ~n ~t oo v0 y ~ ~ ~ cn M ri ~
ri ~.j ~ ~ ~ N ~ p ~ oho cn
N
O Ov oo h 00 h ~ Ov o0 M_ N_ dw0 v0 O~ M
O o0 O O O O O cn ,.a O ~ N
O Ov
M~NN~N~~Nxaa ~~NM~NNNN~NNax
~
O
M ~ ~ ~ ~
00 tyD v0 vi ~n ~t oo v0 ~!'~ ~ ~ d: M M cn
cn .~ ri N -~ N
O ~ N
M N Os N N M h N cn ~ t!~ M h O ~O Ov v0
~O O O h M O ,~ O N
x O h
~ vo
~o
v~ x o ~
w mn ov h v~ ~ oo o
vo ~ M o, h O r
N
~
O M N O ~ ~ N N ~ ri ~--~
_~ ~ N M N -~ N M N N N ~ .~
M ~ M .r
00 ty0 v0 vi ~n ~t oo v0 ~D yi d: V cn M ~h
cn N ~ ~ vhf cn N ~ ~ O ~ cn
p N
~O 00 ~O V M In O~ N 00 M -r .~ h ,~ (y ,_d',
~ x t ~ V~ 00 x p ~
/] p h ~ .-Nr
M
N N N N N N N N N N ~ N N
N ~ x ~ ~ N N
N h
~
0o ty0 v0 vi ~n ~ oo t ~
M N p ~D vi ~ ~ m ri ri N N ri
N x O N
p x
~ O~ h O 00 O 00 M N M h M M 00 d' ~ N N
a a ( ~~ V
/a a ~O
h ~O h d' ~O 00 ~ ~O ~ ~h ~ 00 M 00 O~ 00
M N ~ M ~O O~ N ,~ ~ ~
' ~O
r.; ~ N N N N O N N N N -~ ~
N N ~ N N ~ ~ N N p ,~ ~
N ~ N O~ N
v O ~O
h h
7 'O o0 h y0 v1 ~ V M cn ri ~
0o t~ t~ ~D ~n v) N N x O O M
~ cfi N O O O '~' cn
~
~
' v1 O h d' ~ h v) ~ h O
' a N O_ N v)
cn O ~O Gv N h ~ ~ a v~
v1 M '' ~ N N N N ~
N N ~ ~ N N N ~ N N ~ ~ O
~
'
~ N ~
N
O ~
0o t~ t~ s0 v) v-i oo f~ ~D vi V ~ cn ri ~
V M N a ~ ~ cn N N x x a M cn
m
M 00 O ~O Vi ~ M d' N O~ O O~ v1 O h M
O~ N ~ ~ O M M ~ ~ O ~
v7 ~ Q~ N o0 00 M ~ t~ M ~ Ov oo W Ov o0 O
h O N ~' ,-..i O !~ " ~~ ,-, yp o0
N N N N ~--~ ~ N ~~ N O N N -~ N N ~ N
~ N ~ ~ ~ ~ " w
h a0
~~ ~b
0 0
00 h h ~D V7 ~ ~ 00 two V1 V ~ M M M N ~
M N ~ x ,~ N ,~, ,~ cC ci
M
O ~ 00 0o OWD ~j -i t~
~; ~ -; r' oo
W v ~ O~ ~ N ~i'i v7 M o0 t~
O Ov O~ ao M
O d
_ . NO
_ , N
_ _ N
N N ~ M .-h~ N -h-~ N OM N N O ON N N N ~
O N ~~ ~O O N ~ rj ~ ~
O O p ~ ~ ~ ~ O O O
o x ~ a n
i o n
n x ~ a i
0 n
i i
~
D
i
a o c
W v v ~t
~ r ~ ~ r c
c c
t~ ty r
t
~
N N ~~
.~ V) N V7 ~ N M V1 ~ N M_ ~O M M 00 ~ 01
t~ ~!1 M '~ ~i ~O O~ ~ ,-; --n _ ~O
O ~ N
O ~ C
~ ~~
ON ~h~N N
N M O
N ONNNN
N N
N~
~
NN
N
~; ~~~~~~~~~~~aoo~
p;
~;
p;
~~~~~~~~~o~or;
n x ~ a ~O 00 V'j
0 ~ ~O V1 ~ ~ M M M N N M
0 a a ' M
7
rj
c ( d'
0 ~ O
h [y ~n ~ h oo v0 ~1 mn ~ o0
V Ov OW O ~' '~
~ ~ ( p
oo M O ~D V -~ N
O M ~ '~ M
v) N Ov O ~ M O N ~D h OW O ~t Ov o0 00 o0
N O ~ ~ ~ ~O M Ov ~ ~p V 00
M ~ N ~ -~ N N ~ N O N O
w0 .~
0 M .~
M
~~~~~~~~axac y
~~~~~~~~~~~a~ax
OO h t~ ~O ~ V1 ~ 00 t~ \O v) ~ ~ M M M t~
~ M M .~ ,_; ~ M N ~: .~ ,~ ~-i M
M
h oo v0 Ov ~ O~ ~ h v0 O N d' 00 O v0 N ri
~ ~ ~ij v0 v0 N pp N
NNNN~~OO ~ONN~NNNN~~~~~ v_0
~~ O ~N
N~ N N
~ M v1
N O
~ ~D N
O,O O O O ~1
N ~ N N N
h ~ ~ ~-a~~-ih
Q~O h h h 00
O~ d w~~nv~
O h O O~O,00
h o0 Ovo000h
<t,~ ...i.-,.~h
f~~ ~r
~n
118
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
:-.
Oy N ,-i ,-i .~ ,-h,
O ~ M . v O~ ~ N
N N N N -i ~ y0 ~!'i ~t ~t cn c'i y 0 v1 ~ ~t ~
.-i ~ ',,'[,' N w0 v0 d i., ~t cn c!'i
h M ~ O O v0 ~ O M ~ W .-i ~ .-, N O ~ ~ N t~ ~ M
~ ,_; O O O ~ l~ O ri
.-n .-n N h Ov oo Ov O ~O W N N vO ~ ~' h
O ~ O a
.. N ..
N M N ~ M M ~ ~ N N N N N N N " x "'~ .-. ~' M ~'
op a ~' ~~ N N N
N
~ ~' ~ O
~ O ~ 'i
i ~ 1
n
n
N N N N - .-i W v
~ V
- ,~ (~ ~D v7 ct V cn M N ~t ~ ~ t
v O.. W M c
O -
N
O
i -~ V t~ Ov ~p ~ Ov M M h oo v0 v0 N ~ Ov N
~ v --~ 00 00
O h ,~ N ~ ~Y ~ h N O~
h M .~ ~O h O M -~ N
M O~ ~ ~p --WD ~ M I~ N 00 I~ N N N N ~ N
N O ~ N N O~ a ra (/~ N N
N N N --~ N N ~ ~
r., ,~ v_1
N N _ _" _ N
O ~ WO O o0
O
N N N N - ~--~p" ~ l~ vO ~n ~t ~ ri cn v0 W wi ~ ~
~~ x N -~ O ~ p ~ ~t M M
W o0 ~ O v0 ~' o_o v1 00 O Owt N -y M Ov -~ N r.,
~ 00 ~.'. ri a O a O .-i n O~ O_
~NO xN ~N~NN~O
~N x N
~ N
NN~NN
ON
No ~; N
N N N
N ~ N
0 ,.
N
N
N
N N N N ~ ,-i " ~ y0 v'i v'i ~ c~i ci ~O ~i Vi V ~t
,~ " .--~ N ~ a O O ~ b ~ M M
M O M 7 O ~ O
~ M
~'
s
\O W - y n
V7 ~lWn O h h N h
O O Ov ~~ h V7 O O~ ~
O ~ ~ M h O O M .-r ~j x " x ~ O V1 O
1 -r O~ ~ O ~O h h ~ O r"~ 00
O ~ O ~ l~ Q~ ~
'~ ~ I
_ _ _
_ _ _
x _ _
O h N ~ M ,-.n
o~ O O ~p oo ~
N N N N N ~ ~ ty0 y wi ~t M M N N x ~ ~D ~n ~n ~
~ ~; G p O O O ~ ~t cn cn
~axx ~M~~~o~;~~
v0 h v0 M Ov ~' O ~ 00 h ,-~, ~ ~ N ~
h o0 ~ ~ ~ M v p ~ N O
O O_v N N " .~ " "
N N ~ O ~~ _ N
~' N V M _ v~
x ~ ~ .~ .-~
'~ ~ ~ ~ ~ ~ ~
~
N N N N N ~ O WO v'7 ~n ~ cn cn N N y0 vi vi ~ ~t
~ N x a O ~ O O d cn ri
W n
T' W
~ a
~
s0 0o M ....~ O ~ M ,~ N vD
M Oy'1 h " O N N ~ t~ cn ' ~ c
Ov M W N OWn " ~O v0 O
Ov ,~ ~! ~ ~ oo v~ M O~ M v0 O N h Ov oo v0 00
.. .. ,-, " .. ,-, 00 vD
~ '-' op ~ O ~ N ~ M
' -~ N
~'
N N N N N N ~ N N O N N N N N N
N h pv " ~
:
x h0 ~ ~ ~ N ~ O ~ ~ N
~
N N N N N ~ ~O l~ ~!'1 V1 d:
-~ M a ~ ~ ~O ~O V1 d: M M N N ~ ~ c'~ M
a ~ ~ a ~
h O~ tn M 00 ~ ~O M O M 00
,--~ ~ M .-n ~ M O~ h O O~ M ~O 00 ~ i!1 ~O 00
N O M V'1 " ,-, ~ ~~ 00 ~ a0
OD ~ M ~D h M O 00 M ~
V7 N M h ~ ~ N V'I ~ .. ,~ ~ O
_ _ _
x ~ ~ ~ ~ ~ O M _
O ~ ~
~O "a O
O O
N N N N N ~~ N N ~ IWD v'i ~t M M cn N l~ ~O ~n ~
,-i ,--~ x N ~ ~ a ,~ ,~ ~ ~t cn cn
mV~tW O~O~~ ~~~OvNoOCnIwOW O ,-i~ "." ~~O~nNOOsOcn
O ~O ~O oo h 01 ~~ M N o0 M O~ V'7
M h O~ ~n ~ .. ~ h ~ h ~ h
~ ~ O O
N N ~ N N N ~ N N N N N N N N
~ N pp ~~~~~~~~~~ao~h
~~~~~~~~~ o
N N N N N .~ m ~ tyD v~ ~ ~
.-i .-.i '~ N ~' oo ly0 vi ~ ti M ci ~ ~ M
~ N p ~ x ~ "-a
~
~
M N ~_ N_ ~ ao v_0 --~ M N v7 00 ~ N ~ ci v~ '.,
~ N ~_ v_i OW' 00 v0 ~ N
ON ,-i ,-i ~~~NNONNNN
M N
ONNN~ ~~~N~
N ~~~M
N~o~o~~0
~; ~;
~; p;
~;
~~~~~~~~~ o~~~~~~~~~a
xa
~
.
a
a
N N N N N ~ ,-, ~j O~ I~ ~D v'yt M ~;j Iy0 v'i
,-i --~ ,-; M cn N ~; ,~ ,-i ~ ~ V ~ ~ V cn
~ W
~
~ '~ '-'
W p oo ~ m ~ OO N o0 v0 ~ 00
v0 N t~ " O M O M l 0o v1 O
00 V 00 00 l~ M O O c 1
~ O~ O~ U M N O~ O ~O M h O~ O~ V~ N ~O ~O ~ h
'-" h V1 ~ h O ~O 00 ~ M h
M ~ ~
N N N ~ O O ~ N O O ~ N N - N ~ -~ N ~ ~ ~
~ ~ v~ oo N N
N N N N N ~ .~ ,-~ OW v0 ~ ~ ~ M M ~i t~ ~O
~ ,~ ,-, N ~ .-i .-i ,-; r.;
h 00 M ~D ~ O d' V V~ 1n O ~O ~ ~ V'1 d' N Q~ ~ ~O
O O~ M ~ ~ l!7 ~ y~ V~ V'7 M 00
pv Qv ~ 00 O O h OW t OWO h o0 N v7 N v0 O \O ~
h <l' h M M ~p N M ~ h V7 ~ M
M
N N N N N N N ~ N N N N N -~ N N O N ~ M N M ~
~ N O N N p ~ ~ N N N
O O O p O
NN
OO ~
Oh o0
O
M
M MM ~
h
119
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N (~
~ v1 00
. .--' -i
~ ~ O ~ c~i N N ~
_ M M N N N N ~-! 00 t~
O N ~ ~ .-i a ~
cn N oo ~p ~ oo cri
O ~t f~ O w
~O ~O M O O M O~ 00 ~ ~O O ,-, t~ ~
~ O~ V1 ~O N ~ 00
C~ O n
O O 0 O O
,~ .-~ O~ ~O ~O V
~O I~ I~ ~ ~
x v_D N O Ov ~n M N ~~ N ~ N O ~ --,
O Owp I_~ O ~ ~n ~
~ ~ ~ ~ O ~ ~ ~ O
v7 ~ M M N N N N N ,~
~.j ~ x d' M N pN ~ -~ ~ ,-N~
M N ~ ~ ~ v ~ --~ 00 l~ ~
~
~j
_ , 00 N v0 ~ N Ov Ov '.;
M O ~ p O O ,.'L', ,~ cn ~D ri ~ N Ov ~ ~ ~ M
O O .-r O N M ~~ ~M
f~~..~E-~x ~'"I~,'~ Own~O~_Oo_O~_OMN~:,~O
O OI~OWO~ooNOOVOOV w0
" ,~ ~' _' .-~ M N ~ r. .-~ p N N
N t~ O N C/~
_ ~ ~ ~ O O
N O
a ~ O N Ov dye
cn cn N N N N ri
M N ~ N N ~ Ov ~ I~ 01 I~ ~t N M
r, O ~D ~rj 'O ~ ~ r.,
O . s
O ~
O OW 1 N N -~ ~ V M N N ~ -~ ,~ ~ ~'
v1 l~ Ov O O ~ ~D G ~r O v~
M l~ M x x ''~ ~D t~ oo v0 O I
x ~D d' Ov ~ ~ O
~ ''~ ~ N ~O ~7 O O Ov ~
~ O M ~'~ ~
,. N .--~ ,~ .-.~ ~ .-w Ov M V~ O 00 t~
N c~ ~ .-r ,~ N ,-, N ..r O Ov O~ N N ,~ M
~ ,-, O ,_, ~ N O N N N .-~ .~ ~'
(Y, -~ N O eh
N N ~ N ~'
a a1 ~
~
M G~ 00 ~ ~
M N N ~ ~ O O M M N N N N N ~
~ O ~ th O - n
O ' i
D
~
O N ~ O O rr, vW0 00 N Owt - c
a M o0 ~ ~_t N_ ~ O yp . "~
a ~.~ h ~ O_W _ O~
O M O a a ~ ~ ~ M M ~D N O~ ~ ~
"'~ " O ~ ~ ~ ~ 00 I~
'
N N ~ ~ ~ '-' ~ ~ ~ ~ .:-i op N N ~p
" ~~ N N N N N N N ~' M
~' N ~ M ~O 00 ~ V7 O~ V'7
O
~ ~ ~ N N ~ N N O ~ N N N
M N N ~ ~ x
M oo ,~j ~ ~
~
p O ~ ~ M M N N N N N ~ ~ ~ 00 I~ ~
M N N .-i ,--n O
..
O O ,~, r~ a ~j d' t~ 00 v1 ~ ~ N N ~;
~ ~ ~n Ov O ~
O
N 00 ~ x ~--, l~ I~ V~ ~D ~O WO O ~ O~ I~ ~ M ~ M
~ ,_, ~ r; M N O~ ~O ..r O o0 M ~O O
-' '-' ~'
' ~'
'
-'
"
M M
N N N '-: ,~ N N N ~ -~ N ~
O N ~ O ~
~ ~ '
'
N ~
~?
~-~ N O
~O N N ~ ~ ~ ~ ~ N
~
M O --~ N N N M ~ N ~ ~
~ ~ N N N
~ ~' ~ a ~ ~ ~ ~
V7 O ~O W-- 00 O~ O (~ M 00 V~ O
00 ~O ~!1 ,-; 01 O~ M O M W O O
"' ,~ ~--n ~ 00 O 01 O~ a
M O~ O
~ M "~
I
N N N ~ ~ _ n ~ N ~ ~ ~ ~ ~ ~ ~
0o m O n ~ _ ~ N
O ,n c ~
~ N O t~ oo ~ ~ ri c~
OW ~
l~ I~ O n O V'1 I~ O ~ ~O I~ M 00
00 O~ O~ I
O ~ M N N N N N N '-' N N ~ N O .~
M N N a a (~ -~ ,-i ~ ~ N 01 l~ uj
~ a Vl l~ 00 00 ~ M ~
O W O cn ~-i ~
M M
' N
c l~ ~O O oo vD o
n N ri N '~ ~ N M oo ao O v
~' O '7
N O N ~ ~ p ~ N N M ~ N N N N N N
~ ~ N ~ O~ t~ O M O~ 00 ~D ~
O_ M N O O
~O ~ ~ ~ ~ O ~ M M N ~-! .-v .-r ..r
~ ,--m..n .-r .-~
O ~ ~r~, ~~~ON~~WOOOo
~O l~ d: M N N N N ~ ~ ~
000''x,00 N ~ ~
M M N
~ r~i
i-.a "T'
~
~ ~ ~y M N N N ~ ~ N N O
, ~ ~ ~ O v~ N ~ N
, N O ~ ~; ~ ~ O~ M ~
O OW i ,~ '-' I~ v1 00 O\ U M O~ ~
~; r N ~ ~ ~O ...~
~ M v7 ~ N ..
~
N O O ~ oo ~ ~ N ~ N N N N N N N
~p l~ O N O N
O
~ M M N ~ oo vp ~ ~
~ ~ ~ ~ O
a ~ ~ x "4 ~ ~ '~ U N N v0 M t~ 00 ri 00
, v1 O ~ 00
y0
cn ri N , t t~
-' ~ ~ ri N N N N O f~ N ~ ~ t~ oo O ~O
~ N ,- f~ t~
~
N \O ~ d' N ' ~ ~_n -~ 00 tn M ~ N N N ,~ -i N ,~
~' v1 IW O W -- N N ~ t~ N
N ~ N ~ ~ ~ ~ ~ N ~ N N ~ N ~ ~ N N N
~ ~ ~ ~ ~n
V7 M p
~
O O
O . ~
M x N N v1 O o0 ~O M N v1
O O O rx O x O
,~
a a x v0 ~ M N N .~ ,-,
a ~ .-, ~
M ~ cn N N N N ~ 00 ~D
" N ,-i ,-i ~ ~ ~
~ N M ~ ~ ~ M
N ~
'~ ~' '~
M o0 .~ V N ~; N ri N O O - oo o0
~ ~ cn N vD Ov M ~
.~ v~ v0 vG n ~ ~ ~ I~ ~ ~ O N
~ "" ~ ~ O ~-~ N l~ t ~ 00 M
~ ~~ ~ ~ ~ O N N N ~ N N ~
N t
O O O O O _ _
_
b
O i0o0~OMN0 N
a~xxxx ~
ri ri N ,~ ~j y0 ri M N N N ~~N~ ~
~ .-i ~; ~--i N ~ ~ .-i l~ ~ M N N ~ .~ ~
, ,~ ,-..~ p~ 00 v0
,_, ~ V7 00 ~ l~ M M ~ I~ M M ~ ~O O~ O
~ O 00 O o0 01 ~ V7 O~ M ~ O d' ~~ l~ ~O O
~ 00 ~ ~O M ~O ~O M M ~O ~ ~ O~ ~ ~ ~O Qv O~ 00
V7 00 ~ ~ O O U ~ ~O O~
N N N ~ ~ ~ ~ N N N N N ~ N N N ~ M N -n N N M
~ ~ ~ O N .~ N N N N
O O O O O O O O
O, O
N
O O
M~
I~
M
N
00 ~ O
120
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ os ~ ~
~ ~ .. r. '~ ~
N oo ~j ~ 00 ,~ ~' V1 c~i N .--~ ~ O pv p M N ""'' ,--i Cv
~D v-i ~ ~ cn cn N N ~--~ p p ~n ~ ~ Ov ~~ ,~ .~ ,-, ~~ .-r N Os o0 0o vD wi ,-
a N ~ oho ,~
O oo W I~ ~ ~ M M ~ ''~' O ~ x O O ~ Ov ~ cmn o~0 ~ f~ ~ ~ M N ~°O ~ O
p O N O O
O~ ~ 'D ~_D x O x O ,~ ,~ p .-r M -r ,~ N N N N <t ,~, ,~ x ,~ a x
o N "' oo
s0 v1 ~ d' cn cn N N --~ O O N O ~ ~ v'i ri N ~~ r, O N Oy Ov o0 t~ p ''~ ~ ~
O ~ .-~r N
.. O O
~n l~ l~ ~O M O M M ~ x y0 x O O 0 ~ ~ M v0 00 l~ ~ N N v1 ~ QW!-? p O O p O O
O ~xx~ ,~~,~~.~,~ ~M~,~~. xx
N N ~~ .~ M N N N ~ ~ ~ ~ ~ .~ N O ~ .-r N v-1 ~ E"' r~Ci ~ ~
N r" ~ ~ N ~ M N N N p
0~0 ~ ~O ~ a ~l1 ~ ~O o0 ~!
v0 v'i ~ ~ cn ri N N N O p l~ p ~' ~ ~ ~O ~ N N ~ O N Ov Oy oo Iy0 ~ opo ,~j 0
~i~~o~nosoo..;rioo''ax'~ox~°o ~,~,~,~r..,-~~~:;,~~ooos'°OOOMOO
~n ao M two N ~O -~ o v-; ,~ a ,~ M M Ov N N ,~ ~n ~ ~ 00 0o ri ,~ a x ,..a x
E"'
O N N N ~ N O N M w N ~ " _~ _~ ~D v0 M .~ tw0 ~ N ~' ~-, ,-, ~ ~ <.j N N .~
v1 M ~ ~ N N ~ ~ N N M N N O
a M ~ N t
O O ~ O O M et O O~
tyn ~ ~ M M N N N ,~ O ~ O ~p ~ t~ Oy Os oo r s0 ~ oo ~n N O O
t~ ~ OWn Ov M M ~ N x O x ~ a O ~D ~ N N ~ O ~ V M cW O ao ~.j ~l n-1 V1 tl~
V1 V'1 00 v0 00 M O l~ ~ ~!? n-7 ~ ~ ra .~ ,-i ,--i ,-r .~ ,~ ~ Ov ~ pp ,-,
-, N
N N O N N N N N M N ~ ~ ~ N N N N ~ ~,~ ~j N ~ ,~ .-,
r., ~~ ~ N ~_ O~ ~ p
O d- v0 p v7 N ~ ~ N N N O ~ ~ ~ ~ ~ M ~ O°O ~ M
tyn ~ ~ M M N N N a O ~ M O ~p ~ N ~ Os oo t~ ~O ~ p O O O O O
t~ oo ~Wn ~ oo O ~ dW p" x O ~l VJ ~l C/~ ~ ~ O Ov c~i t~ N °~ ~l x
...7 "x '~' tip
O~ 00 ~ O O v~ v1 N M ''~ ,~ ,~ ~ ~ ~D ~ N N ~ O o0 00 0o v1 ~D "' ~ ~ ,-i
N N ~~ N N N N N N ~j ~' .~ "' "' '-' "" '-' '-' .~ N N N N ~ c~i ~.j N ,~
O ,j ~ ~ can O M ~_ O_ can ~ N ~ ~ ~ ""~ ~ ,n
t~ Vi ~ ~ M M N N N ~ x O x x a ,°~, ~ ~ Oy Oy o0 Iy0 ~ ~ O ~ ~ ~ '~,
M ~ V' ~t O N ~ t~ sD .. ~l ~ M ~n t~ v1 O oo x ~
Ov OWO O O N M t~ V1 .-y.j '-' ~' .-i ~; 00 ~ N_ N ~-n O ~ ~ Wn O ~t ~ N N .-i
,
N N M N N N N M N vp ~ N N N O
,..°a1~~~000~~ OOO~c~nN~~~ 0~~
(~ v1 ~ ~ M M N N N t~ p x x a O M N N N N N N ~ ~ pp" ~ ~p~ ~ O O a ~ O r~0,
M O ~ ~ vp V ~ oN0 ~ O N ~ ~a ~~ ~~ ,-i ,-~, ~ ~ ~ ~ O ~ x N .-i x ri
O N N ~~ N N ~ N N ~ M N ~-~ '-i ~ N N ~-~ N N n
00 c~i ~ M N ~ O O O M ~ M ~' ~O
.. ~~ ~ N
r~ ~ C/~ ~ ~ ~ N N N N ~ Ov o0 t~ ~O ~ ~ V°] "~ ,~ x x
~ 0~0 ~ ~ 0~0 ~ ~ ~ M ~ M N _~ _~ _~ p ~ Ov ~_ Ov M d: n1 N ~' ,-i ~i
.~ N N ~ N N N N N t~ O y~ °~ cn o0 op O pN N O ~ ~ ,~ ~ N p m
''4 O 0 O O O O N ~ ~ ~ ~ ~~ ~ "'~ o p0 O O 0 O
t~ ~ vi d: d: ri N N N ~ '~ ~-1 x x ~ v~ mn O ov t~ O .-~ ov os oo t~ ~ v ~ ~
~ x v~ x
M ~O ~C ~O M ~ M
V7 ~ O 00 d' s0 l~ O M (vj ~~ ,-i ,~ ~; O ,~ p ,-~ N N N N t~ t~ O O_v ~_ ~
~.j N .~ ,-i .-i
ONNNNNNNNN~~~~~~~ ~~~NNNNNN~N
a O ~ ,0~, ~ ,0~., ~-: N ~ ~ ,N-r .-'-'-n ,~ ~ ~ ~ ~ O M ,.°~, M O O
ty0 vi ~ ~ M N N N ~ a ~ ~ N . _.. 0v Gy oo t~ ~O ~n x '~
Ov .OW _O oo W O Ov O_s Oi N M N ~ ~ ~ ~ t~ O oho ~ ao ~ ~ cMn N O ~~ ~O O v0
~ N
NM~~NNN~N'-' ~'~~~0 NO~~~NN~NNNNNp~~o~o~°OOo
'°~''~M,~x~~~d~~~~~~a~~~d~~~~ooo
° °°°°'~ ~ ~
xaxxxx~o~MN~~o ~~xaH~
[v vp ~ ~ ~ M M N N ~~ c~j N ,~ ,~ ,--i ,-i ..r M ,~ ,~ -..m, .-~ .~ ~ O~ 00
l~ ~O ~ ~ N N ~~
~W O ~ ~ N ri ~D M t_mn ~p N .--~ ~ cn ~O N ~ '~ M N_ N ~ o0 ~ N O M m oo N
vW0 N ~n ~_
N N N ~ N O ~ O N N ~ ~ ~ ~ M ~ N N O O N N N N N N ~ ~ °N N N O ~p
O ~O O
O O O O O O O O O O O M O
U
N
v7
U
121
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
" ,~ b " " "
N G ~ N ,_, r-i "~ rr
~" OO o0
o V M M M N N N N ~~ ~' v1 ~ ~ ('n M M M N N N N ~~
W Ov ~ M N N O Ov ~~ ~O ~1 ~D I~ ~7 W O OWn O ~ O~ N o0 O ~ O O °
'O ~O 00 V'1 ~ ~D O 00 ~O ~ ~' O_~ V1 V) t~ ~O 00 00 M M \O O~ O O~ ~ °
°
O G ~ ~ O M N M N N N ~ N O N N ~ ~ N N ~~ N M ~D ~ x ''~ x x
_~'~~~~~~~~~~x ~d~~~d~~~d~~~~~a
N -o r;
~ ~ c~i M M N N N N ~ ~ ~!'i ~ ~ cn tri M cn N N N N N
l~ O o0 M Ov M v0 M 01 Ov ~ ~ ~D ~O W O~ ~n ~ l~ v~ O~ ~ ~f l~
ornoNoo~o.o»oow~ ~~o~no~oooo~~-~a.~,.-~ '~io~ 00 0
~~x~x~?x
,~ _~ ~ N ~ ~ ~ ~ N M N N N ~ ~~ N ~~ N M N N N M N N rj ,~ O " ~
C/y0 N 'n N Ov
cn O
N m ~ ~ M M M N N N N ~ ~ ~n ~t ~ M M M M N N N N N x ri vp ~ ~ ~ O vp
O ~D v0 M W M M M N O ~.-~ ~ v7 N d' ri o0 t~ oo v'i ~D o0 00 "~ ,w0 N O ~ O
"~' I~ ~D oo v1 O~ t~ N N v0 vD oo ,~ oo O O o0 O M f~ ~y W Ov .. p t~ ~l ,~ x
" x
N N N ~ N N N .~ .-, N N .~ N ~ M N ..-y ~p O N ,-, ~
o °o
p ~ M ri ri N N N N N ~ ~n ~ ~ M M M M N N N N N
° x ° Ov ~ O oo n M ~ ~n ~~ oo M d~ -~ O ~~ ~ O~ I~ ~ I~ oo ~
~'' ~-~ ,°,° ,
~ M Qv o0 M l~ ~ N o0 t~ O N v0 OW ~ O l~ l~ ~ N Iw0 00 ~ ~~ M .. Cl~
~ O ~ --, N ~ M N N ~~ M N -~ ~-~ N N ~ ~ N N ~ ~ N ~. ~ O N ~; ~
° O C/yN (~ Ov ~ O
M N
0 p ~ ~ M cn cn N N N N N ~~ v~ ~ ~t c~i M M M N N N N N x ~ x x x
x; ,~ 00 M O l~ 00 t~ ~O ~ l~ N O ~n o0 Ov M O ~ ~n ~n O N v0
~ v0 v~ l~ l~ 00 ~ 00 ,~ N t~ oo ~ t~ N M ~t v0 CW ~ OW ~ O~ N "" N ~'
r.; ri ,--n .-r N N ~ N N N N N ~ N ~-~ N N N N N N ~ O
M M ~ ~ ~ a ~ ~ N I~
p O O ~ M M M M N N N N --~ ~D ~ ~ M M M M N N N N N r.; ~ ~ x O p x O
i-~a ''~ ~ N cfi l~ ~n v~ O~ I~ sO O ~ O ~ O O~ N M M ~ f~ I~ N Ov ~ o0
~ 00 M M In o0 00 I~ N ~ N ~ ~O ~ M I~ O_~ O~ M O~ O_1 -~ M ,~ N ~j ~
I~ O ~ CO/'J t~ N N~' O
M N
f~ O O
a ,~, a ~ M cn M M N N N N ~~ ~O ~ ~ cn ri ri M N N N N N ~' ~ N x ~ U7 x ,.N~
~ O\ ~ ~ Ov O ~ t~ M V7 ~-W O v1 ~~ O N M_ M M t~ ~-~ M ~, O o0 _" .--r
~ N ~ N N N N N ~ N N ~ ~ N O N N N M N N N ~
~~°N°~~~~~~~~~~~
° " ~~°oMxo
,~ d~ ri M cn M N N N N ~ oo ~ ~ M M M M N N N N N
,_; O l~ 00 O l~ M Ov N M Ov ~ ~-~ M ~O N N ~O ~ OW O ~ ~t vO ~t
[~ ~O ~O M O_~ M O ~ ~ ~n ~n M ~ 00 O~ N 00 O~ ~~ O_ ~n N .. .. .. op ..
~N
oN° Ov~~l~lx'~''"~l
x ~ ~t ri M M N N N N -~ ~ W d: M M M M N N N N N
-i -.i .~ v0 ~n o0 v0 ~ C~ O ~D N o0 M o0 V~ .~ I~ O O ~ Ov O M N ~O N ~ cn N
~
w0 vD v0 Ov M oo Ov OWD o0 v0 N N ~O ~O O O~ 00 Ov O oo M ~~ ..
M "' N .~ N O N N N N ~ ~ ~ N N O N N ~ -~ N M N N N ~ M h ap ~O
ONO~~~ ~Oy,°rlr,r°-l~
M M M N N N N --~ Oy1 ~ ~ M M M N N N N N ~ ~ ~ ~
~ O O ~D ~-~ ~ v7 N N N N M 00 M I~ N M Ov ~ ~ O M tn M cV ~'
V'7 ~j O ~ ~O O~ ~ ~~ l~ I~ O ~ ~D O O~ l~ 00 00 M .-..n M OO ~ OWO O O ~ I~
pp ~ V1
~.vO~NNN~NMN~NN ~N~~N~NM.OON~N ~~~~pOO°
V7 r~ C~ ~N a0 ~ ''°'~ ~ x ''~
-i r.; ,~ ~n ~ M ri ri N N N N ~ ,-i U ~n ~ V cn c~i c~i cn N N N N ~ N '-' cn
N ~
N ~O Q\ I~ ~~ ~O <Y O O~ ~ ~: ~ ~O M M O~ ~D N ~--WO (~ Vl ~O 00 M l0 ~'rj
° M O t~ M N Ow0 ~ M O oo ,~ y0 O v0 twD ~ ~n C~ N N o0 00 .~ .~ r, N O
O
~ -~ N N ~ O N N N ~ M ,., ~-~ N N N N N O N N N N N N M M
O O O ° O O O ° O
oNO
M
M
N
Q
00 00 ~
O O D
N M
122
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
r; ~i
00
.--i M pp ~
~ O vy~ O ~ oo W .~ oo v1 N O N vD ~ a ~rj N N
~' ~' M N N N --m, ,~ .-~ O
M N N ~ ~' ~ ~.. .. ty .~ O v0 M ~ ~ VO ~D Ov N N ~ ~ M M M N N ~ ~ ~ .-,
~ M oho N o~0 ~p ~ N ~ N N N ~ N N ~ ~ N <h M p~ ~~ M Iw0 0o O O O
N N N ~--~ N N ~ ~ ~ ~ ,"1", ,~
N N N N N .-~ ~ ~ O M N N
p ~ ~ ~ C~ O .. ~ .-.
00 ~ ~O O O V1 00 l!7 ~ OO V'1 M O O\ ~
ri N N N ~ ~ ~n ~ cn cn cn N N ~ a M N ~
O M v1 ~ OWD N ~O ~ ~ M N N N .-r .-, .~ .~ N . .. . . ~ ~ O O I~
~ N_ v0 00 0o vi oo I~ CW ~ '~ '~ ~' OW ~ WO V1 ~ 0 O O
~" N '-' '-' M n O ~ N M N OM ~ ON N M N N O ~ N N N N O M ~ ~ ~-1 xi
"~ ~O l~ N a N M °~
ri M N N ~--~ cn ~l ~ nj ,-i t~ Ov ~ oo ~ c~i ~--i ~ ~" N V1 ~t c~i c'i M N N
~ t~ ~
O s0 ~n ~ ~O v0 'b 0 v~ ~t M N N N ~ ,~ ,.., r, ~ O ~ 00 ~D t1 M d' vi v0 ~ M
O O O
0o Ov O~ ~ ~O vD ~ ,--i N M ~D N W O~ ~ O~ O ~t Vj
0o N ~t v~ N O M M Ov
~' N ~' N '-' ~ _~ N ,wD v1 v~ Ow0 O Ov O oo ~' N N N O ~ O ~~ t~
N N N ~ ~ M N N O ~ x pp ~ ~ ~ a p N N
~p
O M ri N N ~ ~ ~ rj ~ N N ~ ~D ~ M M cn N N N .~ .-. M vD
N ~ N vi N V O vD cn ~ l~ O ~ ri OWO M ~-~ ~ ~ W n O~ O N I~ ~ ~D t~ O O O
v0 OWE N ~ O ~ p~ ~ ~ M M N N .-r ~ .-r .-, .-r ~ 00 Ov OWE f~ t~ V7 00 xi Vj
r.~
r' .~ N ,-, N N -r ,_, pp M ,~ O I~ op t~ N ~p M ,~ N N N ~ N ~ N N
00 00 O~ ~ M O~ ~O ,~ M \O pp
N ~ ~ ~ ~ ~ N N N N N M O o0 ~ I~ ~O
O ' M ri N N ~ ~ M O s0 ~ M M cn N N N ~~ ~
~ c! O 'ch l~ ~ ~O ~ ~ V) ~ .~ CT M O~ 01 00 M M V7 a
N Iw0 N O ~D M ~D M cn t~ ~ ~ M O v0 cn ...-i ,~ ~n o0 00 v1 N ~D v0 v0 ~n
N ~ ~ N M N N .-i pp ~ ~ M M N N N ~ ~~ ~ N N N N ~ N ~ N ~ ~rj N
N N N O O O N N ~ N
M ri N N ~ ~ O ~ ~7 O v0 ~ ~ M M N N N ~~ O O O
~ c~ N N M l~ l~ ~O '-a M ~ ~1' M O~ O M o0 ~ I~ O a
V) 00 .~ l~ ~ O~ ~ ~ 00 00 M l0 (~ M ~ M V7 00
N N M .~ N O '~ ~ ~ ~ ~ N ~ ~ O ~O M "'' N .~ O N N N N N N N ~ M N
~ O O ~ ~ ~ Ov rNn M N ~ ~ cvi
,~I,' x cn cn N N ~-~ ~ O '-' N N N ~-a M O N N Vj N vp" ~ ~ c~i c~i cn N N ,~
O O a
M M l~ ~ O~ ~D a [~ ~ O~ O~ O V1 ~ O l~ l~ M ~ M N
00 .~ O~ O~ O~ -r ,~
NNNNNN~ ~~~~N~~OI_~~__~O_~ NNMNNN~NO~
~ I~ O V1 M W M O Ov O~ ~ N M
M M N N ~ ~ ,.0a ~ M vD w M vD oo .~ N N N ~j O~ ~p ~ ~ M wj rj N N ~--~ ,~
.. .. r~ N N N O N N N N N N -~ .. ..
O\ V) v0 ,~ V7 O ~, ~ V1 00 ~' 00 N M Ov o0 ~
O ~O ~ O o0 f~ ..~ v7 ~ I~ ~ N v0 0o Ov --~ O v0 ~ cri N
M .~ N N N ~~ M ~ O N N N N ~ N N M ~ N
OO~~~~~~p ~~~MMNNNO~~~~ ~ ~OOO
O " ~l ~ ~D N v0 ~n M .~ M t~ ~ N r!
~ M N N ~-~ .~ v0 l~ ~ d' ri M cn N N
.. .. N O~ O»O oo two ~-~ ~n M I~ O V . .. ..
~ ,-i ~-~ ~O ~ O~ Ov O ~ ,~ ,~ ,~ (y ~~ ~~ M N N ~ ~ ~_t N WO N_ t~ O ~ ~ V1
Ov ~ M N
N ~~-~ N N N N ~ ~ ~ ~ ~ ~ N ~ N N M N O ~ N
x p ~ ~ ~ O oho v0 v1 Owh o0 vi O t~ ~ N O ~ N ~ ~ ~ ~ ~ ~ O O O
c!1 M N N N ~ ~~ .~ ,~ .-w
~ V 'ri N N -~ ~ O ' " " ~O t~ yt ~ ri M M N N
ono O ~ ~ O ~ ~ ~ oNO ~ WO oho ~ N oo v1 O v1 vi O t~ v~ M ~1
,~ .~ M O ~ n .:
N v0 v0 ~D O ~ O ~ ~-~ N ~~ N N ~ N N N ~~ N ~ ~ 00 M O_W O O N -~ ~ OwY ~t r"
~ N O N N ~
0o t~ Ov ~ oo W O t~ ~n N O
t~ cn N N ~ ~ ,~ ~ W ~ M M N N N .~ .~ .~ ,~ l~ ~ t~ ~t V ri ri cn N N ~ ,n
op ' OW ~ Ov o0 O t~ ~ ~ ~t t~ .~ .~ v~ I~ OWO Ov ~ O t~ N o0 O_ vi N cn c_n
r, W _n ~ ~ M
O N O ~ N N ~ ~ ~ ~ N N N N N N ~ N N N N N M O ~ ~ M N N M ~
O p O O O O
O
M
O
l~
O
000 0~0 00
a
o ~ ~Q
123
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
. ~; ~ ,~ ~ 00
r~ . r, os
~o-~so oo~ ~os
N O ~ Ov ~ O "' f~ IW O ~n ~t ~ ~t cn cn N oo h s0 s0 ~n v7 vi ~ ~ ~ cn N
N O O ~ O '~ ~ ~ O h O O N ~D n '-; ~t ~n ~ O M ~n N tW O M O O~ ~ N ~ ~ ~O
C!~ O x O .-WO N O ~_ oo Ov M O O_ v~ ~j TWO O_v O ~ Ov M v0 t_~ Ov Ov ~
~' a ~' x ~ ~ N
"'~ O O ~ ~ " ~O ' Qs
~ ~ v~ ~ ,~-~ '-' f~ fy0 vi v~ V ~ ri ri N oo t' ~D ~ y ~i v-i d~ d: ~ cVi N
,~ .-~r o0
O O O ~p O '~ ,_, oo O~ M W O O M N N M ~ ~D M O~ oo h O Ov ~ ~ O M Os ~ ~ h
~ O x ~ p~ ~ 00 00 M o0 OW M O V1 OO ~ O u1 ~ ~ M h ~D v~ ~ M O ~ N
r., ~ ~ N ~-~ N O O N ~p N N O ~-~ N N ~ N M N N O N
r, .. .. -~ oo ~ ~o
~p N
N h t~ ~D v-i v1 ~ ~ cn ri N ~ ~ oo ty0 W O ~i vi ~t ~t ~ M N ~-~
xx0~70 ~d'MOM~o_ONNV~c%'i~O~~O~00~~hOoOMOvNh_~~D'-'~O
F~ ,-i r; a r.; x ~ N ON N N N N ~ -~ ~ N O ~ ~ N N N N OM N N N N N N N
0~0 M Ov o0 O V7 b N
O O M O ~ oo h ~O ~i v~ ~ ~ ri cn N c~ oo h ~ ~D y0 v'i V7 ~ ~ ~ M N ~
Vj x x a x O '-' ~ h Qv m ~ h N Ov OW O ~ O N d' ~ O O N ~ ~ N h O v7 .-~ ~' h
" a ~W O ~t v0 OW ~ ~O h O ~~ 00 ~' Q~ O o0 00 ~ oo h ~ M v0 t~ N ~--~ ~' N
.. N N N ~ N N N M N ~~ ~ .:..; ~ N ~ N N ~ ~ O N N ~ N N
N o0
O O O ~O O ~ ~ N o0 h s0 v7 V1 ~ ~t M M N . ~ 00 h tW O ~O ~ ~ ~ ~ V M M N
x x x a x a .-i ~ oMO N N ~ ~_ v~ ~D M M_ Oy ~ M ~ ~ M ~ ~ oMO O ~ oho Ov oho
N .-i v0
~' ''-' ~ ~' ~NNONNNNNOM'-:N~NO~N-~MNNNNN
v0 ~ O ~ ~ h V1 ~ ~ ~ r°~r N ~ ~ O Ov
x x x ° x v°~ ~ '~ °° ~ ~° "~' '~ ~ ~" ri
ri tV - ~ oo t= c= so so vi ~; vi ~ ~t r; r; ri
a Ov OWn M N_ ~ O ~_ oo ~-. ~ W N N ~ ~ N v_i vi o0 0o O~ N ~_O
"a N ~ O ~ N N NO ~ N ~ N ~ O N O N N ~ ~ M N N N N N ~ '-'
O o ~ o ~ ~ oo w
a x x '-' N o0 h ~D v1 vi d; d: cn ri N .-; M oo h ty0 vO yi wi v-i ~ ~ M cn N
'-'
W x a ~ ~ ~ 0 ',..; os in oo h c%'i os ~i ~ ~ oo ~ .o M c~i W ii os o ~n r v_;
o_ ~ ~
MONNNNNONpNO ~~NNN~pNNNNNNN
~ ~' d' ,~ M_ p_ c_ri ,_~
~ V7 ~O ~ ~ ~ M h ~ ~ ~ c'1 ('n
O O O O O O
xxxaxa °N~r~O~n~n~vririN,~'~oyr~o.~V;W v»d;~riN°,.~°'o
O O h ~ ~_n Ov ~ M ~ N N s0 ~ O N_ 00 ~ 00 0o h ~1 00 ~n O M
N N N N ~ ~ N N N N ~ ~ N ~ M N N N ~ N N ~ N N
0
~O o0 00 ~ N oo ~ p ri cn
N N vG h vW
O O O O O O
x is a a ~ ~ 00 h ~O V~ V1 ~ ~ M M N ~~ ~ O~ h h ~D ~O V'1 V'1 ~ V ~ ~ M N
N ~ ,-i ,~ .-i ,-i ,--~ r, ~p [~j ,--i ,~ .W_0 ~D V7 ~_ ~O ~ ~ M ~O N M d' 00
~ QWO ~ ~ O_ <_t N N
M ~_ N O d' ~ ~ ~~I" .h-~ N O N ~ M N N N N N ~ O ~ N ~ N N N ~ N N N M M
~D O N IWO h
O O O O O O ~ O ~ ~ ~ ~ ~t
aaxaaa
N v0 °~ WO v0 ~n ~ <t ~ ri N ~ ,_; Ov oo (y0 v0 v7 ~Wn ~ ~ ~ cn N
~p M
N ~' .-i ,~ .-i .-i ~p N v0 N oo Os N ~O ~ oo h vi vC v0 ~t v~ .-~ ~ t~ M O WO
O ~ Ov N t~ ~t
V7 O~ ,~ wj M ~O ~~ N ~_O O_O O_O O~ M ~O ~~ O Q_1 ~ O ~~ O_~ M O_~ ~ 00 M ~_
~O --, O ~ OO N ~ N
~' M V1 ~O Q1 In
O O O O O O
aH~aaa
.-v .-r
N ,~' .-~i .-i .-i ,~ ~-~ ~' ~ lW0 ~D V~ ~ ~ ~ M M N ~~ Ov o0 Iy0 ~O ~!1 ~!1
~!1 ~ ~ ~ M N
O O oo N h v0 ~ M "' 00 v~ ~ vD t_~ ~-~ h N_ oo h M ,-, h N_ h cn Ov ~ O~ h ~
00 v0 ~~ M N ~
~~NNNNNN~M~NON N~NON~OMO~N~NM~N NN
h M M ,W O h O
O O O O O O O
00 ~ O
pp 00 O,
[~ .-i M
vD M
h h
x
Op Ov O
h h 00
124
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
.--. ~ r; ri ~ . .-:
00 0o t~ ly0 v0 W et V ~ N N -~ ~~ ~ M ch N N N ~~ ~ '~ ~ ~' ~ ~ N ~~
~O ~ ~O M V~ ~ V~ (~ ~O N ~ ~-, M N ~ ~ ~O \O ~O ~~ N M V'7 O Vl Np ~ M O V1
N Cv M OWO o0 N v1 ~ a N ~ N o~0 N ~ M ~ ~ M O V7 ,..~ x ~l
N N N O ~ N ~ N M
v~ ~ ~ ~ M N M ~"' "
00 00 I~ t~ ~D ~O V1 'ct ~t N ~ N N ~' ~~ N cVi M N N N ~~ ~ ~ ~ '~ ~ ~ N
~ M_ V1 Ov M o0 t~ N ~ ~ ~ ~ ~ ~ O d' ~ ~ N M p ~ r-~ x ~ O vp
.-~ N ~ M O N O pM N N ~~ M N N M N M N N N ~
O ~ ~ ,jj Ov ~
00 0o I~ ty0 v0 ~n ~ d' N ~ N N ~~ ~ ~ cn ri N N N -~ oo O O ~ O
I~ ~n O m f~ O v1 ~ O O O WG v~ I~ N v0 Cv O M TWO <''~ O O O ~ ~O M ~ O~
O M O~ ~ l~ O O~ ~O M ~O x V) ~O I~ V ~ ~O M ~O O~ 00 M V V7 C~ x " a ~ ~O .~
NNNN~MNONN_. NNNN ~OON~NO _"_ N~~O
N ~ ~ V1 a 00 00 ~ ~ pp -p
- M N ~ °o
00 0o t~ ty0 ~O y0 W ~ ri O N N N ~ N ~ cn ri N N N ~ ~ ~ O O M ~ M ~ ~
dv ,~ M ~w0 l~ O v0 N M_ ~ I_~ vi ~n ~n N ~ ~ ,-.~ .-, Vj r. M_ N x VJ C~/1 ~
O N N '-'
N N N O N NO N N N ~; N N ~ N ~' ~ ~ N pN N ~ N p M ~j r; ~ a N ~
'T' ~D ~ ~ N ~ ~ p ~ Cv O
O ~ O O ~ ra
00 0o c~ ty0 s0 v0 v1 ~ M p N N N ~ ~ ~ M cn N N N ~ '-' p O O O
W_ Ov oo t~ ~ M cn Ov N O_v ~ N ~ ~ M 00 M U (~ O~ 00 I~ M ~ V1 x x ~ ,y0 ~
N ~ ~ N N N N ~ N N ~ N N N N N ~ N N N N N ~ ~ M N --i '~ ~; N N
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ a ° ~ o o °° ~ ~ r°~
00 00 r l~ s0 ~D v0 v-i ~t ri O N N N ~ -~ ~ ~ ri N N N ~-~ N O O ~ ~ O ~i M ~
.~
Qv ~ 00 t~ ~ N ~~ ~ M M "'~ O f~ 00 QW~ ~~ ~ N O ~~ V7 ~ Ov x x " ~ a ~:j m ~~
N
O ~ N N ~ N ~ N ON N ~: ~ N N N N ~ ~ N ~ N N O ~ ~; N ~! w; Ov M v0 N
N N N
p ~ W O ~ a ~ O ~ p
Os oo I~ I~ t~ ~O ~O wi ~ ri ~ N N N ~-~ ~ ~ ~ ri N N N N ~ a x a x a G ri ,~
,~
I~ ~ 00 Ov O N a_0 ~_ _~ M M M o0 O ~ N N ~D ~ l~ N M "
N N ~ N N ~ M N M ~ ~ ~ ~ N ~ N ~ N N N ~ N ~ N ~' M ~ ~ N N N
O~~M~~O~O
Oy oo t~ f~ tyD y0 ~n ~ cn x ri N N ~ ~ ~ d: cn N N N N ~! x r/~ a '~" ,~ ~.l
nj v_0 O O I~ ~ oo ~_--i ~ ,.:-i ~ cn M v1 ~ yin l~ oo O v_0 Ov Ov ,-i ~ ' '
v_0 t~ v~
N N N M N N N N N N M N pN O N ~ ~ ~ ~ ~ N N N ~ p vi N ~' ~ op N N
t~ (w0 ~ O t~ t~
O M O ,0~, O O
Oy o0 t~ f~ twp vp W ~ M x M N N .~ ~i N ~ M M N N N .~ r.a r.-~ "~, " ,~ "a ~
~i ~i
V7 00 O l~ V1 N OO O~ M O .~ ~-~ I~ 00 M_ ~D N O~ M ~O l~ V1 M ~ t!j N ~' '~ ~
~' ~ O~ ~'
N O N N N ~ ~ N N ~ ~ ~ N N N ~ O N N N N N ~ ~ ~" '~ ~ ~ ~ N O
O ,~ ~ ~ ~_ ~ ~ ~ M O O O O O
Oy oo t~ t~ ty0 v0 v1 ~ cn '~'" ~ ri N N ~ ~ ~,~ ~ ri ri N N N ,-i ~l x ~ x ~l
a
v7 N O ~n N ~ O~ ~O ~t Ov '-: M N o0 ~_ ~ O M ~ M O ~n ~~ t~ 00 ~ N M I~ -~
N ~ ~ N ~ N N ~ ~ ~ ~ O ~ N M ~ N ~ N ~ ~ N N N N ~ p ~ ~ ~ ~ N N N
~ C ~ ~ ~ O O O O O O
v~~x~a~
Oy o0 l~ I~ I~ ~O y0 V1 ~ M ~ ~ M N N ~i ,~ ~-~n ~ M M N N N ~~ l~ M N ,~' .-i
,-i I~ N ~--n
I~ ~O O~ ~D OWO W O ~n N v'1 v1 l~ ~ N ~ M N v0 W O O l~ pp O ~D O O ~ Ov Ov
Ov
.~ lp M ~D N ~ ~~ N t~ ~-n ~ ~ N l~ t~ O o0 O ~ ~ WO 00 O ~-~ M o0 t~
N ~ O N N N N N N N ~ ~ N ~ N N ~ ~ O M O N N M N ~ N M M ~ ~ N O
O O O O O O O O
-..~ N M O O
M M
~O ~D
M ~O ,_,
O ~ ~ ~ l~
N M
00 00 00
125
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
N
O ,~ c~
Np~'~noo " ~,'I',N~ ~~O
ri N N -~ ~-~ ~.j ~ oo t~ ~D v~ W ~ ~t ri cn N ~ N ~ ~ M ~ N ,-, ~-' N Op M p~
,_; O
Os O~ O~ t~ t~ .-~ N ~n ~ O ~~ O t~ O O ~1 M Os O O O M ~D ~n I~ N o_o O
00 00 O V1 l~ ~ ~p O~ N ~ 00 O~ ~ I~ V1 00 00 ~ ~ N M M O~
r~i~~ NN~~M ",..]
O N M N N ,n ,~ --~ N N ~ N N N N ~ N M N N ~ ~
r..~ ~ ~ ~ ~ ~ ~ rr ~ v1 ~ ~ ~ N_ l' ~p c,j r;
c~i N N ~~ ri N ~ oo t~ vO v-i vi ~t 'et M M N N N ~ ~ ~ ~ N '~ '-: ~ I~ ~
m ~D M <l' oo vo ~ t~ N ~ OW ~ ~ Qv oo W D cV N O O O ~ oo ~ ~ O yp Ov ~
M o0 Iw0 ~ ~ O o0 N o0 v0 l~ 00 M Ov V1 ~ 00 ~ rW -7 r.~ N l~ ~O
M N ~-~ ~ N N N ~ N N N ~ ~--n N N N M N ~ ~ ~ N ~ O ~ ~ ~ ~ N N
O ~p ~ .~ "
O~
O M ~ O~ a 00 ~O
m N N ~-i ri ,-, ~ 00 I~ ~O v1 V1 ~ ~ M M M ~n N a O O ~ N ~ ~ ~1 O l~ (~ M '-
'
N ~D v0 tY1 M M ~' 00 v1 00 OW 1 ~ ~-~ O T s0 M ~O N x a ~ ~ ~t V O~ x O ~~ ,~
~,
~n Ov ~ M o0 00 ,--~ O V v0 v0 vD p Ov O oo O~ O ~ Ov ~ Ow0 v0 t~ ~ ,~ ~ Cv
c%i
N O N O N W p M N ~p~ N ~p~ N ~ M O O~; oo M vp ~ r, ,-; N ~~; Np; t~ ,~ _. ~p
~ op
~~~"~-~o°°
ri N N ~--i .--~ ,-i o0 ly0 ~ vyY ~t M M ri ,~ N ~ p O p N N '~ '-' O O .-i
~D Ov O Ov M t~ O M v0 00 vW O ~ 00 -..i U ~D O Os "~ ,."'L~, a ~ M v) N v0
',~, C/~ ~
~ ~D ~ O~ ~ M ~' ~D O~ O~ O ~O O~ I~ ~O t~ N t~ O~ ~ " ~O ~O I~ O~ ~ .
N N N N N N nj N ~ ~ N ~ N ~ O ~~ N ~ N M ,-i ~! ~ N ~ N ~~ .r
i...a Q a ~ ~ ~ O M
ri N N ~~ ,.-~ ,~ Oy v0 y0 v~ ~ d; cn cn ri N cn v0 O O O N N ~ ,~ O
~D ~ N V1 00 O M ~ N Ov ~ t~ t~ Ov M o0 O ~!1 OWi ~ x ,~ sp ,--
v0 N l~ N ~D O ~ O N I~ ~ O~ ~D oo t~ O~ M wD ~n M ~ ..-, ~ N ao v0 O ~
.-~ N ~ N ~ M ~ ~'' N ~ N ~ ~ N N N N N O ~ ~ ~ ~ '-' N N ~ ~-~ ~' ,~ ~' ~' ~'
N a ~ ~ ~ N ~ ~ N N
M N N ~-~ -.i ,~ ~ Os (W O ~O V'1 V'7 ~ M M M N M ~~ ~ a O N N ~ ~ ~ O
N ~Y v'1 ~ ~O 00 cG ~ O .--i ~.j M l~ M OWE 00 ~ ~ M ~ "'~'" O~ ~ I~ O "
~O ~O v'7 ~O ~~ 00 .-~ ~O O 00 O_O O~ O~ M M ~ ~ O_0 .~ ,~ ~' ,_, O w--~ .~ ,-
, ~ "
NNMNM~~ ~ ~ ~OpO I~c'~~
r
ri N N .-i ,~ ~-i ~ N Oy oo vD v0 W v1 ~ ~ m cn N M N ~ ~ x N N .-, .-, '"~O''
V1 ~ l~ ~ ~ 00 ~ ~ M ~D O ~ O 00 O 00 M ~ t~ O O~ " ~~ " l~ M O 00 ~
~.-r ~D ,-, OWE O ~,' v0 ~ O ~ ~ 00 00 N t~ O N v0 M ,~ .. ,-, 00 OWO
N N N N --~ M op ~ ~ N N N N N ~ N ~~ N N O O ,_,
N . ~ ~ M p ~ N O N O
~O~n ~ OxO~; ~ NO~O MNN
ri N N N ~ ~ ~ N Ov o0 I~ ~D v7 yi ~ ~ ri M N ~ ri N ,'2,' " ,'S', N N ~
M O V»00 W ,~ I~ WO ~ 00 M v0 00 O O_v OWE lW0 N '-' ~ ~ O N N ~n ~; ,-i
ON ~ ~ O N ~ N N ~ ~ ~ N N ~ N O O N O .-~ ,r ~: 0 N N N ~ .~ v1
cn N N N ~ -~ x ,N Os oo tW O v~ v~ ~ ~ cn tn N ~ V N a x ~ c~a N N .--i .-i x
x N t~ 00
~~ O N_ ~O O l~ '-" N ~_ N M N l~ l~ N Ov M O M_ '-' O o0 N ~~ ~ N O O~ ~_ ~j
~ ~ N N
N M ~ N N ~ ~ N ~ N ~ ~ N N N pN N M ~ N N ~ ~ ~ O N N O N ~'~
,.0~, ~ ~ a ~ a a ~ ~ ~ N ~ ,-N,
yt N N N -~ ,~ . ~ Ov o0 f~ v0 V1 v~ ~h d: cn M N ~ ~t N ~ ~ " M N ~ ~~ ~ r, O
Ov
vi ~D f~ ~ O O ~ O M l~ v1 N ~ v~ ~ v~ N ~ ~ ~ M N ~~ ,W D o0 00 0o N .. v0 t~
Ov
~D ~D Ov OW O OWD M v1 ~ M ,--W O ao M t~ ~t M O O O oo t~ M ~ M f~ QWO v0 N
.~ .-r N ,~
.-w N N N O N ~ ~ O N N M N N N ~ N N ~ ~' ~ N I~ WO op vp
O O O ~ O O O O
C~ N E--' ,~ "~" ,..,J ~l ~ a ~ v~ ~D M
~ M N N ~ ~ ,-.r ~'~ O~ 00 Iy0 V1 ~lyt ~ M M N .~ ~ N ~j ,~ ,-H ,--i V1 N ~ -~
N ,~ ~ N
Ov ~~ ~~ M N Oyp ~ ~O Ov ~ ~ N M v0 M v0 v0 N ~j O O~ ,_; ~j w N ,--i ,~ t~
i.,j cn ~ 00
vD -~ O t~ 00 0o vD w0 t~ t~ N ~~ M M -, ~ M ,~ O o0 ~ '-' 00 0o O m N N ~O vD
l~
~-a M N -~ N ~ ~ N ~ N ~ N N N O M N N O M O ~ N ~ ~ N ~--~ N N ~
O O O O O O O O O
U ~ ~ O,
O M ~ N O
O M M
126
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0 00 ..-.
Iy0 ~ cn N N ~ M M N N N N -~ ~-~ t~ t~ ~D ~O N ~!'i d~ M M N c~i N N N
M .~ t~ O_v oo c_n M O ~ N vD cn -~ ~t f~ ~ ~ vW D oo N N M ~n N t~ l~ I~ Q~
O~ O v0
~ N N N ~ ~ x ~D o0 M .-, M l~ N ~ ..-~ Iw0 v0 ~ ~-~ ~ 00 W O ~ W O N Ov M
~ N M N N M pp ~ N M N N N N N N N N ~ N
two ~ ~t N N O cn cri N N N N ~ -~ ~ I~ ~O ~O v7 ~!'? ~ ~ M N cn N N N ~
00 t~ N N_ ~--~ ~ O o0 M M o0 00 O ~_O N ~ 00 M vi t~ ~O I~ N ~t O ~ ~O Ov Ov
o0 l~
~ N N N NO ~ ~~ ~~-~ ~ N N N N N N pip N N N N N N N N N N ~ ~ N N N
00 ~ ~ ~ ~, ~ ~ r;
t~ ~O ~n ~ N t'!~ 0 c~i cn N N N N ~ ~--~ o0 t~ ~O ~O ~n ~ ~ ~t M N ~ m N N N
~~
~' N t~ O N N V1 t~ ''~' ~-, ,~ t~ 00 00 In v1 00 ~ O t~ Os ~ ~ t~ d_' ~ ~ ~ ~
N ~O ~ M N_
N O N N N ~ ,.~ ~ N N N ~ ~ O ~ ~ MO N ~ ~ N ~ N N ~ N O ~ ~ ~ N N
C
tyD p ~ N -~ p cn ri N N N N ~ -~ oo l~ ~O ~D ~n ~n 'ct ~ cn N '~ M N N N
0 N (WO Ov M o0 ~ ,"S,' ~O Ov Ov ~ ~' W O O O_ WO c~7 N ~ ~ W O N s0 ".". W ~
O I~ 00
N N ~ N ~ N ~ N ~ O N N O N N ~:fj O N O N O N N N N N N ~ N ~ N
t~ vD v1 ~ cn .~ ~ r.; M ri N N N N ~ ,-! oo t~ v0 ~O V? ~!'? d; ~ M N ~ M N N
N -~
in Own v_W v0 ~ ~ vW O t~ ~ oo ~i O M v0 O ~~ O M m m o0 0o N ~ N O~ t~ ~
NONN~N'.~~ N~N~N~NN ~~~NO~NNON~~~~NNON
N Oy
~ oo v0 v-i ~ ri ~--~ ~ ~ M M N N N N ~~ ~ oo I~ t~ ~D ~n Vi 'ct ~t M N ~; cn
N N N
N Ov ~ ~ M O_ O ~ ~ OWO O ~D v0 ~_D t~ O M OW ~ ~~ ~ ~ ~ v1 O ~_ M M M ~D M
N N O N N ~ ~ ~ N ~ O N N M M M O ~ N ~ ~ N N N ~ ~ M ~ M ~ N O
~~~~~~~oo~~~~~~~~ M~~~~~~~~~~~~pNN
M~ pp
0 00 v0 tn ~ M N ,"1~., Cl7 M M N N N N ~ ~ '-' 00 l~ t~ ~O ~1 v'1 ~ V M M N M
N N N
N ~n v0 ~ ~ Ov N ~ ~ v'1 ~ Ov M M l~ t~ O ~ Ov N ~O d' O ~ O oo Ov M ~ O~ ~ ~
00 00 v0 O_ ~_D N '-' '.'.' l~ _ 00 o_O Ov ~ oo O ~O O_v O~ O two O o_o _
0 ~ ~ ~ O O
v~ V
O O o0
N o~0 °W0 ~? ~ ri N a ~ ~ ri N N N N ~ --~ ~ oo t~ ty0 Sri ~i ~ ~ cn ri
~ M N N N N
o~o~~ ~~V NON~~ ~~~~o~OM~~~t~i~~~~N~
O ~ M N N N "' '~ N N N N N N N M -~ N N N N N ~ N N N N N ~ N N
M o0 ~D ~7 ~ cn N - ~ U1 M N N N N N ~ ~ OW ~ tyO m ~n ~ ~ M M ~ M N N N N
N N M o_0 v_0 M t_~ Ov ~ "' M ,--~ t~ v~ V M Ov O~ ~~ Ov Ov ao 0o v0 t~ M Ov N
M .-s ~D oo ~ ~n
ONMONO~~ ~NNN~~N~ ~NOMN~MNN~NNN ~~MNN
00
0o v0 vi ~ M N ~ ~ W ri N N N N N ~~ N Oy~ tw0 W ~n ~ ~ M M -~ M N N N N
00 N N l~ V1 v0 ~~ ~ N ~n ~' N v0 N m OW_O ~ v0 O Own ~n ~O M O V1 O_ ~n v1 M
t~ ~i'~
N N ~ (~ Owe ~ ~~ pMp ~ ~ N N N O N N ~ ~ ~ N N N ~ N N O N ON N N ~ N N N
M N N N N N
~~~~~~~~xa~~~~~~~~
0o t~ yi ~ M N nj ri wi cn N N N N N ~ ~ ~~ Oy~ t~ ~D v0 ~!7 ~ d: ri c'i -~ M
ri N N N
0o t~ O O M o0 --~ ~ ~j nj .--~ Ov Os N ~-~ ~ ~n O ~ c~i N M m N ~-~ t~ t~ O
~t oO O~ N ~ c~i ~D
~D M O O~ ~O O ~O l~ ~ ~ ~O O~ l~ ~O t~ t~ V~ O ~ 00 M M o0 I~ M 01 M O ~O ~O
00 ~D -~ ~O O~
N N N N M O ~ ~ N ~ N ~ N N ~ N N 0 M ~ N N N N N N ~ ~ ~ N ~~ M N N
O O O
O O
N o0
00 Ov
O~ ~ d'
O
x
Ov O ~-r
127
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
N .-i '~' ~ ~' ppp -i ~D
'-
O _
: I~ ~ V)
v7 M ~ ~ V7 V7 V~ ~ ~ ~ M c'~
.~ ~ 00 I~ I~ ~O V7 M ~ ~ N M M N
M O ~ ~ a
pv ~ ~ ~ ~ O W t~ W M <t t~ t~ ~D M ~, t_~ O ~ Ov
p~ ~p M O ~ ~p _~ Ov M V1
O M .-~ ~ pv O O ~ O O x O ~O
,-, N ,~ ~r ~ ~ N N N O ~ N N N
M N N N N N N ~ a '~ x ~ a N
a ~ ~
~ ~
~O
Ov
~ O
a M T
~p O~ ~O O O
~ Ov o0 t~ I~ v0 ~n M Oy ~ ~n vi v1 ~ ~t d~ ~
~ cn M cn N
~ p ~ h
O , oo WO I~ v'i v0 O N
~-; M oo v0 TWO ~ ~ ~ ~ N a0 M O .~ N O
O O O '"~"' O O ~ N ~
a O
~ a
a a ~
' N N N
' " vp
N N N ~ ~ N N N N ~ N ~ a N
~ ~ N
a ~ ~
0N~ O~
Vj~l~0
.-igyp" ~ r-i p Oi o0 I~ ly0 y v0 vi ~n V ~ ~ V cn
~ N ~ ~ ~ O ~ p cri cn N
0 ,~ .~ .--~ ~ r.; N ~t OW '1 M N ~ Ov V~ ~O v1 ~
~i ~ 00 O ~"~ O x ~ a ~ 00 v0 N ,~
" a I~ ~D O I~ M M OWE
~O a O O N '
x
N OW ~ N O
N N ,~ ~ ,~ N N ,~ ,~ ,~
' ~ " ~ M N ~D
M N ~~~ON
N
00 N ~ Ov
NN ~~~N~Oo~onM
~N ~~ ~voM~~~ a
Ov o0 0o I~ ~D v-i ~t N ~ O v0 vi v1 ~ V~ ~ ~ cn
t~ O O cn cn N
v0 ~ ~ ~' O M d' 00 O~ N o0 v0 M ~ Ov V~ N ~ ~ Ov
C~ ~ a x O x "~ a o0 OWD N C~
M r., ..r ~O O v1 r x ~ ~ N ~O o0 00 v0 l~ Ov
O N o0 in N
Nb ~~ -~ ~~ ~~NNNNNMN~ -~',~"' N~~-~NNNNMNNN~O"1
N ~ ~ ~ M ~ vp v7
~Y N
..,O ~ N M r v0
Ov Os o0 0o t~ ~D ~n ~ N O t~ -
~ O O O ~ v1 y ~ d: ~ ~ ri
~ ~n I~ ~ d' M O N ~ ,.'I", ri ri N
x ~ '~'" a x O v0 N ~O t~ oo M oo
' O ~O ~
"
0o ~ O ~t IwD O V v0 ~n N v0 00 ,-, v0 .-~ ~
N ~ oo ~O o0 t~
,--, " ,-.W
O " N N ~ N N N N N N N
O '-: '.". '.'i '-"~ N N N ~ N
N N N N ~ N _ ~' ~ ~
x ~ M ~ ~ ~ ~ V7 00 V7 ~ M
ooyn aO
,~ ~o s0 y yi ~ V V ~t cn
~t Os o0 00 t~ s0 v~ d; N O x ri ri N M x
p ~ a x
a
00 ~D N ~ o0 00 O N N ao ,--~ N v1 O O I~
l~ ~ " " " M t~ W l~ ~O
v1 " ~D o0 Qv o0 ~ OWE ~ ~ ~ ~ a0 00 l~ V1 O Ov Ov
~1 ,~ M V M N
N O ~ ~ O N ,-, N N N N N N ~ ~ ~--~ ~ N ~ N O N
NO N ~' ~ ~; N N N 0 ~ O
~ a
~ ~
~ ~ N
~~D ~~M
DO
OI
OM
O
_ O .b
-i _ v0 v~ v1 d~ ~ ~ ~ ri
,-,_ ri cn N ~ x
O O
00 0o Iy0 v'i ~ N a x ~ x ,~
,~'.L',
t~ O N N M Ov ~ O M " ,-; ~ ~ O ~n M s0 N o0 N ~
00 ~~ '~ N m
~O I~ ~ 00 ~O l O
O ~ ~n l O l
~ M ~f N D ~t V'7 ~
O ~h M O
~ ~
~ O O
,~ .. _
_ _
_ _
~ ~ _
_
~ ~
M
~O O O O O O p" pv
dW O V'7 O~ O ~
~~ ~ooN~~~~.~~~Max~x~x ~~~~~~~MM~;N~xa o
v0 M o0 ~ .--i v~ N v1 O " ,-, Vj vj ,~ I~ OW O N
~ ,~ r, cn N oo t~ ~'
Ov 00 l~ oo tmn ,~ N ,~ ~t cn .w
o0 ~ .. ~ Ov ~ I~ O M v~ t~
~ O OW
NN N~~NNMNNooO~o _
O~' _
N ~~~xM
O
~~~ ~~~p
OO
. M
i N ~ "~ ,~ o
r O ~ .~ ~ M M M M ~ a
OO a
~ M ~ a ~ x x ~
00 OD
~ ~O V
- ~ ~ O
r ~
l
~ M O~ 00 ~
Ov N N ~ ~ ~ ~ ~ l~ v0 O M N ~ p~ Vj ~ M O ~n M N
M cn N ~ ~" ~' M ~ O~ ~ ~ ~' ~
N O '_" ~ O [s M O~ 00 I~ ~ ~O ~ ~O C~ O~ O~ C~
~ 00 M M ~ ~-~ ~.j N
~ N O ~ ~ N N N N N O
~ N M ~
~
~ O p O O O .~ d~~~~~~~~~~
j r; ~ ~~
~
a ~ ~
" xx
N~~~ xa ~ ~
.--iw Ov 00 00 I~ ~O ~ ~ c'n ~ t~ V1 V7 V'1 ~ ~ ~
~ " " ~ M M cn M N
n N ~' ,~ ,~ ,-i
~ ~
O 1
~
--mtc ' N
-~ , ,
Ov O Ov ~ ~n t~ tW0 ,W .--i oo ~ m ,~ M OW
N ~ ~ n v1 v~ t~ ri
N -~ ~ M O w1 f~ N M .~ ,~ N
w0 Ov o0 00 ~O O~ ~ ~ O~ ~ ~ ~ N M O
~' ~ ~' ~ O
W O I
_ _
_
_
a a x x H x ,.
.a
N ,...~ .~ .~ p~ 00 00 tW O ~ ~ v~ vi ~ ~ ~ cn
v0 ~n cn ~ cn N '-' ~' -i ri ci M N N ,
..-i
O Ov - ~W _O t~ t~ t~ Iw_O cn ~ oo O Ov O oo I~ ~ o_0
N O M ~ t~ Oyp ~' v0 N N_ O_ ~_ N_ ~ ~
~ N
O ~ ~ ~
~ ~ ~ ~ ~ O O ~ N
N ~
N
~
N ~ M N N N N
N ~ N
N M
N
N
N
O
O O O O O O O O O
O O O
N
N
O
M
O
O
O
,n
p
U
x x
N M
a\ a\
128
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
n
O l~
trj vi ~ ~ ~ M M W O yi ~i ~ ~ M M ~ N ri
N N N a M N N ~ .-i N
N
00 v0 v0 ~ oo O n v0 00 00 00 t~ Ov oo ~_t ~
O oo N ~ O N M
~ Ov ~ M M o0
~ _ ~ N~ N~N
p N~~MNNN
NNNNN ~~~
~NO
"T'
N N
N
V~ V7 ~ dyT M M N y 0 N V1 d~ ~ M M ~ N M
N N ~ M N N ~ ~ N
N
O M N v0 t~ ~D V7 v0 V7 Qv O ~ 00 f~ 00 ~
~D t~ O N O ~ f~ t~ -W 1 ~O cn
o0
00 ~O 00 ~ ~ ~D 00 .-y0 O O N 00 00 V1 O O
M 00 .--n .. (/~ ~ 00 M V7 N I~ V~
N N N N ~ N N N ~ N -~ M M N N N N M Qv
~ N N O ~ M
N
O
~
"~"'
vi p ~ ~ ~ cn cn ~D yi vi ~t ~t cn ~ N M
N N N M cn N N ~ ~ N
~ . ~ ~ N
'~ i'
N ~ I~ N t~ 00 Ov ~ ~ M i
O N -~ N a vi N v'1 v'1 O vD ~ t O
-r M ~O N 00 N
00 00 O 00 00 M ~ ~ ~O ~
M 01 00 N ~ V O V1
00
01
. ~ O ~ O
~ ~ ~ N N N N O ~ N N ~
~ N N N N
N N N N N ~ N N N
; v~
~ ,.._ ..r
O ~ O
vp v1 ~ ~ ~ ri M ~D v7 v~ ~ ~ M M ~~ N ri
N N N x O b <"~ N N N N ~ N
N
~. M O ~ 00 OW ~ O N M d' ~ I~ cn cn V1 ~
M O N ,T, ~ M N OW ~ ~ O N
O o0
I~ V1 l~ O~ 00 Ov V7 N OWE ~O l~ l~ 00 .., I
O~ M O~ O ~ ~ O~ 00 M N N M ~--~
N N N ~ N N ~ ~ N ~1'N M
N ~ N N N N
~
~'
N N N , 0
N N N ,
I ~
~
yp ~ ~ ~ ~ M M N ~O v1 v1 ~ d: ~ e N M
N N N M O M M N N N ~ G ,~ N
N O N
.-.~
O I~ l~ ~ ri ''~ t~ c ~ v1 N
a n cri ~t v1 Ov o I~ v'7
N QW ~ 00 O v O t~ ~D ~ C~ O p
_ _ ~~ Nix NON
: _
NN~O O
N' NNO
NO~~~ ~x
NN~~
M NM
N N
- N
v0 ~n ~ ~ ~t M cn t~ ~ V7 ~t ~t ~ N M ~t
cn N N v0 x a M ri N N N ~' N N ri
~' N
N M Ov N Gwn ~t ~ I~ N ~ vi o0 N oo M N N
Ov ~ N ~ O ~ ~' M M f~
Iw0 ,~ ~ 00 0o N O~ ~ v~ O~ O V oo ~ O 00
m O M ~ ~-; ~! v0 v1 Ov M ~ ~ v7 ~n
N ~
oo 00
--i M N ~ ~ N O N ~ N N N M N - N N N O
N t~ -' pp N N ~''~ ~ N N
~
i i i n n
n i
i n
~ ~
n
i
c ~ ~ ~ r ...,c ~
r r r N c
~D ~n ~ ~ ~ r c -~ N
N N ~ x t
~
~
N N ~
N N N ~ O O oo t~ ~ N ~D M O N O oo N t~ ~
v0 M s0 ~ .-i ~ t~ OW 1 l~ W ~D
O Ov
W D w0 ~ Ov OWD N ,--~ ,-i ~O V v0 00 t~ v~
M W ~~ .. t~ O vD oo v0 ,~ 0o I~ O
N ,~ N Ov
N ~ N N N ~ ~ N N N M ~ N O N N N N N N
N N ~p ~ N N N N ~ N
N N
~ O
x
~O W ~ ~ ~ cn M M t~ ~n v1 ~ ~ ~ m M ri ~
N N ~ ~ ri cn N N ~ .~ N ri
~ N
W cn ~ M ~n ~ Ov ~ cn ~t v'i ~ ~ ~ N s0
~ ~ Ov O ~ ~' t~ O O V O oo ~ O ~
t~ ~i
M N ~~ O~ l~ 00 00 N N v0 M T I~ V1 O O~ o0
~W O M l~ w .-v t~ Ov Ow--v N ~O I~ 00
Ov Qv
N N M ~ ~ ~ O N O N N ~ N ~ ~ N N M ~ --~
N ~ '-' ~ ~ N N N N N -~
N N
O O
"T' x i m i n 'i
~ n i
~D W ~ ~ ~ ri cn ~O vi ~n ~ ~ ri .- c v
ri N N ~ r c N r
t --~ N
N N ~
Ov cn cn cn W N OWn t~ ,-; ,--i ~ .~ M O O
I~ W O ~~ ~: oo ,--i r'i t~ O ~n oo
~D Ov ~ ~ t~
~O d' 00 -~ O N O~ ~ I~ ~O ~ O l~ 01 00 0O
V~ N O~ 00 ~ M 00 M ~D ~D ~D M O
~D
N - M N N ~ N N N N N ~ N N ~ N N ~ ~ M
N ,~ t~ N N N O N N N
~ N
y0 V7 Vyt ~ M M M t~ ~O V1 ~ ~ ~ M M M V'7
N N ~ ~ M M N N ~ ~ N M
~ N
~ n M OW t ~ U f~ O d' OWn M v0 M v) n O\
N N O N ~O Ov N ~ ~ ~ W N t'i
~--~
4 _ ~ NN NON
N~ONNN~NN~ ~~~O
~ NO~O
N
NN
No M N N
0 N
N
v0 y vi et ~ ~ M Ov ~O ~!1 ~n ~ ~ cfi~t ~n
cn N N ~ ~j ri ri M M N N --~ ~-~N ri
-~ N
v0 t~ 00 et et M N Os M ~ N ~ M O N ~ w0
cn -~ O o0 ~D wj v0 Ov M O M ~n V
~ ' M
~O O O ~ l~ I~ M 01 M V ~ N ~f
O~ ~O v7 O~ 1 ~ I~ I~ M 00 M .--~O~ I~
N oo M M ~ O
.--~ N M N -~ --~ ~ O O M .-r .-, N N N
O -~ O N N ~ .~ O .~ N N N N N ~ --~
O O N N
v~v'7 ~p~p I~ 00
O O O O O O O
M M ~ M
I~M -~ ooN ~ N
N ~ M o0I~ N M
~ ~nN ~nI~ W M
M I~00 M N <t'
00~ M N ~D M
0000~ ~OV~ ~
pp ppO
M M O O
U U
vw D ~ 00
129
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~a
c!i 0
~
, 0
~ i
~ N '-' ~i O ~ ~
.~
-i .-.i .~ O p ~ ,- N N -~ p d: m cn
~ ~ ~ ~1 ~ ~' N l~ ~O ~O v'i ~ ri ri N
V ~t ri M ~
W V s0 ~ ~ p ~ ,~ y0 f~ ~ .-. oo ,~ M o0 Ov W O o0
~ ~ ~ O M ~t t~ Ov ~ v7 .~
O O ,~ O\ Qv O~ l~ O_O O_~ M M ~O 00
N Q ~ ~ x x .-i O~ O_~ ~O O_ M 00 O_O O~
a V'7 M
~ x
i.. .
v~ N ~~ .~ Os ~
,~ ~;
.-i ,-i ,-i a ~ ~ Iy0 ~D v'i ~ ~t cn N ~!) ~ tri
N p O ~ ~ ~ M M -~ ~~ ~ tn M M
N
cn ~ Gv O O O x ~p ~ 00 M ~n O vi -~ vi M N ~D .-.
~ ~ ~ ~_ O vi ~_O ~ O l~
1 a ~ ON ~ N N N N l~ N ~ ~ N
O ~ N O N ~ N N N
a x ~ - ~ N
~ M
~-
~
Ow0 ~~ ~ ao Ov
O ~ " "
~p ,n N ' N tW O ~D ~n ~ cn N ~n ~ V M
~ x ~t cn ri .-r -~ ~ M M N
~
~
'~ ~ M Ov ~ M ~ N
O O O ~..,'' ~ ~Q1" Ov ~ N_ ~ ~ O O t~
0o M O ,(j ~ O p l~ r_i v0 t~ O_ ~
O O
x
N~~ M~NNMNN ~NNO N~~N
x_'-'aaa_ ~ ~N NN
N ~ ~ t~ O~ O Ov
i ''4 ~ c~i N v'i d
~ W O v0 ~ ~ ~ cn ri
i i M ri N
i -
t~
.- c ~ N oo :
~ ~ O x v~ ~t ~ c N O v0 Q~
op . ~n O~ o0
.- :
r ~ ~ oo M v1 t~ ~
0 Ov N ~
vD ri M v~ x O O
a ~' I 0 W O ~D Ov oo
pp ,~ oo ~ x x ~ w0 vn M v0 O N Iw M .~ oo M
a ~ O
N M N ~ ~.j N r"i _ ~ N ~ O O -n N
~ ~ ~ r; wj ~ N O N N N M N N N N
~ V~ ~ M M ~ N ~
l~
N "
.-; ,-i ~D d: ~
'-' '-' '-' \p" oo r v0 vi d: ~ ~ M Cri ri
p O O x O O O M cn N M N N
Ov N '~, OwD m v'7 v1 0o O ~ Ow0
~ x ~ O~ N M ~''~ ~ N oo v0
a v0 t~ N
l a
, N ~O M O~ ~ O ~ t<7 l~ lW O lW
,. 00 M 00 ~O \O O -~ O~
~ M 00
01 00 ~O O~ ,~ ~
N O ~ ~'~ N N r-i '-' N N ~ N N N N N ~ ~ ~ ~ N
~ -i .-i ~' N N M M .~ N
M V
~D ,~
O N O~
i M M N ~ M N .~ M M M N
i t .~ .~ ~O V
, O O O x O O O ~ ~
.- ; ~ ~ ~ ~
,- ~ ~ ~ ~ ~ ~ ~ --n ~ 00
.- h M l~ V7
x W -] ~ ~ ~ x ~ ~ ~ N ~O
~ ~ ~ O
h
O
~
0 o T ~D ~D
~ o N ~ ~ oo ~ Ov
O N N N o N N N
N N ~' ~ ' o ~ ~ N N
': ' M N N N
': ' ~ N N ~ N N N N
~ x
~
. ~
'p ~
.
.
x N ~
O ~ ~ ~
~ ~ -~ op" n ~ ~ ,n cn N 0 ~t ~t
~; ~ O O O x O O ~' ~ M N .-, N ~ M cn cn
O w N
VJ ~l VJ ~ ~ ~ ~ ~' M Ov
t~ I~ M oo " .~ O OW O M ~ OW ~ ~D N v1
~ . ~ M cn ~ O O o0
N
l~ M ~D r1' N N M OWO O M O~ M V~ O ~O O~ M I~
~ ' .-r .~ ~'~ N Q~ OO M I~ O
N N ~ l~ ~ " " N ~ N N N N O N 00 ~ N N ~
N ~ M -~ N N N
~ N N
r.7 x
O N Ov ~ ~ ~ ~
O
O ~ N oo Iy0 v'i ~n M N N ~D ~!p ~
O ~ ~ cn N ~' ~ ,-i M cn ri
O O O N
-i ,-i ..-i ,~ V1
,..~ c/~ 'T'
.a r4 ~7
" r ~ ~ ~ O ~ tw0 N N M ~ D - O v_0
~n twD N " ~ ~ Ov ~ ~''~ ~_n Ov --~
N N ~ O OW M
N N N N ' ~ ~ N N
O N N O O
~ ~ N p N
N vp O ~ N N
M I~ ~ ~ N ~~~~a~~d~
V1 tn N v0 In M N ~~~~~
~~d~~ooo~ooo N
O
~~~~~~~~~d~x
-i .-i .-i -.i a ~ ~ oo ly0 ~n ~n c~i N 0 ~i ~ ri
~~ ~ '~ ra ~ a ~ ~ cn N ~, N --~ cn cn N
w
N ~D O O M N ~' ~D ~t Ov M Ov oo
~ ,--~ ~ ~! -~ ~ p l~ ~ N ~O M v0 M f~ f~
~O U7 t~ ~ O M
00 ~D N O ~ ~: pp _ ~D o0 00 O Ov
N Ov ~ M ~ ~ I~ -, ~O ~ 00 v0 ~ ~ O v0
l~ ~ d' v'1
N ~ N N N N ~ N N N O --~ M ~
N N N N N N O
O O O O M O
"a~~xxax
~
~ M M ~ WO V7 ~ ~ M N N V1 ~ M M
cn N ~ M N ~ ~ ~~ M N
--~ ~--~ I
.. ,-..m ,~ o_o N ~O O t~ OW O n t~ ~n
cW O v0 ,~ O v0 M N O ~ N oo cn O ~n
.--r N vp v0 O v0 OW -~
~' O
N N N ~ ~ ~ ~p O
N ~ M
O O
axxx~~
.-i ,-i .-~ ,-i ,~ ,~ oo t~ ~D ~i M N N 00 ~n V
~,~ N ~; ~; ~ ~ ~n ~t ~t cn cn ~ ~--~ cn ci ti
,_; ~ .-i N
M ~ ~ V~ ~; M I~ O O ~ O~ M N ~O V1 M O~
M V1 M oo ~ ~ ~. ~ M 00 O~ t!~ V7 ~ N M C~
~ ~ ~ ~ N l~ d' 00 ~ Ov oo O 00
~ M W O -~ N OWO N ~ I~ oo
v0 Cv <h ~ Ov
N
N N N ~ ~p ,N M ~ N ~ N N O N N ~ N N N ~ O N
~ N M .-, ~ N M N ~ N M N
O O O O O O O O
O~ O
O
op o0 O~
Ov ~ N
.~ 00 M
O O N
N ~ ~O
V7 M ~D
.~ M ~D
U
C7
' o 0
130
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
. .
o y"
_~ o~ ~; ,~ _- o ci ~_.'.' .~
N N ~ x N ~ ~ N .~ ,-i ,-i O M tin ~_ vN_1 N_ ~~ O_ N °.~ ~ ~ ~ ~ ~ c'~
~" x v~1 N ~O O
-~ Q_s M ~'? 0 x ~ r; O v0 ~ O N O N ~ N ~n CW ~ ~ l~ 0~0 Ov ~ ~ ~ gyp" ~ ~ O
t0/7
N N NO ~ x O ~' ~ N N ~ x O O ~ 00 N M N .-, ,~ N .~ ,~ .-, N l\ x x _.
r: x ,~ N _ M M ~~ N N '~ ~ ~V cn (~j '.': '-~
O . . oo ,~ O
O '~' ~ ' O ~ ~ t~ Iw0 t~ Ov N ~ ~n O oo N
l~ O M O O ~ G o0 v0 ~ ~ a O O o0 v~ O N I~ N o0 I~ v0 v'1 ~ ~ M ~
r, N M m x x O c~ ~D N ~ Ov ~ x N ~ ~ ~ ,~ ~ N o~0 0~1 ~ ~ V~1 ~ ~ y-O-1 C~
'T' .-;
M N N O " ,_; ra ~ N N N ~ ~ ~ ~ ~ ~;,~ ~ 0 O .~ rr N N N M
~~~x~ ~~
N ~ ~ M ~ ~ ~ a ~ N N M M N N M ,~ N ~ ~ O
N N N y0 O M O N N '-' '-' O ~ ~ ~,~ oo Ov t~ 00 ~ ri ~ f~ ~D r
,~ O~ N N O x O ,~, ~D O C~ I~ ~.'? O O o0 tW D ~n ~ ~ M ~~ l~ v1 O O x
N Ov ~ ,n x ,. ,.,~ " M v0 ao M ~ C/~ ~ cn I~ O Vi oo ~.j ~.j ,~ .~ ~ O .~ 0
v0 ~l ~l
N O .-.~ ~ ,..~ N O N N M - v0 O m M ~ O ~ Oy~ O Ov OW ~ ~D M v0
O N .-.r ' W D ~~ N N ~ ~-! ~ ~ ~ N N N ~ ~-~ N t~ M N
n M ~ 0 M ~' ~~ t~ ,~ 0 v0 ~ 0 O~ r
~h N 00 I~ .. .. i-.a M .~ ~ ~ t~ ~-a O~ ~ ~ V'7 d'
N N N ~O t~ O ~ O N N ~ ~ M N N N N O ~O v1
~ M O O a x ~--~ a O~ O~_0 V7 M ~ x ~ ~ N 00 Op0 ~D V7 ~ V M pN .r ~ x x x
N N N oo N ~ ~' N N N ~ ~ M N M ~ oo ~O t_~ t~ cn ~j
NONo~o ~ NO~.~~~ NN~N~~N~NN~oOMM
N N N ~ p a O ,.~ N N ~ O ~; ~ ~ ~ ~ n O ~ ~ ~ ~ ~ ~ O p O x
.-i 'a ~ ~ N ~ ~ M "~i Ov "' N N N N N N p' O O Ov O ~D l~ O .-i a ".~ x r"i
-, N ,~ N c~j .. ,~ .. N N .-~ N ~ .~ O ~ N Ov O N_ Ow0 v1 M O v_1 ~ N op v1
O O ~ ~ '~ V "'W n o0 O 01 ~_D N_ ~ ~ N N N N N NO N N ~ M O O
N N N ~ ~ [-F,~ O ,.a c~ N ~ ~ ,-.a .-r ,~ ,~ O ~ ~',
0o N .~ t~ "'~ ~ a ~ M N cW O ~ ~ ~ p~ ~ oo N O ,~ ~ ~ a r.7 ~ _
M N N N ~rj ~' ~'rj y0 0o v0 ~; N oo N oo O ~ ~ ~ 000 ~ ~ ~ ~ M N
Oo0o0 ~~ c~n~ ~~~NOoNOOO~N WO~O~~O
N N N ~ O x 0 a M N ~ ~ ~ 0 0 ~ N N N ~ N N N N O O O x
00 Ov ~ O a .-i 'l ,-i O Os N t~ I~ ~ a M N
O Ov M v0 N .~ ~ ~ 00 ~f Ow0 ~ M N
M N N N ~ ~ N N O N N N ~ ~ ~N ~ ~ M O O ~ N ".., ~ N M v0 00 0o N_ ~ O
~ O O N O ~~ M ~' M O d' Ov M ~ 00 00 Ov ~ ~p
NNN~,~xa_ MN~~~x~?~~~~~~~M~OMO_00_OV'7~_OOOM~,x~x
v-i t~ ~O ~ ~ ~ N ~O ~i ~ Vi ~ ,.,~~ ,,,,~~ ,,,,~~ ~j ,-:
NNNN~~~~ ~ONONNNN NNn~ON~O~~~ ~~~pNN
r., et O~ t~ l~ M N ,--. ..-~ ~--n ,~ ,~ ~ 00
I~ p oo ~ M ,-, ~ v~ ~t M N ~ ~ ~t t~ ~ O M_ ~ ~ ~ O
N N N ~ "~ x a x M N ~ ~ ~ a a N N N N ON O N OW O o0 ~D O I~ ~ 00 x ~
.. ,~ OW 1 I~ M OW ~ v~ N
vo vp oo N ,--~ .-Wi ~ M v0 <j N ~ ~~ N ~ N N N ~ N
O_ o_o W ~n ~ p ~,~ O v0 N v0 O N ~ ~ ~ ~ ~ ~ ~ N
0 O O ~ ~Q ~ ~ O 0 M N ~ ~ ~ ~ ~ ~t ~ ~ ~t vi t~ Ow.-~ ~ O O O O~-,r
~,~xax . . _,~x O~OOI~~OV'1~MM~,~xxx
N N N ~' N r.i ,...; ~-i M N ~-'~ ...r .--~ ~ ",~ ~ ~ ~ ,~ p~ ~ 00 N M ~ ~O \O
Vl V1 d n~--i .-i
M vp c_~i ~_ ~ ~ .. . . ~ ~ O M .~ ~n M N ~ ~ M N N M N N N o_0 M v1 Ov N oo M
v_0 ~ ~ N ~ ~ w
N N N N ~ ~ M °~ ~ ~O o0 ~O O O O p~~" ~ ~ ~ 0 00 O O
1 CO/1 O x ~ ~ ~ ~ ~ x odo N v'i O ~ N v0 x x
N M o0 W N ~ o ~ V ~ ~ Vi l~ O~ cV W '-~ V1
N N N ~ N ~: ~; ,-i ~ N ~ .-i ,-i N r,; v1 N .~ ,~ ,~ ,~ .~ Q~ 00 l~ ~D V~ ~ M
M yp" N N ,-,
N ~ O V7 p~ ,--i p W N ~ N -~ ~ wj v0 ~W O ~--W~ O ~D t~ OW 1 O ~ M ~ N l~ N
o0
~O N O W ~ op ~ p~ .-~ 00 00 ~ ,~ ,~ O~ O o0 ,-~ (~ ~t ~ WO t~ 00 f~ t~ N v0
00 ~ O N M
N N M N ~ M yp N N N M ~ ~ -~ N ~ M ~-~ N M .~ N .-r -~ ,~ ~ N ~ N ~ ~
O O O O O O p p O O
l~ N M
O ~
M ~-v .-.i
M
M ~ V'7
M ~n ~O
~O ~ N
w
N M
O O
131
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
r'
p ,-i I~ M .-i Oy oo t~ ~!i
.-i M N r.; ,-i t~
O
~ O I~ ~D V'7 v'1 ~1 N N N ~ ~ .-, .., ~ ~ V'i
~ ~ M M N ~-~ ~ .~ ,~ p~ a
N M
M M O N ~n ~
(v ~!1 M ~O O~ ~O M _ M ~ M
[v O -~ N M ~ N tn pv
~ ~
O O ~~ ~ ~ N ~_ oo V N
~O h (_~ ~ N N N ~ N ,-~
N N ~ O N N ~
..
0v ~ v1 M N ~ ~ O
oo t~ ri ~
i O
~ ty0 ~n v1 ~n ~ ~ O t~ ~D
v1 ri ri N ~ W ~n vi
O O ~ N N N .~ ,~ .-~ .~ ~
N .., ,~ ,~ ,~ ....
N ~ p
O
~ O O ~ M_ I n ~ r, N M oo v0 t~ ~_ v0
~_ O Ov O ~ ~ ~ 00 O N N O t
r.; ~ N N N N N ~ ~ N ~ ~ ~ O N ~ N -~ N N N
a O O N N ~ N ~ ~ ~ N
~
UJ
N n
O M tW O ~n v1 ~i ~ oo ~t ~ Ov OW ~ v'i ly0 v1
M ~t cn tn N ~ ~ cn N -~ O ~ ~ v'i
N ~
x O .--~ ~ r, l~ y0 N N N .--~ .~ .~ .-, ~ Ov
O ~ O in oo N ~ .~ ,.--~ .-.r ,-, oo .w0
,p Ov O v0 ~-.~ O~ ~ O ~O O
V7 ~ O ~ 00 O ~ ~ O N
M '~' ~
~ ~1
W
~" -~ N N M .-~ N .~ M ~~ M
M N n OWO O M OW O M N
N M O M
l
N ~
~ . op ~ ,-, M M ~ t~ op
~! ~ ~ N N Ov O
,-; O O N N O N N ~ N N
N N
~ ~
~ ~; t~ s0 v0 v'i v'i , oo ~ t~ ~D
~ ~t ri M M N y ~n
~l o0 Ov ~ Cs ~D O ~ ~ ~" O Ov h vW t ~D t~
O O Ov ~ Ow0 M N ~ O p x M -~
O V
O
x UJ v oo O~ M N N N N ~ ,~ ,~ -m, ~
o0 v0 --~ oo N ~O -V ~ ,~ pv D O o
M O o Ov
O
_ ~ _
_
Ov Ov v0 ~ Ov O M I~
l~ t~ M t/~
dyj N O .~ .~ N --~ N N
N ~ N N
O oo IWO vi vy ~t ~ ~ ~ ~ O~ O ty0 v1
O ~ ~t M M cn N ~~ ~!'i
~ x
p . .. V] ~O O
,~ 00 0o ri oo M c~ ~ O~ ~ ~ V1
U7 O W O t~ N ~ ~ N O OW ~ in ~ M 00
~ v Own f~ N ~ O ~
l~ N l~ M M M Ov ~ 00
O OW ~
-~ I
~ _ N N N N ,~ ,~ ,~ r, _
.., ,~
M ~ N O Ov ~ cri M
O O ~ ci o0 0o v0
o00 N N v0 t~ OW O V1 M
~ I~ O~ ~n o0
M ~ N ~ ~ N N N N N N N
O a0 I~ ~D W V1 ~ -~
d~ M M M N ~
~ ~ y0 O
~ ~r ~ M O~ M l~ M ~ ~ ~ ~D
00 00 00 N ~
v O O ~ 00
j t~ Ov
r., W O y N N -~
M ~~ Ov M ~n o0 N v0 ~ ~ N O OW ~ ~n ~ M
~ M ,-, oo N ~ O N
N N N N O N N N N .-.n .-r rr
~ N O vp ,--i ,~ ~ ~ .--i
~ ~ ~ o0 OWn
~ ~
D o
O ,-i _
O O 00 l~ ~D ~1 V1 ~ _ IW O
O ~ M M M N N M N N N N N N ~ N ~n ~n
xi M ~ N O ~ N ~
a M ~ Ov ,~
~ ~ ~ ~ ~
~
'-'
,--i ~ ~O ~ o N ~D
'-' 0 M ~ N N t~
-i N
. N -~ --a N O N N ~ N O ~ N N
N ~--~ N ~ O ~ M N
~
O
b O
n O ~ Ov cn
M Ov ~ oo N
O o0 fy0 ~ V'1 ~ ~ ~D ~O IW O ~ O W O IW O
x M M M N C OW O W O ~ ,~ v'1
v~
. .. cG N ~ ~ ~ N N N N N N
r.; ~n ~t N M O ~D ~O N N ~n
~ o0 OWn t~ ~, ~~ N M ~
v M ~ ~ ~ ~ p s0 M
~ .. ~ N N
0v N oo v ~ O
O Ow, ~n O
_
_
_
~ ~ ~ ~ O
~n N ~D N O Ov o0 v0 ~
~p M N ~ O
"~ N N ,~ ~ ~ .~ .~ ,~
O ~ .--~ O
~ M
O O O . N oot~~iviV
xax~ ' MNW ~nOVNImnO~OI~~x
iNE'-'
i
n
~
op 00 .~ ~ ~O ~ ~ t~ ao ..
~ fy0 ~n O O ~n O v'1
~ c N N N ~ N M ~ N N N 00 N
c N O N v1
!7vl~~c ~ ~ ~ WO N N ~
.. ., N N
I~ l~ N l~ V7 N
Ov O~ 00 ~ .~
N N N ~ ~ N O~ ~O
N ~ p N
_ ~ ~ ~ ~ ~ ~ 0 o
O O M
~
~ O
O O ~ ~O ~1 M N
t~ N O Ov o
O
M N N N ,~ ,~ ,~ .~
~ ~ .-~ .--n ,~,
~ Oy v0 vi Sri ~ ~ ,n ,~ ~ oo ~ t~
~ M M N ~ O c_n W W
.. v0 .
. v0 O ~ N O~ ~ ~j ~
a ~ ~
~n ~W O tW0 Ov ~ ~ N ~ N ~ ~
~ ~
~ ~
~ ~ ~ _o ~D _
N c N o _
~ n O v0 M
O N I~ ~ O oo t_~ O M
_ O
O O ~ ~ ~ O ~
O ~ x t~ f~ N O ~ oo t~ Vi
v7 M N
~
.-i Os I~ ~ vi v'i V M N N N - ~, .~ .~ o0 t~
,-i ~ ~ cn ri N ~ .~ ~ ,~ ,~ p~ M ~n v~
r; ~t
~;
s0 v~ W ~ ~ N ~ t~ Os N M v0 v'i Vi M N M
~n O ~n ~D M v~ .-~ N M t~ ~ W t~ O
O~ ~ I~ 00 00 l~ ~ O O a0 ~D ~D N OW ~ D Qv
M l~ ~O OW O Ov O --~ oo I~ ~ Ov N I~
O~ f~
M ~ --~ N ~ N N ~ N M N ~ ~ N N N N ~~ N ~ N
N ~ O ~ ~ ~ M ~ N ~ ~
~
, O O
O O
O
p
O
M
O
O
O
N N O
Q
O
O O
132
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
M
~' ~~ ~! ~ '-: O ~
-;
Ov ~ N ~ ,
n cn M N W O ~
t ri ,~ --~
ri ~
t ~
N ~ ~ ~ n
M
~~ N ~ ~ ~
c ~ ~ ~.~. v
WOI~NrO~ c 1 c
~ _
N ~~M~xO
,
_,
~o~o~oMOMM~o00~p~~xONa
NN~NNNM ~N~NNN~NN~~ ~~~~~O
~~ ~x
~a
~
_ _
_ ~ ~ O ~~
_ O
p Vmlj "" Ov ~:
d; ~ M M ~ vD W ~ ~ M M N N ~ ~ ~ '~ _
M N ~j ~ M ~ ~ ~ ~ ~ '~ ~
O N
I~ ~O N O O\ ~ N M l~ u1 ~ 00 M ~ O O ~O O M M
01 O~ ,~ O O M ~O O O
~t OWE O
N ~D N v0 ,-r v0 00 00 00 O N ~D I~ ~ O
x x x x ~ O "'~ x O
N N ~ N N ~ N N M ~ O -~ N O _~ _~ _~ N N ~p VJ
N O ~ _~ ~
x N
~ ~
H ~ ~ Ov O ~ ~ O N N O
~ ~ ~ ~
~
O
<"~
~t M M cn 7
N ~''~ N
N v0 ~n ~ V cn m N N N
t~ N O O ~D N O N ~ t~ Ov - O ~O ,..a ~' '~ O x
M vi ~ C/~ ,..] O r.a O
V1 v'7 ~ 00 ~O ~D ~ ~a M O~ ~O M l~ ~O O~ ~ a
O~ M O~ x x ~ ~ a ~ C/~
~
N N N --~ N ~ N N M N - N N a ~ N ~ ~ N N
N ~ ~ .~ ~ ~-! O N M ..
00 l~ I~ .. ~
~
~,~~_~~,~
cn cn c~i ~ sD v1 d: ~ ci M N N N v0 N ~' ~ ~
N ~ ~ O ~ O ~ ~ O p ~O
''~
"~ a r~
.~
0
n M
O
~
~
Ov N_ N v a ,~ .~ ~
~ O~ .-r . i
N N N ~ O ~ N ~ N
~ ~
I
~_--~
~
.,.~
; ~' r'
~ ~'i
~ N ~ ~ N N ~ N N O N
_ .-
r _
vp ~ O O ~ Ov O ,~ t~ ~ oo
O
O
~
yt cn cn N s0 ~i ~ d~ ri cn ri N N ,r N ,-i ~O
ri N ~ O ~ O O O ~ O O b
0 ~ O M cV v0 a
~ -~ 00 ~ O lw0 ~ ~ O d' ~l Cn ~
'~' ~ ~ "~i
M o ~~ ~n 'n
00 ~ l I~ ~ ~O v0 ~ N OWE O O N ~ cue
O ~ ,-i ,~ ~ .--~
a0 O v0 Ov
M Ov O
N N N N O ~ ~ ~ O N ~ N N x M ~ ~ ~ ~:rjO ~ ~
~ ,=-Wp x ~ in Ov
~ ~ ~ ~ N
~
N
O Ov
d' ~ ri ri -, ~ ~ N ~ ~~ O
M N ~ ~p , a O O
O ' ~
N ~D v-i V7 ~ M cn ri N N cYi
O E-~ ~ x r."~ O '~' ~.'
a
a
O I~ N M ~ O ~ ~ ~O N N ~' ~ N N O v0 v0
O~ O M ~j ~ ~ ~ ~
~ 01 00 O~ ~ ~ij O V'1 .w
00 ~D 00 l~ ~O ~D 'O 00 .-r M ~O M O ~
M ~' ~'V ""~ ~ '-; ~ ~
OW
N N N ~ O N ~ N ~ N N N O N O _
N N ~O ~ N ~ O x _
_
~ ~ ~ Q'
v0 ~t
O O O ~ O ~ ~ O
d: V ri ri N ~O v~ ~ ~ cn M M N N ~ x N ~ ~ O x
ri N ~ '~ x x x ~ ~ ~ O O
~ oo M j ~ ~-) t!J
~ ~ ~ a
oo -
- v~
~
W 'i
N l~ t~ O .~ ~. ~
t ~ -
,~ 00 M Ov ~ r.; c0 N .
O ~ ~ O , N o0 ~D ~j
- ~' ,-; ,-r
v~ M N O ~O
O
N OW O N o0 Ov M O O~ ~D M
.~ ,~ .-w ~ ~
N ~ N ~ M N N N N ~ O N M ~ O N ~ M N N '~ '~ N
N N ~ ~ ~ ~ ~ ~ 00
N
'et M M M O O O ~ O N -~ .~ a
N N ~ N I~ ~ V't ~ M M M N N ~' x '~T'~,
'T' ~l ~l ~-~, ~ x ~
~O v~ ~ O\ ~ l~ M o0 ~ O l~ ~ V~ ~D ~ \O o0 t~
00 ~' l~ ~rj N ,-i ,-i ~ r"~ ,~ ~ ~ ~ ~
,.., 00 ~O 00 O OWE M O O~ "'' .. ~ ~p ~ N
M N O~ 00 ~ ..
~1 M N ..
N N N N N N ~ N ~ N --~ O N ~--~ ~ ~' N ~ N ~ ~
N ~O ~ ~ N M op ~ ~p ~~~
p ~ ~~~"T'OOO~OpO O
~ ~
x p0
M cn ri cri ~ x x ~-1 '~'~ V~ ~j ,-i ,-i
N '"~ N (W0 yt d: M cn N N ~ ~ ~ xr
O N O ~-~ N OW Owl .-m0 Ov ~ N N M N N O ~ nj
~ O N ~' ~ ~' ~ ~ '-: ~ ~ ~.; ,~
N ~O M ~ \O M 00 V'7 -~ M N t~ -~ ~n N N N ~"~
M M ~ p ~n ~D ~j ~p N ~ ~ O N ~O
NNONNNN~ ~NNNOMN ~MN~MmN~.,~~ ~ O~'N
~
~~~~~~~ ~~~a~~a
~~~xxxa~axa
"
cn cn ri _.. ~ 'p N ~" .~ ~
M N ~ ~!o ~ ~ M M N N ~~ nj ~ ,-i ~ ~
M ,-i ~ .-i ~ <j t~ Vi
M v7 O N r.
O -! ,
N 0 O
v M ~. ,~ '
O v0
O
_ ~ . _
~O 0
v v O O
Ov v
M _
Ov
V
O
N
N O N N M ~O ~ N N
N ~ ~ ~ N ~ N ~ N ~ N O ~ N ~ ~~~a~
M W
~ ~
~
~
cn M M ri r ri..
N .-i r --
-~ tW O Vi ~ ~ cn cn N N ~~
~ N
v~ oo ~D ~n M ~t M d' 00 0o OW ~ N v0 ~ V1 ~ N
t~ M ~D p O O N t~
v0 op M m O O
vW ~ 00 0o ~ ~ ~D ~ y0
M N v~ ,~ M I~ N
O ~~ N N ~ N Ov CWO ~n N OW ~ t~ N N N ~ N ~ ~,,~
O N N M m oo W O o0
N N N N - N N N N N N ~p vp
M ~. ~ N ~
O O O O O O p N O O O O O
O~O l~ 00
M M
O O~ l~
~ O N M
M M I~ M
N ~
00(~t~ ~O
O O 'n
M M M
pr
O O
133
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ ~ Oy vp ~n ~ O o0 fy0 vp V'7 ~ ~ M .-N-~ ~ ~ ~ ~ ~ N ~ .-N-a
O~ oo M v0 N O M ' ' Ov O ~ .. v1 O ~ N cn ~t
0o I~ 00 M ~ M V~ N ~Y ~ 01 O~ ~p ~p N ~ M O~ M ~ ~ ~'~ ~~ O r O ~ N v7
.~ N M N O M N ~' O o0 N N O_ ~ t_~ ~O M t_~ O_WO vD O O x N ,~
C~ N x N
~t Ow0 ~ N ~-~ O M O ~ O~ l~ ~ ~ 00 ~ ri
N r, .~ ,~ r-, .-.i .-r 01 ly0 ~D ~ ,-, ,~ ,~ 00 I~ ~O ~O ~ V1 ~ M N N_ O ~O
l~ N .-~ .--i
v0 v~ vy0 O O ~ ~''~ Ov o0 ~ v~ ~:rj ~p N N f~ v~ O_v ~ o_o Ov I~ oo ~ M E--~
N a W O ~--~
NNQNOONNN~NO ~N~Q'I~N~N~N~NNx"a.~a""; NNON
M
N ~D N
~ OWO ~ N ~~ O OWE ~O s0 p ~rj p N oo ty0 ~D ~!'yn ~ ri N N p O ~ ~ N Ov M
N .~ ,-v .-r ,-n ~ ~ ~ t~ t~ .-n N ~' "'i N ~_O ~_ O t~ ~ I~ ~ ~-~ 00 N O x N
~"a ,~ M
N ~ N N N ~ ~ ~ M M N ~ N ~ N N ~
N
O~ I~ ~O ~O V1 00 I~ ~ ~O ~ V'1 ~ M M M
~ O I~ ~t ri N O ~ ~ ,~ O I~ ~ O N N ~~ O ~ O M ~n cn O O O x a '"~ ~ N ~_ ~_t
N N ~ ~--~ .~ .-, ,~ O M h f~ ~-~ ~-, ~-, p~ t~ Ov CW '7 O~ O M O
N o0 l~ ~ O "~ N '~ '-' N vp N ~ ~ .~ N N N ~ N N ~ '-' ~ ,~ c6 y~ ~ V1
v0 v1 v0 M I~ Ov ~ 00 ~O ~ l~ N
NNNNNN~~~ ~ N~~~ p~pMMO~M NON
Ov o0 (~ s0 v'i N o0 t~ t~ ~O ~n ~i ~ M cn ~ M O ~ O ~
.. . oo .. . O N x O v7 O
N ~ ~Wn ~D N ~-'~ OWn O ~n ~ M O ~'~7 x ~l
..~.i ~ ~ ~ ~ 00 I~ O ~ ~ ~D O ~ N vp Ov O 00 I~ ~!1 Ov O ~ ~...-n ~ .~ x M Q
vD O ~ 00 Ov ~, Ov oo v0 ~ ~ ~ ~ O O ~-M-' ~O ~ ~ O_~
N ,~ N N ~-a N ~ O pp" l~ l~ ~O ~ ~ ~ M M O ~ xi O x
~ M ~ O ~ ~ N N v1 N o0 t~ M oo ~O N x ~ - ~ ,.~ U1
~O O N C~ ~ I_~ WO ~O ~D M ~ 01 M ,-; "'~ .--r
v7 O l_~ ~_n M_ N_ O_ N N N N N ~_ O ~ N N ~'-~ N O ~ ~~ N N ~j v0 ~~ N O ~_
ri ~ I~ N Ov oo r, .-, Ov ~ ~ M ~ ~ ~ ~ oo N
~O ~ ~ 00 .-~~ ~O M O~ 00 V'7 Q p Q p N ~D
N N -~ N N N ~ gyp' ~ ~p~ Vj .~ N N ~t pp" ~ ~ ~ Vj ,~j ~ ~,j wj M ~ x O
M ,-, v0 O O ~ ~ ~ M ~ "~ Q M O ~ ~n O ~ "" ~ a ,-i
O N N N ~ ~ _ O -~ N M N M M N N N O vp '-'
.ON.'-' ~~QO~OM M(V
v7 M v7 O~ ~O M O l~ ~O ~ O x x O d'
vG ~ 00 Ov N O N Os o0 tW O V'i N N N O OO t~ t~ ~O ~ v'i ~t M M
~n N N N ~~ y0 ~ O v7 O o0 N f~ Ov
OW ~ I~ ~ N v0 OW ~ 00 W O t~ ~-~ M N
N N ~ N N O O O O N N N M p
~ ,-~-n .~.~ .-Nr ~ ~ ~ N ~~'r ~ ~ ~ O O O O ~ c'Mn N ~
W O ~ ~ O N cn ~ 00 I~ y0 V7 ri M oo s0 pp" t~ t~ ~D y0 v1 ~ ri cn x ''T' x V7
x a cn N cn
M O1 M l~ f~ O~ M . . 00 ~p l0 .. . ~ ,~ ~ ~ ~ ~O ~ ~--n
O ~ N ~~ N ~ N ~n M t~ ~ d' N N ~--m0 M ~t v0 v_0 ~wD O~ N ~j '.'.' .. .. .. ~
-~ N N
N N N N N N ~ ~ ~ N N N N N N N N N ~ ~ V ~' ~ M
N N o0 Vi ~ N ~ ~ ~ Ov ~ O ~ ~ ~ ~ ~ ~ p O x x x O ~ cn ~n
~x
M N ~w .-r '~ ,~ '~ ~ 00 l~ ~O ~!1 <h N .~ ~' 00 00 [~ ~D ~O ~ ~ ~ M
N M .0v M v0 M Ov . . V~ 00 M .. ,~ .~ ,~ ,-i ~ v7 ~ cn
~ t~ N G~ -~ ~--~ 00 00 00 ~O Ow0 v0 M V7 ~O d' N ~n l~ N Ov O ~'~ O M '-: ~_O
N -~ N N M N ~ 00 O Iw0 'O ~ N N ~ N N ~ ~ d' OWE O M ~ ~t ~ M ~ M M
N M ~ ~ N N ~ ~ ~ N N N N N ~ ~~ N ~ ~ N
.~~~~~~ ~~~~~~~~~~°°ooo
oNO ~axxxa
N .-i .--n .--v .-i ,~ ~ 00 l~ ~O V~ <Y M ,--a ..~ 00 00 l~ ~O ~O V1 ~ ~ M
~.,~ .~ .-i .-i .-r ,_; M N ~--~
M_ vD O O~ (~ v7 I~ l~ 00 ~-i I~ M M ~ l~ v7 ~ Ov ~ l_~ Ov M M_ O_ ~O ~ O~ M
~O N 'p N ~!7 N
MONNN~~NNMONNN NN~NONNNONNN~~~M~~ NNpN
p O O O O O
~~ D N
.-'i ~ N ~ N
M ~~ M ,~
D ~t ~ ~t N
0~0 ~O ~ ~ ,M_,
y~ 00 00 ~p
N N A ~1 >
U U
ov o
0
134
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
00 0v o0
p ~~ ~ N r-i ,-i
M
"'w N " ~ .-w '-' ~ N '_.' ~ O ,-i
v0 v0 V7 .~ M N N ~ VW~ N ,_-, ,~ ~, yD v0 vi ~ d M N N
r Ov O f~ ~D vi t~ ~ "., oo ~O .-~ N N Ov ~ '~ O O
N ~ ~ Ov ~ oo v0 ~ ~D oo x O N N ~ M p~ N N N ~ N O N ~ O M ~ O ~_ a_
N N N N N N ~ x ~ ~ ~ ~ O .., O .-~
.. ..
~ .~ ~ a ~ N N
I~ ~D ~n ~ ri cn N ~-' O ~ N ~ ~ .-~~ 00 f~ ~D Vi ~ ~ m N N ~' ~ O O
a0 .., [v O O M ~O O x M ,ri ~ ,-; p~ Q1 ~~ M v) N OW t ~' ~t 00 M O x a
,_, 00 v0 O Ov l~ M 00 ,~ O M .--m0 O M (~ .--~ 00 iW0 O_ O~ I~ t_~ ~O ~ ~
N ~ _..
N ~ ,~ N N N N O ~' M ~~ ~ ~ ~ ~ p ~ ~ ~ ~ a ~ N O
-i I~ ~O ~n ~ cn ri N r-! p ~ M v0 N ~ ~ °,~ IWO vi ~ ~ c~i N '-' N ~
r,~ O O O
'-r I~ ~ a0 00 Ov ~n ~O ~~ f'-~ N N ,~ .~ ,--i [~ M M ~O O ~ ~D ~ M cn ~ p
Ov ..~~ ~ N ~ N N ~ N --~ "'~ cV dwn Ov oo M O ~ ~O M ~n ~ '~ OW ~ ~ " "
N Ov ,~ .-, -~ N N ,~
~ tWD v7 ~t ~t cn N ~ a ~ ~ " 00 f~ ~O vi ~ ~t ri N ~ N r-i ~ ~ O x
~" M M ~O ~D M M 00 t~ N M t~ N ~ O~ O ~~ O~ 00 V1 t~ l~ N ~ t~ O x
'-' Ov o0 ,~ I~ I~ 00 ~ N ,-i ~ M N .-r ~ ..r o0 M O Ov ~t o0 M ~O ~' 00 ~O ~
r~
~ ~ M ~~ N N N ~ _~ ~' pp ~j op .~ ~ ~ N N N N -~ N N ~ N N t~
N Ov ~ ~ l~ O~
.-r O
Iy0 N ~t ~ M N ~ x ~ G o0 lW0 v7 ~ d; M N x (V N ~ ~ x. x
~ ~O t~ ~ M ~n Wii v~ ~ a ~ ~ ~ O o v~i ~D ~n v~ as sO ,~ vi os c~i ,~
oW ~ ~n ov M a~ oo ~n ~-~ vi oo ri ~ .~ p~ o t~ ~n t~ t~ ~O ~t vo 00
~' ~ O N N N N N N O " ~' N ~' ~' ~' ~ M N ~-~ N -~ ~ N ~ N N N ~j
N N ~ ~ ~ 0 ~ ~ N N ~ N N ~ ~ ~ ~ ~ ~ O
(y0 wi ~ V ri N ~ VJ O O ~ oo tW O ~1 ~ ~h cn N ~ cn N ~ O x Ul
Ov ,mn ~ sG o0 N O_v ,-i a a O N_ ~1 00 .-m0 v0 cn N Ov ~ t~ ra " ,-,
N_O_~NNNNN~N ~t~"~ ~~_~_"~'_-'O_NMNNNONNo00 ~~NN~O
00 N ~ ~ ~ ~ ~ ~ p O n M ~~ N vp ~ O v1
v0 Ov o0 O N t~ vW O t~ ~ ~ ~ ;1,,
tW0 ~n wt ~ ri N N ~ ~ ,.~ N '-' N '~ '~ 00 IyD v»t ~ ri ri ri N ~~ O x x
0o N ~ O V1 ~O l~ O '-' " ~ ~ O ~ 00 t~ l~ M Ov o0 M N v0 M '~ ~ .-i
O~ ~O 00 M w O M ~O ~j '-i '~ oo .~ O~ t~ ~ v1 ~ ~D N OwD o0 <.j
N O ~ N ~ N N N N N ~ ~ pv ~ ~ M ~ ~ ~~ M ~ N N N N N ~ ~-~ N ~~ ~ N M
O V1 p O~ ,--i ,--i V'U'~i ~/1 ~ ~ p O
cn N V1 ~ ~ O
t~ ~O v1 wi yt M N N N ,~ "~ ~ N N ~ N oo l~ ~D vi W ~ cn ri ~j M N ,~ ,~ x x
Ov O M M o0 O O_ wt _~ .~ O I~ N Ov o0 0o Ov O ~ v1 N O
OM~~-,NNNONN~ f~j~ NO~~ONNON~ O~OI~ .N~.
°°o
x
0o vD ~ ~ ~ M N N N a x N ~ ~ ~ ~ 00 IyD v0 v'i ~t cn M ~ cn N ,-i ~
N N ~ Ov V O ~ Ov oo sO o0 ~-; ','.' N N N N ~ M N t~ O v0 Ov N M v0 ~--~ M oo
N
pN N ~ ~ N N N N ~ O N ~ ~ ~ ~ ~-~ N N N N ~ N N ~ ~ N ~ ~O
N O ~ ~ ~ ~ ~ ''a O O o0 O ~ N O ~ ~ ~ ~ ~ ~ O O O
~ ~D l!1 ~ et M N N ..-~ ~ x N N ~-n ~ .~ ~ ly0 ~O ~ ~' M M .~ tri N ..-i "'~
M O ,~ r; ~n s0 O Ov ~ .. ..
~ I~ OW D ~ N ~O M o0 N v0 Ov ~ I~ O ~n O ~ M O ~O ~D M ~t M v1 N -~
O ~ O_~ M M 00 O_~ O ~O M in v~ O ~ N ~ M N o0 Ov o0 O ~ N o_o O t~ N w0 Ov O
O
M f~ M
~ O O O O
~ ~ ~,~~x
N O ~ cV O
~ .-., 00 ~O V7 V'1 <t M N N ~ ~ ,~ M N ~--~ ~-r ,~ Oy v0 ~O V1 ~ ~ M N ~ N ~
N .-i .-i
Ov Ov Ov M ~t O ~ N Ov ~ oo ~j ~ W O N O ~-i ~ Ov ~ oo O t~ M N M ~--~ vy,~ ~t
cn
O 00 M ~ M ~D ~ V1 ~O ~O ~ O ~ ,~ ,~ Ov ~' ~~ 00 V7 N l~ ~ I~ N M O ~ O~ I~ ~
00 00
M O O N N O ~ O N O N ~ 'p N M .-r N N ~ N N N N N N N N N N N ~ M O
O O p O O
M N ~ V7 M
N ~ ~ N
M ~ M M
00 N 00 O
M ,--i ~ ~ l~
N ~n N I~ in
00 ~O D\ ~ ~O
~p ~ 0~0 ~ 0~0
N M
r,
135
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
_ ~ _~ .--i
O v0 M N ~ h W M O ~ Ov ~ ~
0o N °~ M ri N N N ~-! ~ ~ N ,~ ,~ ~~ ~.-W~ 00 tW D y0 vi ~t N M ~
~p~~" ~~°ooo~_"ooxooo ~_vho~_a~~'°~~~oMOO~"'~,ah°°
x ~~~d~ ~ a
~
O°N~ N ~ cn N N N ~ p ~ ~ ~ ~ ~ ~ .-~.r N o0 Iy0 v0 W ~ cn
O M v0 O <t v0 cn x O O ~ ~j ~ ,_; op ~~ oo v0 W O ~ t~ N O a
a M .-mn O ~ M a O cy h ,.., op ~ ~~ ~~ O v~ ~O N
O N N N N c'n x ~ x N r, M rr N N M N N O N h ~ ,~
0
0
h ~ N ~ ri N N N ~ O ~ ~ h o0 ~ c~i .-i p ~ Iy0 ~D Vi ~ c~i "a O O
a N ~ v1 O_ ~ N oo ~ O a p ,~ ,-, ~.r ~~ ~ ~ ~ ~ M v~1 N C~/7 a C
,..; ~ ~ N N M ~ Ov OM ~ ''"~' ~ C~ N h N Ov
h ,..., h h O N N O N N O N ~ ~
M rj ~ ~ ~O Oh .~ M O M M
C/~ ~O ~f1 M
p N N ~ ri N N N ~ a can ~ N ~ N oo t~ ~O v0 v~ ~ M p O
a ~ v1 00 N T N ~D ~ ~.] N O V7 M ~_
N v1 Qv ~ 00 M o0 ~ ~ a N
~' O ~~ N N N N _~ .--~ _ ~ ~j ~ p N N N N N N ~ ~O ,_,
N ~ ~ ~ O ~ ~D N ~ ~ N ~O .. h ..
O O N y0 N
O N N wi M N N N ~ a ~ O ~
M_ ~ ~ M I_~ ~O C/1 a ~ O~ 00 O ~O 00 ~ ~O Vj x C~
p M N N N N ~ d' ,~ ~' a °N \O ,-M, ~ O ~ O N Ov O N ~ ~ ,-; .-i
O O
N N vi cn N N N --~ ~ a O r; N o0 tW O v0 v'i ~ cn v1 ,,0~, x
dyD ~ N M h O~ ~ ~ a ' ~1 O ~ 00 ~i o0 M
O N o0 N h ~n ~ ~ ~' ~ h ~ 01 ~D o0 v1 M h ~
M o0 N ,-, M .-w0 ~ N ~, N ,~ N N N O h N ~:,
,n N N N N N N h ~ ~ h N
O O Ov a ~n M v1 -~ ~ ~ a ~ N
O
N vi M N N N ~-! ~ V] a ~ 00 ly0 ~D V7 ~ M M a r~r a
y0 M ~ ~ ~O M ~ ~ M M N O~ h O~ 00
~; ~ ,~ h ,~ O~ N ,~ M N .. ,~ .-r ~ h ~D v0 v) N M ~ N
MNNNNN~ON~~~ N~~N N~NNNNN
N ~ ~ a ~ O vp ~ vp W_ O c~ Ov ~ ~ ~O p O
~ vi M N N N ~-! oo a ~ ,tea a N N N O ~ oo h ~D v0 ~ ~ ~t ,~ x x a
chn M WO O N ~ "' "" h ono oNO vp ~ ~°O cNn o0o N ~-s ~-;
~ O ~ N ~~ N N O N oo ~ p N ~p N N N N N N N O p~ M N
p ~d ,~ r-; ~ ~ a O O ~ O N ~ ~ ~ ~ ~ ~j h0 O O
r~r c~C N n v7 M M N N ~ ~ ~ x '-~ a ~ ~ ~ ~ ~ 00 ly0 ~D ~ ~ ~ N ~-1 x r~r
~ ~ N oo ~ -~ Ov N N ~ ,-, N N ~ N OW Ov h O Gw0 p N ~ ,-i
N oo v0 MO N O yp Ov ~ ~ ~~''jj ,,,,~~ N ~-~ °N N N O O O ~
p 0 ~ ,-, ~ 0 0 ~ 0 ~ h ~ N O ~ ~ ~ ~ ~ a 0 0 0
ax ~~ _~ax~a N~~~~ ~aHx
-i .-i ~ ~ ~ M M N N ~~ ~! N ~ ~ ~t M M N M ~ IWO ~D ~ ~ ~ N N ,~ ,-i
N ao ~n ~~ ~ s0 h W ~ --~ N ~ ~O ~ M O ~ O M h ~D
v0 N ~ tw0 00 00 ~n Ov N ~ ~ h O N N M ,-~ N C~ Ov ~ h O o0 h N Ov ~-~ h
O Ov -~ O N ~ N N ~ M N O d~ ~ ~~ N N N N ~~ ~ ~n ~n o0
~~~~d~a'~~~xxx,.°aa ~~~~~~~~~~~~xa°a
~ c~i . .. ,~ oo ~ ~ cS o ~
--s .-r ~" ".'~ V1 M M N N ~ ,~ N ~a ~-.i .-i N ,~ .~ ~ ~ p\ 00 ~O ~O V1 V~ d'
N N
OWO N N v~ 00 ~ W jj p ~ wD Ov W O vD M O ~ ~ N oo
~ ~t O ~ Ov Ov O v0 ~ ,n O ~ O h h ~D v0 h Ov Ov oo Q~ M o0 0o N ~ h h
N N N N -~ N N ~ N r., ~ M N ~ ~ ~ N O N ~ N N ~ ~ N ~ ~
O O O O O O O O O O
vp N h o0 O~ ~n
~ ~ N
M ~ M M M
(~ ~ ~ ~ N ado
00 N o0
N ~ M M h
O ~~ 00 t~
l~ V1 M 00
h M M M M ~O
W U U U U a
136
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~° r; 00
N ~ N ~ N O .~ t~ vW O Ov
N ~p
cn ..m N N N ~ x '-' N_ v0 ~ I~ t~ vD ~n wi ~ ~ d cn N ,~ .~ ,-, ~ ~n ~ M N
0o O v7 O oo M W O O ~ M v0 M O W D V M_ v0 Ov O_v ~ ~ O O ~ M
N N N N N N ~ M Q "x p °~ ~ N O ~ N N N N ~ N '~ ~_ N ~ N N M N N
N N ~ ~ ~ p
d; cn ri N N N ~ x n p O ~ ~ t~ t~ ~D vi v~ W ~ d ri ri ~ t~ n l~ ~! ~ M N
~OOmn(~~~~00 ~OaO 00O~~Ol~~OM~ ~MM V7NO MOO~00M
01 I~ I~ IW O O M ~! O "~[,' ~O ~D O~ M ,--.~ O ~O t~ 00 N ..~ r., ~-r O~ 00 ~
~D ~D ~O
op O -~ ~ N N N N ~ a ~ .~ x ~ N N O N M N O N N N ~ ~ ~ Ov N M N N ~-~
00 M ~ ('n N ~ ~ N N ~ O
'Q ~f d: M N N N ~ ~ O ~ l~ l~ y0 ~ V1 v7 ~t ~ M M ~ ~ "
I~ I~ t%j ~ 00 d: O ~ a O l~ ~ 00 v0 V'1 O 00 V'I ~-V d' ~ V~1 ~ M M
Owe ~D O ~ t~ 00 ~ x x ,-i 'x W _O O_~ N ~ I~ ~ O ~ ~ ~i O oo ~ Ov O O o0
~ N N N N ~~ N ~ ~ ~ ~ v_~ M_ O O~
M pp O Ov
N ,.p..~ N M °o M W I~ oo Q N O N N
d: ~ c!~ N N N ~ p 0 x ~ ~ oo f~ W O ~n vi ~ d: ri M ~--~ N ~ M
Ov oo v0 l~ OW n M ~ O Q ~ O v~ v~ ~ N v0 N O .-. ""' ~ ~ ~ O O v0 0o N
M ~ ~ ~ N O~ M ~ C/~ "~ ,~ ~ ~O O I~ I~ OWO ~~ M ~ t~ M 00 ~O d: M M
O N M N N ~ O M ~ ~ ~ ~ M ~~ N N N N ~ ~~ ~ " _" N N ~ v~ o_0
p ~ ~ ~ ~ ~ ~ 0 ~ ~ ~ ~ ~ ''"r' ~ ~ ,~ ~ N ~ N N N
V7 ~ M N N N ~' v~ O p ",I", O _- ~ ~ I~ ~D v0 V» ~ d; M M ,~ ~-s ,--WO Ov
~' ~ ~ oho ~ N ~ ~ ~' Cn x ~; ''~'. 'p ~ oN0 ~ ~ O ~ ~ ~ ~ o°~o N ~ 00
0o N
~' N N -~ ~ N .~ rr M
a N~ M ~ ~ O ~ ~ N N N N N N N ~-~ N ~
_ 00 .~ N O ,~
O ,T, N ~ ~ ~ ~ O N N
~ v1 M ~ O
~n ~ ri N N N ~--~ vi O O x O ~O ~ oo t~ s0 ~ vi Vi V ~ ri ri .~ r, r, ,~ ,~
O N N ~~ ~ l~ ri I~ ~ ~ ~; a ~ OWO oo W O ~ Qwt O o0 O Vj N M .--a
l~ N t~ I~ Ov M ,~ ~ ~ oo ~ N Wn ~n Q~ O Ov o0 .-, ,.~ ~ M M ~." irj Ov Ov N
~' .~ N N .~ ,~ N N I~ N '-' 00 '~ .-y O~ O N N O N N ~ ~ N N N M "-, O N op
~O ~ c.n M
N ~ Q ~ yD ~ can ~ WO
'-"' ~n ~ M N N N ~ ~ O O x O O '~ 00 Iy0 ~ ~n vi V ~ M M N p yp" O N N N N
M t~ O O T N t~ t~ '~ x ,~ a x ~ 00 ~ ~D ,-, U1 ,~ M O I~ 00 N ~ ~
N ~ I~ ~~ O ~ t~ N cn nj -~ l~ I~ M ~O O~ M O~ O 00 O I
N N N N N M M ~-~ N ~; ~ ~ ~ ~ ~ ~ N N N ~ N ~ N N M -~ op nj vj op ~ ~.,~ ~
p" N
N N N ~ ~ ~ Ow0 t
v'i V cn N N N ~ -~ gyp.] ,.p4 x ,pa p ~ ao tW O v0 p ~ ~ d: cn c~i N ~ ~ ~ O
v0 0o OW
.. . .. C/~ r~ . . ~ N O O N
.~ v1 N ~ O ~W D ~ ~' " ~ N t~ O ~t I~ N t~ Ov M N
N ~n ~O M ~D ~n N M ~.'? N op '-' ~~ oo ~W O ~ M N ~ t~ 00 W N N v0 I~ O
N O N N O N N N ~ N p pv ~ ~ N N N N N N N ~ N N ~
N vW n ~t °~ ~n O ~ ~ ~ ~' vp ~' N cn
f~ I~ O I~ ~ ,y0 v1 t~ t~ ~ ~O v1 ~t M
cn " " ,~ Q ~ a p M ~ N N ~~-~ M N O o0 N
V'7 ~ M M N N ~~ ~ a x " a ~ 00 I~ I~ ~O ~ V1 ~ ~ M M N [~ 00 vD V7 .-r
~ ~ N v0 M ~D ~~ ~O ri ~.j ~ ~ r; ~ ~ N O~ t~ ~ M ~n t~ M v_i O ~ ~ ~ ~ N N O
N M
~N~~NNO~~~~N~ ~N~~NNpONNON
~~~~~~~~~ooxo~~~~~~~~~~~~~~°°~~~~~M
V7 V M M N N ~i .--i "~ '"~ " a C/~ '~ oo l~ Iy0 ~ ~ ~ ~ c~i tai N
. .. ,~ - cn . ao 00 Ov Ov N d' M vD
v0 WD M f~ O N t~ M M N '-' ~' ~ O ~D V ~1 M N M IwD O ~ t~ ~--~ v~
N 00 l_~ 00 Ov 00 O_v O~ M 00 ~ M ~ M O_O ~_O l_~ M ~t ~ ~D .~ oo t_~ N O N N
N N
O O p O O
a C~ _ ~_i M O t~
.-N~ v1 ~ cn ri N N N ~; cn N '-' ~~ ~-.i "" °~ t~ I~ ~O v~ v~ ~ ~ M cn
N N ~ ~ ~ ~ ~ v~7 ~ can
O V1 N M V'1 V O~ V1 ~:,~ ~ ~p d' ~ O~ N O~ M ~ M ~r O~ ~ V1 00 ~ ~ M O ~ (~ N
00 ~ rr
~O O l~ ~ ~~ O~ l~ M o0 ~ N ~ ~O ~ N O~ M l~ ~ 00 O~ 00 ~ OWO O~
M N N M N ~-~ N -~ n p ~ ~.,~ Q N ~ N ~-~ N ~--~ ~-~ N N N ~ N M N N N N N ~-~
M N
O O Q O O
NO N N N
M~
M
N
O N
M
M ,~ 3 °°
137
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0o n ~ r: ~ ~ " ,~
~ .-~ r.
~ N ~ ~ wj N .-r ~ ~ .-i (V ~' ~p ~..-i
.-i
M O I
_ ~ M M M N N N N N ~ ~
t1 M Ov O ~ N a O~O ~ N N O ~ ~
~ ~ ~ ~ ~j v1 0 M M ~
~ ~ 0 I~ ~
0 0
~ O ~ O ~ l
O ~D ~O ~ 00 O 0 N
00 ~!1 00 00 ~ l~ ~ ~ O ~O O~ ~ O N O O O
N N ~ -~ ~ '-' ~ O O 0 x O a ~ O a v1
x x a O O '~
~'
~ ~-1 x I
~ ~ ~ N N N N N M ,
, ~ ,~ "~ _~
~ ~ 00
N
N t~
M . ~O
O M '
,~ ~ ~ r, ~ ~ ,M ~ ~ N i M N N N N t
N O t~ N ~ O ~ ~ ~ ~
~ ~ ~ c
M r
'1"
N
O
~
O~Oxxxa00 ' ~O~
''
a"~",
r,0''
O~N~~~,~
M~~o
~
N ~ N N ~ N 0 ''~ 'T' _~ ~
,...; .-i " ~ ~ ,
N N N N N N N N N x "
,~ ~
M
M
O I~ ~ ~ ~ ~ O ON cn O
_ M '~ ~ ~ ~t f~ O O ~ ~ .. ~D
N N ~ ~ M .. ~
0 " ~ .-~ I~ ~t ~O ~
~Y cn cn tYi cn N N N O
N r! ~ ~ p ~ ~
O M
W C ~
O x O O
~
v0 O a p ~ ,. t f
.,~ E-~ ,~ O O p Ov
' Ov Ov N O
~ 00 ~ M M
a x
O~ 00 ~O I~ ~ O~ ,.~ ~ ~ N M ~' N N N M N x
~' ~ " " a a ~.; ''
N ~
'
.., _~ _" ~ ~ ~ p M N ~O ~~
d~ oo I_~ O_v
~' ~
0 W
dN ~ N N v1 V
N ~O~
O N
p
OO
pp ~MMMMNNNN~~ I~
p0 ~ ~-r p v1 ~ WG ~ O O 'fit
~~~p 0 M x a O N
V7 x x C/~ O M O ~
~ ~ O ~
~ ~ ~ " ,...] C/ y p oo ~ ~ N v0 ~ ~D ~l W
N N ~ ~ a x D
N Ov a V~
_ ~ ~
p0 O
rj ~ O
~
M N N O ~
~
p ~ M ~Y ~ M
N ~ M M cn cn N N N N ~ t~
~ O ~ n x p ~
a ~
~
O O O O M M
~ V7 C/~ (/~ a O '
"~ a
N ~'
a
"
r
a ~ v
C/7 O~ M 7
~O -~ Ov ~ ~ v~ ~ ' ~D Iw0 ~ O l~
N .-r .~ ..-n ,-.y ~l " OW
,.
I
.,
es I~ O~ N t~ t~ N Ov
M Ov ,.., "
N
'
N N ~ ~ ~ N ~ ~,j N N ~ ~ ~ N N N N N O O ~ i'j ~
~; ~ ,-; .~ ~ N
~ ,~
~ ~ O
~ O
~
O
x N ~ V vp
'7 ~ ~ M ~ oo
O M
N ~ N
N N
~ t~ O 0 p x ,~ ~ ~ O ~ ~; ~h M M M N N N N ~ ~
x O O x O O V1
~ a ~
a
~
N l~ ~ oo O I~ Ov Ov Ov ~ ~ ~
; ,~ ,-i "~ N Os
a ~
~ '"
x
_ _ ~
". N oo Ov Ov O N N N N N N
t~ ~ ~_ ~_ O_ .~-~ ~ c~i M N ~ '~
N N ~; p O ..-~ .-i ~~ ~
~ ~ ~ ~1 ~
- ~
i
- O
V M , 7 ~
.~ I~ ~ V1 ~ V1 ~O O O V 0
oooyn . oo~t vi
N ON N ON Vj oo p ~ p x ~ ~ M cn cn N N N N ~
E-~ x x O ,0~, ~; 0 a E-~ a O ~'
~
N "" V~ ".'~ ~ .-i ri ..~ M M v0 v~ v~ .~ M t~ N c~i
'~ '-' ~D a ,...; _~ ' ~n
' N
~NNON~NONN~N~~~~~~ ~N
NN~~ W-1 Ov~~7O000~Ox WOpM~~I
~~~d~d~~~~~~
o
o~~ o0 o xxxppb o ~
x axa ;
x ~
~ . ~a~ ~ ~, ~ ~
~~~a ~MCnr!oNNNN~a
a " ~
N ~ ~ N
N ~ .-, .-, .~ ~ ,-i .~ C'1 ~' N ~ r' I~ ~ ~t 0
M V .. Ov Ov ~ N ,~ .-r ~ y N
~O ~ oo Ov OW ~ oo ~ .--~~O
00 I
~ '-'
N I~ p~ ~ ~; ~ ~ N M ~ ~~ wj ~ .~
N ~ ~ N N N N N N O ~ ~O N
~ ~ ~ ~ ~D ~
0
~ ~ v1 N v~ .w0 ~ 000000
l~ N Ov ~ ,~
NN~~~ ''~~O~O
00
x,~,r~r0 " ~ ~ x ~ r~
M N ~ ~ 0 x 0 x v OO
n-~ x ~ M M M N N N V7
~ ~
' r.W
~ 7 ~
.. N
" ~ " ~ ! ~ ~ ~ ~
Ov OWE M ~ m
N ~ ~ N N ~ O ~ N ~.j N
M
~ ~
N W
~
~ ~
~ M rw M n o ~_
i _o o ~n
N O
N ~D ~ ~ ~ M V~1 ~ t~ ~ v0 cn c
O
_ N
oo O
M O M ~ 00
0o N O~ I~ ~ ~ ~ O O p p ~ ~
O O O ~ O p O O 0 O O
1 ,.'T'., a a a ''~
~ x x x x ~ 1
N N ~ ,~ .~ ~ V1 ~
.- ~- Oyi
, r ~
00 ,~ vD oo ~' ~ N ~ ,~ Vi ~ cn ri cn N N N N 00
,-i .-i ~ " ~ N ~ ~ ~ ~
-r ~ N N ~' . .. .-~ .~ ~p v0 l~ ~n l~ N o0 O
.~ ~ v1 ~ N ~: ~ ,~
w0
O~ l Q_1 v_0 ~ ~ l!1 N O ~
Ov ~~ 0_0 Ov Ov ,-r M
N M ,--n ..-n ,-y_D t_~
V~ ~ l~ O '~ '~ ~ V~ M
M
~~d~~~
~~axxxxaax
N N N ,--n WO N Vj N N .-; ~O <t c~i tYi c~i N N WO
.-i .-.i .-i ~ .-i ,~ N N N ~ N .-i ~ .-i ,~
v0 ~!1 lWn N 00 M ~O M v7 ~~ 00 N OWE m 00 M V7
O ~ ri ~; ,~
~O O~ ~ ~D ~ ~O ~ OW O ~ M 00 00 ~' 00 .-.yes ~
v7 N ~ ~ M ~ O~ 01
~
M
N ~ N N ~~ N ~i ~ N ~ N N -, N ~ N M N ~
O ~ ~
O ~ ~ ~ ~
O O O M O O O y~ ~ 0 O O O 0 O O
.-rOv O
N N M
M
O M N
M 00
O I
v~~O M
M M
N
M N
z ~
a~ o
N
138
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
cs " ~ ~ " ~.; _;
M ,_, pp ~j
t!~ N ,~ ~ ~ ,-i .-i
M ri ri N N N N N ~-! a ~ M ~ ~--~ ~ ~1t ~ ri M N N N N ~! ~~ O ~ ~
v0 ~ Ov Ov m ~D O Os ~ c~j N O O '~ r O M r. 0v oo O v0 O M ~D '-a O t~ O x
'~'~ Iw0
N N N ~ N N N N N ~ ~ x x N ,~ ~ ~ ~ N ~ N N N O N ~ x i-1 x ~; ~; ,.Ø]
''0,I,'
O
~~0,-,~~.~ noNp'Noo V~~~ ~ ~"
O Ov ~ O N ~ ~D ~-r
cn M M M N N N N ~ a ~ ~ ~ ~ d~ ~t ~ M M N N N N ~ ~! ~ M ~ l~ O O ~ N
c~i ~-: 6: c%i oo ~ ~ M v-i ~''~ O O x t~ o o vi o0 0o t~ ~:i so o c%i cn o p
° x x 'r' o O
ONONNNNNO~xxr;a"~ OO~NNNN~~ON'~W'""~x~-~~--i~x
r~.,~NON
cn M ri cn N N N N ~ v~ ~ O ~ O ~ ~ ~'~ M N N N N ~ ~~ ~l ~t vp
O O Ov OWD v0 I~ ~D ~ M O O x N O OWD f~ M ~ ~ N v0 M O O O x x O p p
M ~ N oo Ov N ~t m O~ O ~ x N t!l O x
d~ M O~ O O~ M O~ ~~
N ~ N ~ N N N N N ~' ~ .~ "'a ~ N ~ N N N N N ~ M M ~; "' ~' " " ~
O
O ~j .-, .. ~ ,-~ ~ ~ ~ p ~ ~O ~ N c~ ~ N
O V ~ ~ O " ~ ~ M O
cn ri cn M N N N N ~ M M ~ O N p ~ ~ ri M N N N N ~ ~-~ "x O O O x ~
00 V'1 N ~ ~ O ~ O ~ M ,~ (/~ '~' O Cn O ~D N N v7 v0 I~ N ~ ~ ~D Cn ~ ~ ~ ~
r.a C/1
~O t~ M O N ~ ~O v1 O ~ " (/J ~ V'1 t~ ~~ ~~ I~ -~ ~ I~ ~-~ M ~ ,~ .-i
N N M O N ~ O ~j .-i '~ _" .~ N ~-~ M N ~ M N N N N ~ M ~ ~ ~ w
x M M ~ O~ ~_ ~ ~ ~ O V~ ~ ~ V'7 ~ \O In O~
~ M cn ri N N N N ~~ ~ O O O ~ O ~t ~ cn M N N N N N ~~ '~ O ~O ~ O O
xxpoo
~~~M~~.;~o~.;~xxxa~ ~NNO~~r~ost~v»'O"-7x
N .~ M O M M V'1 ~O 00 ~ ~ ,-r " .~ ~D C~ 00 l~ t~ M 0O O O ~ ~ ~.rj ,~ ~ .. ~
" "
NNNNNONON~N~~ ~~r., .. N~-~N~-~NN~NNN~ ~~N
O h N ~ ~ a ~ ~ WO O M N M
~ M M M N N N N ~ ~ ~ ~ x O x V? ~ M ~'~ N N N N N ~~ ~ x O ~ '"O~' x O O O
t~ O v0 0o d' N N ~n N t~ ~ a ~ M ~n O t~ O ~ m O 1~ t~ ~ '-~ " ~ ~ '~ x UJ
Ov o0 O~ M I~ .~ l~ l~ Ov O N ,-i ~' " ~~ ~O ~O ~ ~~ O O N O ~D N ~,,~ M ~j ~~
.-n ~
N~~NNM~-aN~O w ~~ '-' w N~~NNM~NNNN _.
C/1 O p O ~ O ~ O y0 y0 O O O
~ M M M N N N N N ~ x ~ ,"~.., ~ ''~' ~ ~ M M N N N N N ~ ~ ,~ a x x x ,~ ~~"
x
0o O~ ~D N O f~ vi oo ~D N " " ~ M rr ~ cn ~n ~ oo ~O QW oo ~; .-i -~ ~ ~ ~
000~00o0,~NO~O~~~N~~'ri~'' oO~Dt~O~oOI~oO~M,--n~MN .. ~~ '~.-r..i
N ~ N N N ~ M O ~' ~ ~ ~ ~ N ~ ~ ~ ~ N O N I~ ~D ~'
ooo~o ~~~~~~~~~~aooooo
~ M M M N N N N N ~ x ~ x a x ~n ~ M M N N N N N ~ ~ ""~ a x x x x ,,°~
,
N ~ t~ l~ vi O v~ t~ M O r; "~ ~ ~; M oo v0 N N V o0 Ov s0 N O M ~j
~~ l~ 00 .~ ,~ ~ N l~ ,~ 00 N . ~ .. ~ ~ v0 ~O o0 ~' ~ N o0 T ~ t~
N ~ N N N N N N M N vp ~ N ~ O N N ~ ~ N N N O N N ~ ~ ~ ~ ~ ~ N N
~ O O p O . ~ ~ ~ ~ ~ O ~ O O O O ~ O
c'1 M N N N N N ~ x x ~ a x ~ ~O ~ V cn M N N N N ~ ~ a '~
00 N ~ O o0 Ov O I~ O ~ ~j ~~ ~' ,-i ,-i ~ V1 N ~~ O~ O~ ~ Ov ~ N ~1 O M N N
~' '.~ "~ ,-i ,-i
OvOOW ~oOI~O~00vM " wN ~t~Dt~oON~DMG~N~~oo ~'
M N ~ N ~~ ~ N N N O N ~ ~ N '-' O N ~-~ N N N O N ~ N N M ~ ~ ~ ~ O N t~
O O O O M b O M ~O M M ~ M O ,
"~x~.~a G ~~d~xaxxx~a~~
~ cn ri ri N N N N N ~-~ ~ " " ~ t~ V ~ M M N N N N ~ ~ ~,,~ ~ " " ~
V'1 I~ ~ I~ WO ~!1 Ov O N N ~! ~-" ~~ ,--~ Ov ~ 00 N 00 v0 W O V~ v7 N N _ "~
.--m~ M I_~ t_~ O ~ o0 O~ O O v0 ~ cn oo N ~ O WO N ~ N N O N N ~'~' vD ~ oo ~
'~ vM1 N O
O O O O O
~d~~,x~,~~ ~~~xxaaxxax G
~riMCnNNNNN-~MN,~~,_;,~~~~MC~1NNNN~~~MNN~,'~
N V1 M M M M ~ ~ ~ ~~ ~ ~ ,--~ M O M ~ O~ l~ ~ ~~ M 00 Ov ~ ~ (~ O O
00 M oo yn Ov o0 M ,~ o0 ~' v0 ~ ~t v0 ,y t~ ,~ ,-, OW ~ N N o0 ,--m0 O v~ WO
N N ~ N O N ~~ N N N ~ ~ p ~ ~ ~ N N N M ~-y ~--' N N N N ~~ N ~ ~ ~ ~ ~ M O N
O O O O N O O O O O O O O O O
M
N
O
.
a
N
139
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
Oy
" ~t
~ .-i M '-' y0 v'i O Iw0 ~ M N O N
O pp ,-i
~ Wn ~ m ri M M N N ~ x d' M N ,-, ~ - ,-, ~ ,~
~ O ~ ~ ~ vj. '4 O ~
N N
~
W O oo N O t~ ~n ~ ~D Ow0 N N N O t~ M
-..n ~.~ ~ ~ ~ p ,~ ~ ~ I~ o M
~ o
M ~ ~ (~ (~ O M N ~ ~ N N ~ ~ N 00 M
O 00 00 M ~ O x N x
_ ,,yy N
~ ~ ~ p
M p ~: p o0 a
""' ~ ~n ~ M M ri ri N N " " N M
N ,~ ''4 WO ~ "' ~ ~--W v0 ~ M N O I~
-~ M . O l~ O
M ~ M N ~ ~ .~ ~ ~ ~ I~
~ N ~O ~f
.. ~D o0 ,mn N M ~D O~ M O~ Ov .~ ,n o0 V1 ~n ~D
l~ ~ ~t ~ x O I~ ~ ~ ~ O M
O~ N f~ 00 M 00 M M o0 O O ,.., ~ 00 ~D t~ N v0
O Ov ~ ~ ~ ~D ~ ~ ~' ~ x
,.~ ~
N ~~ ~ , N
~~ ~~ N ~ N N ~ N O M M N N -~ N ~ N N N N N
" ,., _" ~
O vj WO
M N N v0 ~t ~ cri M cn N N ~D N Iw0 ~t ri N ~ ~ M
~~ N N a ~O O '~ ~ ~ M p ~ ~
o ., p
W ~n M N ,-, ~, ,~ ,~ .~
~ x .~ p 0 op ,
M O 0 Ov ~ N ~ ~ I
t!1 v0 O O cn 00 M ~ 00 01 O I~ lW0 N
~ n Ov M ~ C/7
~ O~ l~ O x " x
,~ O
O ~O O
v 01 M O
_ ~' '-' ~ N N l~ N
_ O N M ~ ~ O ~ N N M O
_ '-'
O ,~ O
O " Uj ~
x ~
N M O O ~ I~ ~n ~ p ~ ~t
.- y0 ~ ~ cn cn M N N N O
~ o
n N ~ ~
WO ~
0o x x '"T,~' c,~
M v0 ri Ov M v'i ,-i ri c
v0 o0 00 00 p~ p~
~ -~ t~ N oo I~ ~D t~ 00 WO N I
0o N ~ F" W M N .--~ .~ ,~ ,-.m-,
.~ N ~p ~ ~ x
N ~ op v1 O vp M v0 O .~ O N
~ ~ N ~ N N N ~ N N ~ ~ N ~' O ~' ,-,
N ~! ,~ O ~ O ~~ M O~ O~ O~ O
M " N ,
M N N M O ~~ ~ ~ M ~O
-i cn c'i cri N N N t ~ ~ y0 ~' O p d
cn
O
v0 ~
p
0 ,. :
, ~., ~' V~ ~ x x N
~
~
~
M v0 M
~
~ ~
Ov D Ov O t~ N o0 vD ~ ri N
-r Ov ~ N v0 '-' "' '~ '~ '-' '-' p N
..r l M c
Ov " ~"~ N O O ~'
N o0 t~ ~ ~ Ov ~ M ~
~ ~ ,~
~'
N N O ~ ~ -~ N N O N N ~ ~
N ~O
V
.~
M
M
~ ~ x
~ n ~ ~ ~ ~ ~ O
p p oo -~ N
.
o
O
~
M N N -a N ~ N --~ N N
M ~ W O ~ ~ cn M cn N N N ~ ~ M O O v'i
~ O O ~~~d~d~d~~~~~
x x
~
w . ;~~~
f~ N ~O O I~ ~O l~ N 00 ~ N
~ O N ~ r-i ,_i ~ ~ M M N ~; ~;
N .~ -~ M ~ O ~ N N N N N ~ M N ~ ~ ~ ~ ~ ~ ~ N N
N ~ ~ N N ~ ~
~ \O ~ V'1 M M l~ V~ ~
l~ M
~c ~ ~n ov o r N a, 0 00 00
m ~i W O ~ d~ M M c!o N N ~n
-~ N ~ O ,'~,' a N O N N N -~ N N N N
a
~O ~ M V1 ~ V7 I~ ~ ~ M ~ I~ x . l~
N Ov t~ " Ov Ov N .-.~ ~ O
~ ,~ .~ N N N ~ N
N N O ~ M ~ N ~n O Ov Ov
O ~ N
N N N N N N p ~
M 00 W o0 v0 v1 M N ~
O l_~
V-t [v ~ O O O ~O M_ 00 ~ O_ V1 ~ V7
cn w0 d: ~ M ri cn N N N O -~ O O .-r
.~ ~ E-~ x a N N ~ ~ N N ~ N O N
,
c W O o0 tw_G wt ~ t~ l~ v0 ~D M _~ _.. o0
~ ~ N " ~ ~ N N N N
~ N
M O
N N ~
Ov ~ ~ p~ Ov p
M N M
N
p p O -~-i ~ ~ .~, ~
~ t~~n N ~ ~
.-i , I
~ x x ''~ M N O O ~ N N N Ov o0 0o
~ pp" l~ ~ x '~ ~
N ~ s0 ~ ~t M M M N N N ~ v7 ~ N N O~ ~D Ov o0
Ov N . . ~ .-i N v0 .. " cd
. ~
-
~
; ~
N d' ~ t~ ~ ~ N !~ oo t~ ~n ,..., N
N O O N ~ _ ~ N N N N ~ ~ N N - N
N ~~N~NNNNNN~~NNx ~
~t
r
~~~ ~~~NO~~N
O ~ y ~
~ ~ ~
~ ~
~ ~
~
~ a .-
-1 .-~
- ,.
.7
~
~ v N
.~
d' ~:,.j W n ~ M M M N N ~ v'f (~ ~ O ~D N ~ O~ t
N N ~' ~ .-i v1 ~ I~ ~ - r; ~
~ ~
v0 , vp O Ov N W O t~ Ov o0 00
0o ~~ v~ M Iw0 cn o0 ~ O v1 O ~D Qv ~' ~'. M
v0 O ~ N .. N N ~ N N ~ ~ N N l_~
O M v_0 .~ dw0 O~ ~ N M I~ M ~ ~ .-~
O ~ O_v OW 7 ~O ""' M ~ ~ ~
~O O O O
M
O O
'-~ ~ x x O
v Ov ~ N oo IW O ~ cn ,~
p C/~ ~ V7
. " t~ ~ M ,-, .~ ,~ r, .~ 00
cV O ,~ .~ pi t~ ~ N r, ~;
,~ ,wO ~ ~ cn ri M N N N
~! ~.,~ "-.i ,~ r;
Ov cn M O ~ N ~n o0 ~t mn ~'~ N Ov N Ov ~ Ov ri t~
O ~y m v0 O oo t~ Ov o0 v0 ~.j M
t~ tn ~D ~ (WO ~ ~ M M 00 ~D ~ M ~ 00 .~ Q~ 00 l~
~ I~ 00 f~ ~ ~ N ~
00 ~ ~
~
~
~
O N n N O N ~ N ~ ~ ~ N ~ N N
N N ~ N N N N N N N ~ ~ ~ ~p ~
~ ~ O ~ O
O O
O
O O
N M
M M M M
N N
N O
O
~O I~ I~
a
a
N - N N N
140
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
yD M N N N ,-i ,-i ..w v1
00 M ~ (~ M N
N N ~ ~ N N N ~ ~ '-' ~ ~ V ~ ~t M cn N N N ~ --~ N ~ ~ oo N
O r ~ ~ M t~ O N_ Ov O M N~ ~ (y M N t~ Vi ~ ~ Iw0 ~ p N '~ n v1 ~ O O
N~~ ~NNN~~N ~NMNNNON~NNN~''T'xa"~x~x_x
a ,ri N y0 ~ N ~ N
N N ~ N N N N ~ ~ ~ ~ ~ ~ ~t ~ ri M N N N ~~ ~.-~ s0 ~j ~ ~ ~ ~ n O p
OW O ~n ~ 00 ~O l~ ~ I~ Ov ~ ~ ~O N Wn vi O d' O d0 O~ O ~ O ~ p O ''~"" C/~
O O~ M [~ O M v7 ~O ao '~ O~ O~ N o0 00 0o O~ O O ~O ~O M x a x .. ..
M N N in M N N N N .-~ N N N N N N ~--~ M -~ O ~-~ O
x ~ ~ ~ ~ ~ ~ ~ x ~ N N ~'~ ~ ~ N M
O
N N ~ N M N N ~ ~ x ~ '-' ~' ~ ~ ~ M M N N N ~ ~ ~ ~ ~ ~ ~ O ~ O O
N v0 N N O oo ~ ri v~ ,-; N ~ M v0 U N ~ ~ M N O~ ~ N ~ O O O O O O E"' x
Ov ~ N N t~ N ~ O t~ ~ ~ o0 O ~ Ov ~~ t~ ~ M Ov N Ov O v~ ~ a C~ a '~' F' x ~
"
N N ~ N N N N ~ O N "~,' O N N M N ~~ N N N N ~
O ~ C ~ ~ ~ ~ x "-' o_0 N ~ ~ op O~ ,n
N N ~ ~ M N N -~ --i ~ ~ ,.._, ~ ~ ~ ~ M M N N N N ~ ~ ~ ~ ~ p 0 ~ O O
v0 I~ --~ O~ ~ ~1 I~ d~ O '-' ~ ~ ~' N o0 ~ ~-~ f~ I~ vW0 O M a ~ a x x CO/~
'~' ~l
~D ~O M 01 I~ 01 O ~O O p 00 l~ 00 .-r M ~O I~ 01 V1 ~ ~ l~
N N ~--~ ~ N N ~ M .~ O N ~ N O O N N O N N O ~ ~j ~.j N ,~ r.,
O W M N O O
~D I~ ~ ~O O O
r, . N I~ ~O O M O O
N N ~ ~ M N N ~--~ ~--~ ,-; v1 ~~ M ~ d: d; M M N N N N ~~ ~ O p O O O O x x
'-: v ~p ri Q: oo M ,~ ~_O O O N ao ~D N ~~ M ~ M o: oo ~ a x a x ~ W "
O~N~~-, ~NN~M~ N~' ~N~~N~O~N~NO~cnNN~'-
x ~~~~~~~~~~~N~~~~N~oo
N N ~ -~ M N N --~ ~ N ~n N N yi d~ ~t M M N N N N ~ ~ a O ~ O O ~ x x
V1 V7 00 Q~ V'1 (V ~p OW ~ O O~ ~ ~ V7 ~ O M M M N ~ O M V] x x " ~
-~ v~ v0 00 ,-~ N Ov oo W ~'~ O ~ ~ ~ M ~ -mn OW_O o_o O
~j ~ M M O
M "o0 O O O O O O O O
M N N ~-n M N N ~ ~ ~ ~ M ~ v1 V ~ M M N N N N ~~ '-' ,"~, a V~ ~r x C/1 x x
M N ~ ~ ~D l~ ~ M V7 Ov 00 I~ 00 Ov I~ ~D I~ Ov 00 M d' M ~ " " "
N t~ ~D ~ ~O Owl 00 O M ~-~ I~ ~ O ~D O~ O o0 00 00 ~ t~ ~ ~!'? cn N '
N ~ ~~ N N ~~ N N N N N N ~ N M N N N N ~ N N ~ a ~ op ~ O
-; p~ ~ O ~ 0 O O O
M N N ~ M N N ~ ~ ~-~ ~O M N V1 ~ ~ M M M N N N ~ N a a x is x, ~ x x
M N l~ ~n ~O l~ Ov oo M ~ cn ~ ~ Ov N M N v0 Ov s0 v7 ~~ Ov O ~i rrj N ".
~O v0 ~ OW ~ I~ O t~ OW ~ ,-~ O ~ ~n ~~ Ov Ov N oo Ov o0 I~ ,~ ~ ~ . . . . N N
~
-, ,-.~ N ,~ ,~ ,~ M ,-.n N .--~ M .-i N O M rr .~ N N N .-r .~ ~ Ov M O v~ ,~
N
.-r ~ ~ ~ O ~ O ~ ~ O p O
M N N ~ M N N ~~ ~ ~ ~O M y0 ~ ~t M M M N N N ~~ ~ '~ a x a a x x x
.~ ~O W O ~n N ~ I~ t~ ~ ~i v0 N O O M dW ~ ~O N oo ~D OwD '~ cn N
~D t~ ~D 00 M lW0 (~ ~ ~O o0 ,~ Qv ~ ~ ~O M ,~ ,~ 00 ~D O~ M 1n O~ '~ ~ pp ~ M
O
N N ~~ N N N ~ ~-a M N M N ~~ N N N N N ~' N O O O p p O ~ O
~~~~~~~~a~~~~~axaaxxx
cn N N ~ ~ N N -~ .~ .~ n M v0 ~ ~ ~ M M N N N ~ ~ ~ " "
v0 cY OW ~ ~ f_~ oo M ~-r ~ v1 ~p oho ,~ ,-..~ ~n ~n v) v1 ~t t~ ~ M v1 ~ M N
N N '-
N ~ N N N N N ~ N N O O ~ N N N N ~ ~ N ~ N N N
O O O O O
~d~a~~~~~~ ~~~~~~~d~~~~~xaxaaxxx
M N N -~ ...; s0 N N N ~~ ~ I~ tri -~ ~O ~ ~ ~ M M N N N ~ "
N M t~ 00 p 00 O~ 00 M ~O \O \O M I~ O M O ~O 00 N ~ O~ ~O O O~ ~ ~ N 00 00
N N ~--~ N n N ~ ~ N -~ --~ O O N N N N -~ O N M ~
N O v~ ~
O O O O O O O O O
N ~O t~ M ~ 00
N M M N N M
M ,-..~ .~ M M
Ov o0 M ~ ~O ,r
O O O
00 ~O
N N N
141
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
-i ,-i ~ .-i " Oy.,j N .-i "~ ~ '~ O N
-! 00 M Ov 00 ~D ~ M N ~~ O pp O N M '-' ,--~ N V1 ~ ~ ~ pp
M vD ' M ~ CV N ~ ,~ ~ ~ .~ ,--~ ,~ ..-i ~ ~O N O ~O ~ ~ M pp ~ O ~ f~j ..~ ~
.r ~D
O O ~ ~ ~ vj N I~ Wn ~-~ v0 Ov oo ~n oo t~ ~D .-, O ~ O O oo ~ x
°~ ~O
O .-, ~ ~ ~D OW O Ov o0 M ~ N ~D v0 ,~ O O ~ O O ~ ~ ~ b ~ ..m-i ~ I~
xxMO~ MNN~~N~-MONO ~~~0 x0 x O G
~ O x ~ ~' N ~' O ~l f/~ x ~ ,-, M N ~ N
N t~ a r~i ~ ~ ~ ~ ~, x M N N ,-; ,~ . ~ ""~
O O ~ M
O O ~ ~ ~ N N ~ 00 vp ~ ~ ~-.-Nr ~ ~ N o0 I~ vp ~ ~ O M M O p N ~ ~ ~ N .r ,-i
r-i
xx~i~p0 ~ONvOcn~NCW~W O c'~OO~n00~00 ~''"T,'O'-'f~OV~OO
.-i ,-i ~ x ', ~ Ov .-, V O v0 M I~ ~n Ov ~ ~ ~ N O a x x ~ ~~ x '-1 ~ ~ N ~ N
O x
N O N N N
~_~~~~ ~~~~~~~~~~~~~~NMM~V,~M~~~D~~~~~~~
O O ~ O ~ p ~ ~ oo v0 ~ M N ~-~ O N 00 00 v0 "-'' 000 ~ ~ O ~ O ~ p ~ ~ M N .-
i ,
'~'' t/~ ~ O M N ~ ,~ ,~ r, ,-~ .-. .-i ...~ ~ ~ M °o O O O O '~' x O x
O '-' N ~' O N a
~ r; a v~ ''Wn oo ~ c~i ~i ~i c%i oo vo oW~ oo M ~ ...7 x ~ ,~ ~ a " v7 ~n ~ M
t~
';"; " ,~ Ov T O~ ~ ~-~ l~ 00 00 M .-~ N '~ N O M N .~ ~~ ~ ~i O .-"~ N
'-' ,~ ,~ N N N N N N Oy ~ ~ a ~ N ~ °N ~ ,m-,, ~ O N
x x v0 ~ 0 M ~ ~ ~ ,r p O ~O ~ ri N ,-i .
~ a a a M N °' oo .~ ~ ~ ~ ~ ° v~, ~ ~ M "a W ~ v~ x x a x W N
yo ~ ,.a
~' ~ M .~ M M N N ~--V M v0 N N N ~ M N .-~ .-~ "' _~ ~ ~ ~ N N M N
O '~ ~i "~ d: ~ ~D ~-r l~ ~ V'1 ~ 00 ~ 00 ~ ~ ~ ~ ~O ~O ~O M 01 ~
yij ~ N N M N O N O ~--~ M
O O ~ ~ O N o0 0o f~ ~ O O n O O O ~ O O ~ ri N ~-i r-i O
ra ''~ a M tn O o0 ~O ~ M N ~-n O ~ N a~0 l~ N x x '-7 x x ~ a x
'-n _. ~ '~ M N N ~ ,~ ,~ ~ .-H ~ .-yy .~ .~ (V M N N .--~ .-~ ~ .-i .--i ~ N
.-~ O N w'7
M ~ ~ v'i oo O v0 cn c~ O N ~ O O .~ iV ~ O
M v0 ~-W O v0 Ov ~ l~ Ov ~ ,~ N ~ ~ in ~ N ~ ~n ,y0
N N ~ M ~ .~ ,-, N N N v~ O ~ ~D O
x a a ~_ M ~ ~ ~ ~ ~ ~ O I~ ~..i 00 ~ x n.a x x x O x ~ ~ M N ~
_ _ ~ ~ ~ ~ N W N v1 I~
~_ O ~ '-' ~O ~ ~ V1 ~' 00 vp ~ M N ~~ O ~ N N O N M N N r~i .-i M ~ r! .~ ~
0~0 NO
O_w ' M N '_n
~D O ~ ~ ~ x v0 ~ N ~n O V l~ O Ov ~ ~ ~p ~ O '-' ~O t~ ~ ~ vyD
O O M ~D O .b O ~O I~ N I~ 00 ~ .--~ O~ t~ ~O O ~ 00 I~ ~O O ~ O O ~ ~ O
xx00~ ~N'~'~N".'iNNNN~~ap~oot~N OOOxa aop~.,lN~.--n,,$,,
-i ,~ i"'~ a ~ ~ ~ ~°D ~_ M N N N x ~ .-i x ~ N
O O ~ ~ O ~ I~ ~O .~ O~ l~ ~ M M ~~ O ~ ~ ~ ~ O M M ~
M N N ~!
xxOOxO~o°o~~MONOOnOv~N OOOOOxOOa~ _" O
_. ,..] a ~ "~'' ~ N N N O N M .-i N N N ~ ~ ~ ~ x ~ a a x ~ ,.a x _. ~~ ~ N ~
N a
O o0 '-: ~ O ~ ~ ~ ~ N Ov O O ~ N .N~. ~j '~ ~ t~ N ~ N N
O O °N ~ O ~ M N N ~ ~ ~ ~-M, ~ ~ ~ ~ N ~ ~ ~ O O M ~ O v0 ~ ~ ~ ~
O
O O x O . .. .. . .. O O p p O ~ ~
x ~ ,~ ~ x ~' 'n yn v~ N v1 ~--~ ,-, Iw0 op" oo tW O x x ~l ~l ~ x ,.p.~ ~--~
~ M N ~ ~-: '
~ 00 O ~-~ ~O ~O T o0 vD ..~ O~ 00 " ~O
-~ N N M ~ N N N N ~-~ O1 M O V7 ~ N N N .-i '-' ,-i ~ ~ O N v0 O
o_o ~ ~ ~ ~n N N ~ N ~ O ~ Ov p ~ N ~ ~ N n ~ N
M l~ V'1 ~
° ° p O p O ~ l~ ~~ OW ~ ~1 cn cri N O O ~ ~ ~ ~ O O O O p
° p O ~ ~ ~ °
x ~ ~ a x C/~ ~ N N .~ .~ ~ .~ ~-r ~ .~ ,~ V7 V1 '..a ~ (~ ~ U7 ~ x r' ~
Ov 00 ly0 " ~ N ~-a
-i ~O N l~ I~ ~ O O~ M 0O ~ ~ O 00 I~ O ~ N N N '-i '-: ,~ ~-i '~ 00 ~D M M O
-.i ..r ~ . ~ ' ,_, . . ~ ,~ ~ ~ <t o0 N
NN~~~O NN~ NMON~NN~~N~~~~~NN~~'M-' ~~~''~,I,'
OO~~O'°~~~~~~~~~~~~~~~~M~~N°~~°~ O
O O OOOOO OO
xx~ax,~~~M~:~~~~N~o a~aa~x~,~xo
,_; ,_; .--i ,_; V~ N N ~ ,--~ .-..i ~ ,~ ,~ ,~ .~ Ov 00 (~ ~O ~ c~j (~j N ,--
i "w ,--i ,~ .~ N d: N ~
s0 ~ ,--, N .--~ N N ~ m ,--~ d' ~-W j O vW O v0 Ov O Ov y0 OWO O cn N N N M
O N N ~ N t~ O --~ O t~ ~O N O~ O ~t ~ ~ ~ N O ~ ~ O O~ l~
~ N N N N N N M M .-~ N N ~ N N ~ ~ ~ ~ ~ ~ O ~ ~ ~ N ~
O O O O O O O O O O O O O O
O~ O
M
,_,
O O
M ~O
O t~
O~ O
N M
142
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M ~..~ ~ .-~ ~-' ~ r':
r-; ~ h N .-i ~~ cn ~ .--~ v1 ~j vp
~n ~ v~ et V M M M N N N ~ ~ ~ ~ o0 ~ ~ ~ ~ ~ r N ~!1 W ~ M N N N
O ~ p ~D O M O_ N cn ..-i ~ ,~ v_i O O p t~ yn O h ",~ Ov oho N oho ~ ~ ~ N
"'~ N N ~ N ~ ~h-~ N N N N N a x a O '~"p~' '~" x ,°~ C/~ '-i ~ N N N ~
N N N
h o0 N fV ~ ,~ .--i ~O ~-s '-, h
h ~ tn ~O ~ ~ M h ~ ~D oo ~ M v7 h O h
O ~,~ ~n ~ ~ yT cn M N N N ~ O O ~ h o0 W O y0 O N vi W ~ M N N N
O O N ~O ~O O o0 v~ ~ M O M O a O O op ~ O O ~ x ~ h N N ~n h OW O rj
a N ~O ~ O h ~Y Ov Ov o0 M v0 ",~, a O O x '~ a O ~ O ~D N O h M Ov ,-,
x ~ ~ N N ~ N N '.r .-~ N N ,~ x _~ r., a ..~ N N N N O O N
ppp ~O M V1 ~ ~ O\ ~ ~ M .-w
~1 d; ~ ~ M M N N N ~ p O ~ ~ ~ ~ p ~ ~ p N ~!1 wi ~t M N N N ~' h
~~,a aW ~ooosc~as~v~~~-.7 OoM~xOOx ~~~~_c~;Vioo_sVi.,..
N O N N N N N N ~ N cn x a ~ "~ ,~ .~ a "'~ ,~ N N N N N ~ N
N ~~~~~~~~~~~_o~~~_~~~~~° ~~~~~~~~~_~
~ N v1 ~t N O N h cn v7 '~' x a O N "'~', r~,~ a O ~ O o0 h V' h ~ ~t Ov
h ~D o0 h r~ h M ~ Owl v1 ra a ,~ O v0 N O v0 ~-~ N ~D ~'
N ~~ N ~~ N N N N N N ~ N ~j ~ ~ .-i ~-! ~; ~ N ~ N N N N N N ~p
tV ~ ~ ~ ~n Oyj Ov N ~ O ~p ~
r' O ~p ~ h W ~ O ,~ O ~n O v0 ~ v7 ~
0 O O ~ ~ s? .~ ~ M M cn N N ~ a M p ~ ~ O O O O x N ~D vi V cn N N N
C/~ x x o0 ~t ~ ~D M h N ~D n O M ~l ~l ''°~ "~' ~-1 ~ OW ~ ~ ~ N -
-~ OWO
.wo ~ mn ~n h h O ov oo ~ E" x ~ ~ ~ "'~ r. M h h h ~ ~n o0 00 ~
'-' ~ ~ N N ~ N N N N N ~ ~ '-: '-: ~ ,-, N ~ N ~ M O O N ~'
oopo ~r0~
', tn ~ ~ ~ M M M N N N V] O O ~ ~ a a O p x yp tf~ ~ M M N N
x '_' ~ N ~ O M N Ov N ~O o0 ~ V1 a x x ~ ~ r~ a ~ OWD ~ M M TWO M
N M N ~.-~ N N ~ N ~ Nrr,,~~ Nrr,,~~ oo N N N ,~ ~ ~ ~ '~ ~ N N N N pN N N
00 N
N ~~ ~~~pn~N~ O ohoO N N
.--i O
x x x ~' O~ V? ~ d. ~ ri M M N N N ''4 x ~ O ~ ,~ C/~ ~ O x N ~O v'i ~ ri ri N
N
~ ~ O ~1 ~ ~O ~O 00 ~ ~D h M O~ V1 ~ a ~ ,~ ~ '~ ,_; ~ ~O M ~O ~O 00 ,~ h ~D
~ ~ M ~_O ~O O~ M M h N 00 M I_~ N N ~ ~ ,~ ~' ~' M O~ 00 00 ~ N
v0 ~~ ~~ ~"' ~ ~ ~ ~ ~ ~ O O ~ ~ O ~ ~ ~ M ~ ~ N N N -~ N ~ N N
O O O 'b oo a ~ O ~ ~ .-r O O ~ O N ~ tai
~t cn M cn N N N Cn r.7 a ~ a x' ~l ,~ x ~ ~D ~n ~ e~i cri N N ~~ N
p o0 N ~01 00 ,--i ~ 00 O ~~ h ~ N f'1 nj ,-i "" ~ ~~ ~-i '-' ~ ~ N ~ y0 OMO
00
N ~_ o0 00 ~_O oo O_ v'1 O l_~ N ~ ~ ~ ~ ~ h ~ _ _
0~0 ~ Ov ~ ~ ~ ~ N M Ov ~ 00
0 0
ax~x~~D~n~~MMMNNN~ ''r'v~C~ ~ ~ W O~~~i~~MNN~!N
N ,-i ,-i r-i h ~j ,~ ~ M ~D O ~ t~ Qi ~ N N N ,-i ~ ,--~ ~i ,_"; ,-i ~ N o0 N
~ O M o0 Ov V~ N
N N ~ Ov oo ~ ~ N v0 N ~ ~ ~ N M O ~ ~ O N WO Ov M ~n Ov h
oho ~ N M '-' ~' M N N N N O ~ .~ N M ~ ~ ~O ~ N "' x
a° Na.°.~x~~~~~d~~~~~d~°a~~~ox°a~ax ~~ ~o
s0 W ~ V M M cn N N N Os N ~ .-i .-i .~ ~ ~ ,~ N ~ ~n ~t d: cn N N
.-i ,-, M ~ O OW i M N N OW i .--~ p~ N N .-~ ~' '.-: 00 cn ~ (~ tn N ~_ (V o0
O
~ h ~ N N oo Ov O ~ O ~ N N oo O ~ ~ ~ ~ ~ ~ ~ N ~ N N N ~ N M N ~ N
oooo~~~~~~~~~~~°°poo~oo
xxa~xxxaax~;
nj .-i ....i ,~ ~' y0 y7 <t ~ M M cri N N N ~-yj N N ~ ,-i ,-i ,-i ,-i ,-i ,-i
~' ~O ~ ~ ~ cn N N ~ N
v0 00 00 h Ov O oo cn .~ M M v0 h ' M O O .. .. ~ ~ O "~ p~ h ~n O O ~t
O~ ~ O ~G ~ '-' O ~~ ~' l0 v0 v7 .~ .~ ~ ~O ~ ~ ~ ~ M N O p V1 00 h M ~O 00 O
~~ ~ h ~O
h O ~ ~.,~ ~ N M N O N O N M N 'p ~ h ~ M M ,-, ~ ~ ~ ~ N N -~ M N N -~ O N
O O O O O O O O O O O O N O
.--~ N M
M
NO
N
M
w U
U Z
3
N M
M M M
143
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
r;
v
v ~; '°
O ~ ~ ri ri N N N N
~_~ ,~ ~ 00 I~ f~ ~D V1 V1 ~ M ~,'r,'~ ~D \O d: ~ M M M cn N N ~
N ~' M (~ Ov N V1 O ~ N o0 V1 ~~ ~D ~D (~ O o0 ~ V~ y0 V~ Ov M N o0 (~ t~ Ov
,~ N op l~ O_v O_v o0 t~ ~t I~ O N O_~ N .r M o0 M r~ o_0 ,~ O ,_, OW _~ OWn
~~ O t_~ 00 o_0
00 t~ ty0 vi vi d: ri N v0 ~O ~ ~t M ri ri ri N N a ~t ~ ri ri N N N N ~-;
O~ .. .. . ..
M V1 M Q~ V'7 00 O~ ~O M O~ 00 V'7 O l~ '~ N O~ ~ V~ ~D M ~O 00 ~ rr O
r~.,~ON~~~NN ~~ ~~~NN~~~ ~~~NN~NN~Ox
~ 00 I~ lW D V1 ~ ~ M '~~' ~O \O ~ ~t M cri tri M N N ~ ~1 ~ M M N N N N ~ N
-, ~-, ,W D c~i M O O WO cW O v1 0o M O ~n o0 Ov ~ OWE ,-i ~i ~-i Ov V ~ I~ cn
N o0 0o f
v0 N_ 00 ~' ~ 00 O O O_W1 M .~ ~ O V»O o_o t_~ 00 O N 00 .. ~ ~ 00 t~ N v0 Gv
M M 00 v1
N ~ ~ ~ O O ~-~ ~ N N N N N ~ N
~~~~~a~~~a~x
OW ~ ty0 W ~ ~ ri '~O' ~D ~D ~ ~t cn ri M M N N x b ~i ~ M M N N N N ~ --a
~ N O ~p ,~ d' ~ ~ l~ O OW ~ ~ Ov M V1 00 O I~ ~ M O ~, q M OWO I~ I~ O v0 vi
.-r ~ ,..-~ M 00 l~ ~~ O ~!1 G~ l~ ,~ ~O o0 ~ O~ M O Qv O ~ O~ cG ~~ 00 OWE O
01 ~ V7 V'1 00
N ~~ ~ N N N N ~ N O M N N M ~ N N N N M O O N N N N N N
~' N N ~ ~ ~ O M
Oy~ tyD vWn ~ cn N t~ ~O vi ~t M ri cn ri N N x p s0 ~ M M N N N N
~n N O p oho ~ 0~0 ~ ~ ~ N ~ ~ ~ oMO ~ Ov ~ ~ ~ pv a ~ ~ ~ N -~ ri ~D O ~ O
~~~~~~~~~~~x~~~~~~~~~~~
0o ty0 vi W ~t M ,~ ~ !~ s0 v1 d; ~t cn cn ri N N . O vp ~ ri ri N N N N
O W ~n l~ M v0 O M dW O M \O v0 ~ O ~-~ O v0 cn ~ ~ ''~ O v0 N t~ ~ Ov N N
~D oo t~ ~ ~ ~O M oo ~ ~ ~ ~ OW O t~ Ov O N M v0 Ov ~ twD Ov ~-~ ~ 00 t~ ~ f~
O
~ N O O ,~ N N N N N ~ O ~ N O N N N N N O O ~ .. N ~ ~-~ N N N N N ~ N
N ~ O ~ ~ ~ -d
x l~
N O N ~ pp' ~ ~p ~p ,n ~ ~.rj ~ ~ ~ ~p yj ~ ~ M M M N N N a ~D ~ M M N N N N N
01 .--i M d' OWO ~ O ~ ~D M ~O (~ ~O ~ Ov d' Ov ~-~ ~ . 00 ~ M I~ ~~ V1 M .-r
N V1
01 ~ ~~ ~n N N O~ O~ ~ ~D O~ ~~ ~ v1 ~O O M M M ~ .~ M ~O ~ M I~ ~ ~O ~ ~h O
N M M N N N ~ ~ N ~ N N O N --~ N N N ~ " N ~~ N N ~-n N N N N
~ Ov o0 h v0 v0 ~n ~ M .~ ~; two vi ~ ~ ri ri ri N N N ~l vD ~ ri cn N N N N N
-~
~ v0 O_ ~ ~O O N ~t Ov N M O ~ ~_O v_~ M ~n cn oo v0 00 ,.~ Ov oo Ov O M vD N
~1 M ~
~ONNNNNNN~ NO~NMN~NNN~~~ON~OMOMNNNN
~~°~a~~~~a~~~x
~ Os 00 t~ s0 ~O p ~ ri ~; ~ t~ ~D vi ~t ~t M M M N N ~ x t~ ~ M M N N N N N
N t~ V'1 O»O o0 Ov ~ N " ~O N ~ O ~ t~ f~ M .--n N M I~ .-~ O o0 t~ I~ s_0 O
~t N O O
~N~~N~NN~N ~~~NNNN~~NNN~ ~NNNM~N~ON
~~~~~~~~~~d~d°a ~~~a~~dd~d~~~~~a~~~a~~a
Os op two v0 ~n ~ ~ N ~ t~ ~D ~n ~ ~ M M M N N N . t~ V M M N N N N N --~
-~ ~O N N M ~~ OWO N t~ ~ O O ~~ N N M O N t~ N o0 ~--~ O "-' N N h N ~ Os v7
V1 t~
N ~~ N ~ ~D ~~ M O~ ~O M ~ O N ~_O I_~ 00 O_v ~ v1 ~n l~ ~--~ N ~D ~ 00 ~O N
o0 O M o0 v1 N Ov
-~ ~ N N N N ~ O N
a
~o ~ ~ o ..
-.~ Ov oo I~ Iy0 ~n vi d' N ~~ fy0 v7 d: ~ ri cri cri cn N N ,~ 00 ~ ~ M cn N
N N N
~ N ~n M M ~-r v0 O M t~ oo t~ d' N Ov N t~ v'1 v0 N Ov O M oo M ~ ~~ M O M Ov
O o0
~D vp OWn M Ov o0 00 O N two ~-~ N O ~ t~ t~ OwD oo Ov O N °~ oo ~O N
f~ M .~ N ~D o0 ~-w
~ O O N N -~ N N ~ N N M N N N N N N ~ N ~ -~ ~ N -~ N N N O N N
O
~ d'
N ~ et
M
I~ ~ N
O
v~ v~ O
M M 00
V~ V7 M
V7 ~ M
V1
M M
144
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
t~ N
N
~O ~ -i ,-i -i ~~i (~ ~-i ~i o0 N v0
ri N N p v0 ~t
M d. " O Ov .~ .~ ~ M O M Ol N O
N ~ ~ ~ M M M N N N ''~ ~ oho ~ O ~ ~ ~ ~ ''~ ~ ~ N ~ V7 ~ ~t ~ ~ cfi ri
~~ I~ ~t v0 M O ~-~ ~t I~ M ~ O O O Ov ~ ,--i
~O~DI~~OM01M~M~OOp°xraOx~ V1O~° ~' .r. M~N~~OO
N ~ ~~ ~~ N N N N N .~ ,...~ ~ x z _~ ~ a _" ,n ° ,..; ~ op ~ N N
N N O N
O O "
~j N x O op op ~n M s0 °o O ~l oo v0 O o0
,..., ~i V ~ cn cfi M N N N v0 ~ ~ ~ O v0 O ~' x p ~ M ~ ~ ~!1 ~ ~ ~ M M
d~ oo v1 ~D v1 f~ oo Oi N °~ M O t~ O O O op ° p~ N x O ~; O t~
r ...r v~
~~.~OO~c~c~o~~n~~~i°,.,aOxx~Ox ~"~~; "x ~ ..a ~OMO~I~MM
N M N ~ ~ N N ~a N ~ ~l ~ ~ ~ ~ ~ op ~ -~ ~' ~ N N N N N N
O~
W-°-1 ~ ~ N O n ~_ ,-1 ~ ~j ~ x N d' ~O ~ °
,<j N vi ~ ~ ri cn ri N N N ~ N O '~ M O O ~ O ~ ri ° ~ O ~ ~ ~ ~ d: ~
ri cn
~ M N O ~-~ I~ I~ 00 t~ ~ O ° p O x VJ O x O ~ ,n '~' O '~ V7 ~ d' O N
N
~ O~ N t~ lW0 00 N N ~.,~ x x ,~ x ~ ,~ O " a ~ N ~ N ~D o0 I~ M
rr .-r ~ .--n ~
,.., M N N N N N N " x ~ ~" _ ~ ,-, N N N N
N ,~ .-i M O v0 ..
°p a ~j ~ ~ p tin ~ O ""~ N ~ O ~ ~
Vi d: d: M M cn N N N Ov ~ ~ t~ ~ O O M O N ~ ~ ° ~ ~ ~.j O ~D ~ ~
~ ri ri
~t f_V ~ OW O cn ~h Ol O o0 a C/~ ° x x a ° ~, O O ~ x a ~ x N
o0 .~ r v'i c~i
N M N N ~ N ~ 00 Ol ~ ~l ~ ~; ~-1 ~ C~ ~' p1 ,-, " ~ ~ ~ t~ tw0 wt I~ t
~j _ ~ Q I~ ~ M r, rr ~ N
M .. O .. ~ N .. N
.. o ..
° O ~l ~ ~ O~ ~n ~p ~ ~ t\ T N ~l O ~ C°!7 wool
N v1 ~ d; ~ M cn N N N ~ O ~ O O ° x O ° O ~ ~ x O ~ N yp
M t~ 00 ~~ \O ,--~ t~ N M vD ~ "~ V] x ~ ,~ x ~ 'ct ~ ~l ~ M M O~ N M v0
v1 w0 ~D ~ O v1 O M ~n " ~ ,~ ~ O p .~ ~ ~ N ~ vp o0 M oo O N
~' O N ~ N N N N N N N ~ N '-' " ,-i '-' ~ '-' ~-~ " ~' ~ '~ ~ N N N N
~ v1 ~ ~ ~n p ~ ~ '~ O ~ ~ ~ ~ ~ O ~ ~ x ~
N o0 ~p O ~ M d' O ~ ~ ~ M O M
Ci y ~ ~ ~ c!o M N N N ~ O x o O ° x o ° o ~ ~ x °
°° ~ ° so ~t v ~ r; r;
,~ 6v aW os o "4 a ~ x ~ a x a o, ~ ~ os '~ os oo ~ o o: M
can oo Ol 00 f~ N ~D N .-i ,-i '~ ~ ...i " ~ p1 ,-, .--i oo ~, ~O M M ~ l~ N
~_ ~ N N N ~ ~ ~ N N ~ ~'1 .. .. ~-v .. ~-~ ~ N
N ~ ~ ~ O ~ o0 VI M ~ij ~ ,jj ~! ~ N O ~ N N N N ,~ N
O_Vl~~a ~l~~~p~~~ ~ ~p~ N 0
v1 ~ ~ c~i M N N N ~-~ a x a x x '~'~ ,.°.~ x ~ ~ 00 x V°7 N v0
a ~ ~ l~ O Ov O
V7 M M ~ v7 I~ ~O ~ N ~O ~ ~ 0 ~ ~ ..
~ N ~ N °N N N N N N 0 ~; N ~D ~' ~ O Ov ~ ~ Ov ~ ~ N O N N
~_~~~~~~~~~~~ooo~o~~~~~~~~
N N ~ ~ ~ ~ M M N N N ~~ ~ ~.7 ,~ C/~ Vl ~ ~,.~ x C°J~ 0 ~ x ~ N ~ a ~O
Vi V, ~t M M
00 l~ N N M I~ 00 00 M ~"~ ~ N ,~ ,~ '~'~ ,_; .~ .-~ N .-i .~ M ~ ~O V1 00 l~
V'1 t
Ov Ov N Ov p ON N N °N O N ~ p ~ O_ N oo G~ ,-, ~ N ~ N ~ M ~ N ~O vp
'I~-' N N
0o M O N ~ N O p ~ ~ ~ ~ O O ~ O
,~ ,-, ~ ~ ~ O O O O O ~-x O O O N ~ ~ ~, o ~ i-~r
y0 ~n ~ ~ cn ri M N N N "~' x ra x ~ ~ ~l x ,.a ~ 00 '~'" " ~ I~ ~ s0 V~ ~ ~ M
cn
O M O ~ O v1 N oo ~ ~D O f~ ~!1 N N N ""' ~ -~ ,-i ~ N Ov ~' ~ O Qv '-' N Ow0
O Owt
.~ N N N ~ N N v0 O oho ~ ~ ~ y0 ~ ~ p ~ ~ ~ p O ~ N ~ ~ ~ N
or~;~~~~~~~~~~o°oooo~ooo os~~°-: r;~°
x ~ ~x..~ x
v0 O ~ ~ ~ ~ t'i M ri N N N ~ N N N x ~ ~ ~ a ~ ~ ~" ,-i ~ M ~ ,-; ~ Vi ~ ~ cn
c~i
OWD v1 M N v'1 00 v1 N M ~ oo '~ '-' ~~ WO oo ~ .. .--~ oo N O
O O N N ~D vp N o~0 ~ N ~ N V~D1 om0 ~ ~ vp N O ~ ~ x x ~ ~ ~ ra
~a~~~~~a~~~~~~°xa°a°xa°°a~,
M ~~ ~O ~ ~ ~ M M M N N N Vp M N N '~ '~ ,-i ,-.s ,~ '~ T .-r .~ ,_, ~' I~ ,-n
00 V) ~ ~ <t M
M ~_ Os v1 M_ M O_ ~O ~n O ~ Ov .~ " " M ~D ~ ~ l0 M O °_~ v0 ~O v1 I~
O 00 v1
NN~NN~NNN°N~N~OM~~~~ON NN~M~ ONE ~ONNNN
O O O O O ° O O O O ° O O
d' N ~
r, .--.~ ,~ M ,~
O ~O
N
M .~ V7 ~ M
M ~t ._~ .--v ~~
Q U
00
M M M M
-, .-i
145
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
M
Q; ~ ~ ~ ,~ ~ ..-.
Vi r; N r: ..; p p ~ ~ ~ N ~' ° vi ~
N N ~ ~.f.'. M M N N ~ C~j --~ ,~ ~ ~~r .-i .~ .~ 00 00 00 t~ ~O V1 d: p ~ p~
O y
t~ N ~D '~ ~ V v1 Ov cn Ov oho ~ ~ ~ W O Wn s0 O N t~i M '~ ~ W O O v0 O
-~n p~ ~~ .WO O o0 Ov O N ,~ N N ~~ N ,-, l_~ Cv WO O oo fir; O x C/~ O W_O O
N M N ~ N ~ N O N o0 ~ ~ ~ ~ ~ N N x N op ~ op
r
M N ~ ~l M cn N N ,-i r, v'i c~i N N ~ O O ~ O N °~ ~ M vt N
.-i .~ ..-n .-n ,~ .~ ~ ~ 00 ly0 ~D ~ C/~ Ov ~ ~D O V'1 vi
N ~D ~1 .-i ~ cn N n ~n Q~ M yn ~ O t~ t~ ~ Ov t~ oo Ov N o0 p N O O ~D O vD
t~
v0 00 00 .. v0 ,--~ ~~ O~ OW O M ~O N 00 I~ M .-, oo N ~ ~ M N ~ x O x ~ O C/~
N N ~ ~ N M M N ~~ ~ p .~ N ,~ .-r N N N N N N N N ~ x ,-; ~; ~ ~; ~ NO
ri N N '~ ~ cn N N ~~ yp M N N ~ O O ~ Ov oo t~ ~O ~O ~t '-~ ,N N ~ p ~ p in
v1
~ ~O O~ '." N v7 Ov ~--~ ~ 00 .--~ ....~ .-r .~ .~ .~ .-~ ~ N O V~ ~ 0o O V~ O
~ ,,a x O x OW ~
00 ~ O~ l~ ~D M C~ N ~O t!j V1 V7 M ~i' ~ N ~ 00 I~ V7 V'7 ~D ~ x Cn ~ ~ ,.,~
~ ~O M
N M N ~ ~ ~ O N N N p~ ~ pp ~ ~ M p N ~ N N N N ~ ~ .--i
M N N ~ d' cn N N ~ ~ ~ ~ Oy oo t~ ty0 W v0 f~ O O f~ O W v1
Cv oo M v0 Own v0 v0 OWE M N N ~ O O ~ ~ yn QW ~ O ~ ~ O x x a x ~ os
Q. o0 00 ~ ~ o~ ~O ~O ~O M ~ ~., ~-, ,~ ,-~ ,~ ~.~ Q, Q. oo r ~n o0 0, x ~ O
o,
.-a .-~ N ~ N N ~ N N ~ ,.:.; ~ ,_; ,:..; op ~p N N ~ ~ N N M _~ '-: ~' ~ ~ ~
N
~ M O p~
N N ~ "~ N N N ~ ~ ~ ~ ~ ~ ~ ~ vW O Oyp
M N N ...; d; cn N N ~ ~ °~ ~ 00
N .. .. ~ ~ ~ ~! ~ ~ O O ~ O
M N v7 ~ ~t tn t~ ~ ~ ~D Ov ~ N v0 Ov ~ ,~ t/~ x x a x
O f~ ~n ~ N N N t~ ~ dW~ ~ N N ~--~ O O N M M lmn ~t ~ ~ .~ r, ~ ,-i oo v0
O ,n N N N N N "' '-' ',-; ~' ~! '-' ~' N O N N N N ~ N .--i ~ O
x ~ ~ ~ ~ O N N ~ oMO ~ ~-N~ ~ ,~ v1 ~ ~ O O M
N N N ~-~ ~ N M O ~ ~ O O ~ O
cn N N N ~t M N N ~ -~ Os oo r l~ v0 V1 0o O O C/~ O ~ vi ~n
I~ v~ ~t O M l~ 00 O O~ O ~ ~ N l~ I~ l~ ~ 00 N ~ a C/1 ~ 'T'~ ~l ~
N OW ~ O N l~ O OWD ~ ~ ~ t~ ~ 00 O O~ O p~ N ~ .~ " ~' Ov M
N N oo N N M N N N ~ ~ ~ ~ ~ ~ ~ ~ N N N ~ cwp
0
M N' N ~ V ri N N ~ .-. N N M M ~ O N ~t ~ oo t~ t~ s0 U1 °.~ O v0 x
t/~ O x ,-i ~n "~
~O O 00 00 M O ~ l~ O ~ ~ 01 ~O d' ~O ~ 00 l~ "~ C/~ a ~ p~ M ~O
Ov O~ ~n w0 m O ~~ ~ O N Ov Ov ~ W .-. '~ N ,~ . .. vD N O~
N N ~ N N N ~ ~ ~ N O ~ M O N '-' ' 'n Ov oo ~ N O
o: ~ ~ ~ ~ ~ ~ ''a ~ N o o ~ o x
~ .~ os oo ~~i v o ~ ~ o 0 0 0 0 .n
M N N ~ ~ M N N ~ ~ ~j ~ N N N N NO N N ~ 00 00 two v~ N ~ x
~' s0 cn Ov N O OW ~ cn N ~''~ oo Ov Ov O ~ Ov Ov N .-
N Ov ~ M ~ t~ OW O M v0 ~n ~ ~ M Ov O O ~--~ -~ M N ~' oo v0
N O M O N N ~ N O N O N ~~ M M M N ~ O ~ p ~ N ~ N ~-~
b N ~ ~ ~ ,-~.~ ~ ~ ~ ~ ~ ''~ O ~ O O p O ~
ri N N ~ ~ ri N N ....i .~ ~ O ~n oo v0 N v0 M ~~ ~ 00 00 t~ ~ v1 N '~' a x ~
'~ "~' WO v1
.. ~W O v0 v0 v~ O IwD . ..
O Ov O_ N O ~ M_ v0 O~ '-' N .-. .~ .~ O N N O Ow0' M_ t~ -~ O v1 N N '-' ~ ~'
""' .-i ~ O
N ~ ~ N ~ ~ O N M ~ ~ ~ ~ ~ ~ N M N N O N '-' ~ ~ v0 ~
O N ~ cn N ~ ~ O O ~ ~ ~ ~ ~ O O O N O O O
~aM~~~~~~~ xxa
M N N ~ ~ tri N N ~ ~~ ~; vp ~ ~ N .--mn ~ cn ~ 00 00 (W O in '~ x "'~ ~ ~ ~ x
~
v0 l~ M O -~ -~ M ~ ~~ M " 00 ~ N l~ N ~ O~ --~ t~ O O OWn M O N N '-: '-' W N
-n OWO v0 v_0 ~~ V'7 ~ ~_ o_0 '-' .~ N N ~ N ~-~ N N ~O ~-~ O_W O ~ M M ~ t~ ~
M ~ M O ~ ~_
~~~~a~~x~~~~~~~~~~~~~~~~axx°aa°~~
M N N ~ ~ ~ M N N N ~ .--i M ,~ ,~ ~-~n .~ .~ .-r .~ Q~ 00 00 t~ ~O V'7 ~ ~ N
,~ ,~ r., ,-; ,_; l~ V1
Ov V o0 N W O M M N -~ s0 N N cn W vD v0 Qv -~ O ~ OW 1 ~ij p~ O N
~ .-r o0 O ~. ~ 00 l~ O\ Ov o0 ~ ~ ~ ~ ~ O\ t~ M Ov o0 ~ l~ O ..r M ,~ 00 ~ N
(~ N
N M O ~ ~ N ~ ~ ~ N M N N N N -~ ~ N ~ N N N N N N M d. ~ ~ ~.~, ,n ~ ~ O
p O O O O O O O O
O ~ N
O
NO
d
O ~ N
146
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
"
" v
r.;
~D N
O ~ O
~ O ~ ~ ~ ~ ~O V1 ~ ~ M
('n M M M N ~~ ~O ~ ~ ~ M M N
Ch M N ~~
a ~ O~ N N O~ M .--i
M O O~ ~ ~ ~ ~ ,~ ~ ~ t!1 O M
N N - , ~ ~O ~ ~ O~ N o0 N ~ ~D M
~ ~' tn M M M ~ O
~ M
~
~
00 OWE t~ ~ 00 ,~ ~ ~D Ov o0 O v
N t t M~ ~~NNNNNNO
.~ l ~O
.-r ~N~~~NNij.j~.i ~ (
~NO~NMN~
M M M M N N ~ ~ l~ ~ ~!1 ~ 'Ch ~ ~ ~ ~ ~ V' M
a M N N ~ M M N
t~ I~ ~ ~ 00 N ~ ~ ~n Ui 00 I~ ,-, oo ~ M v0
I~ N O ,~ 'C IW O N_ ~ ~' 0o v0 ~D o0
NNNNNNNM~ ~ ~N~~N~~OMN ~~ ~~NONNNNN
cn M ri cn N O ~j t~ ~ ~n ~n N y0 v1 ~ ~ ~
N "~' ~ ~ m N N . ri ri N
O M O~ ~~ t~ '~ M M ~O ~ ~ ~ ~~ l~ O f~ N
In M O ~~ O ~O ~D ~ ~_ ~ ~O 00 ~ N
O ~O ~ a N N O ~ ~ N N N ~ ~ N ~ N N
M N ~ O N N N N ON M ~ N N N
~ _
M ch M M N N ~ ~ t~ ~O ~i ~ N ~ ~O U1 ~ ~t
~ ~ ~ M N N ~ d; M M N
00 '~ O - o
s p ~
oo ~ ~ N
~ ~
'
~D vD ~ M t~ - ,~ 0
O ~ _ ~O I
N~NNNN~~a oo v0 t~ v1 O I
o0 . ~n O
_ N f
~NNNNO~~N~ ~~NNNN~~OM
cn ri cn M N ~ ~, ~ ~ '!? ~ N ~ ~O p ~ ~ ~
N N O ~ M N N m N ri M N
' ~ ~ ~
00 M 0O M ~O ~ M V1 l~ ~O ~ V~ ~ ~O l0 ~O O~
O~ ~ ~ O l I l~
~D N l~ ~1 a0 M ~ O M v1
O N o0 ~ ~ ~ N o0 N N o0 ~ ~ N ~ ".~,,
.-~ N ~ N N N O N Cv O a N N N ON N
N N M
a
M M M m N N M N ~ r ~ ~O ~ V~ ~
x ~ ~ l~ ~O V'1 N ~ M M M
~ ~ M N N ,., ~
~
~
v0 ~ O OW ~ -~ l~ t~ ~n t ~ ~ ~ ~ Ov ~ M
~ N ~ pp 00 ~ N .~
I~ ~-i r' ~ ..r r Ov O~ ~t I N ~_O O_ O ~O
.-r ~ M ~' ~ O I~ M M ~ O_~
..-m.r ~ ~.,~
~~~~~~~~a ~~~~~~~~~a ~~
~ ~ N ~ v0 ~D v7 ~
M M c1 M M N O ~ l~ ~O ~ v7 ~ ~ cn M M
~~ a d; cn N N '~
v0 W N l~ cn ~ M o0 I~ V1 N l~ N O ~n t~ Ov
O~ ~ l~ M ~ O ~n Q~ N ~ N ~-~ t~ Ov ~
NN~~~NONNO~ NNNON~NONN NN ~OO~NNNNON
~
~
"~' 00
d: ~ M tYi M N I~ ~O v1 ~n N y0 ~D W d: d:
M M N -n ~ ~ M N N ~ ~ M M M
.~ pv r Own .~ Ov M O N M I~ in O O M N_ vi
C~ 00 v0 oo ~ Ov ~ M ~ OW ~ cn
N N ~ N ~ ~ ~ ~ ~ ~ N N ~ N N ~ ~ ~ M N N
N v~j ~ N ~ ON ~ ~ N O
0 ~ 00
~t ~ M M M M ~ ~ 00 v0 V1 V1 _. ~ ~O v0 ~!')
N -i r-~ ~ M M N ~ M d: ~ ri M M
~
oo
M In ~ N M 00 ~ M V'7 O 00 ~O O O ~ ~ M M 00
~O 00 N ~ '~ ~ ~ ~ M M ~' M V)
00 Own ~D ~ Own ~ N t~ O v0 ,~ ~ ~ N o0 00 W
~ ~D ~n N N o0 t~ O t~ 00 Ov
N ~ N N N N N ~ I~ N ~ ~ N N ~
N N ~ (~ N N
O
~
~
M M c'n M N ~~ ~ ~ ~ 00 s0 V1 M y0 ~D v1 V ~t
.. ~n ~t ~ M N ~--~ ~ M c'n M
'~ ~
M oo .~ N M v0 t~ Ov N -w0 ~O N M O v0 O M N
I~ O ~ O Qv ~ N N ~ OWn O
.~ N v0 v0 t~ v o0 .-~ ~ o ~' ~ ~ 00 r M
oo Ov Ov ~ ~ o ,~ t~ 00 0o O O ~ ~ O
O O v0
~~ N v ~
M N N N ~ N N _ _
~ M v0 _
_
~ ~
O
~
wi ~t ~ M M cn 00 ~ v~ v-i ~ ~n ~~ ~D s0 ~n
ri N ~ ~; ~ cn N ~ ~ ~ d: M ri cn
~ ~
~O ~n O ~ ~O M 00 O~ O M O Ov M V~ ~ V) t~
O O M O~ O l~ O 00 V1 00 00 V'7
O l~ M I~ 00 M M N O O M O~ ~O ~ ~D I~ 00 I~
t~ .-~ O ,-~ 00 O~ I~ l~ ~O O N O~ o0
O N
N ~ N N ~ ~ N N N N N N N -~ ~ M ~ -~ -~ N
N ~ N N N N -~ N N ~ N
~
O O
M ~ l~00OvV'1
v~ v7 N N Nv1
.-r M M M
O ~ N d'NN
M O~ ~tN O~N
O M ~nd'OO
N l~ O~O ~n~O
v~ ov o0o W~n
M M M MN
w A
w
M 'cY V1
147
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
ri
r~
so ~ "
M
OfV~-r~ct~ ~~'; N~-i
M M N N N .-i ,-i "'~ ~ ~ p ~ ~ '~ ~ ~ a0 I~ I~ \O V'1 ~ ~t <t ~
M O ~; t~ oo Ov Ov oo M v0 v~ N M °~ M O O ~ ~ yp O ~O O N N ~D Os
M N
.., .. G N O o_o 0o v0 ~ v0 0_o M ~: O O x a O ,-, ~, pv O ~ o_0 o_o t~ 00 t_~
~n O_v O
O oo O can N
nj ~ x O M ~ c'n M N N N ~ ~~ x ~ ~ O ~O ~ ~ .~ Oy o0 I~ ly0 V7 V1 ~t <t N ~
00
00 ~ N p ~n ~ ~ ~--~ oo O O M ~ O O O O p~ r, M O ~ N t~ o0 O Ov ~~ N O N
N ~~NNN~NN~~~v~la~xa'~' ~NNN~NNNONONN
N r, ~ O M ~ M M N N N N ~-~ ~ O ~ p p O ~ ~ ~ p o0 f~ l~ ~O V'1 V7 ~ ~ N
~O N ~~ N ~ ~' M M ~' N I~ t~ ~D x ~l ~ .. .. .. ~ ~ M ~ ~ O O M Ov a O
r, O M N ~ ~ oo v0 ~ ~t Ov o0 t~ ao M x x ~ " ~ t~ .-. ~yn '~ M oo v0 O O M .~
O VI
N O O ,~ ~' N N N ~ N N ~ ~ N ~ ~ ~ ~ ~ p~ ~p op O "'~ N N M M M "
~~~~N~~~a~~~~~~a~~~~Nx
00 ~ O ~y ~ M M N N N N W O ~ ~ O O ~ 'C ~ ~ l~ Iy0 y V1 ~ ~ N O O
a. os ~~ .o ~- o cn M c~ t~ ,--~ ~ ~ ,~ U? a c v; ~ 0 00 0 0. ~ r ~ oo W t
00 ~O N ~ x ~ O I~ I~ ~ r1 O~ O O~ ~O x ~, ,_; x cC .--i ,~ .~ ~.r, Ov M M l~
I~ N ~D O
N N ~ M N N N ~ ~ ~j ,-, .. .. ",.,~ ~-i p ~; Vj N N N N ~~ -~ N N N N r;
~l ~ "-a v 00 M ~ M N ~' N N ~ oho
N ~ p ~ O ,_; ~ M M N N N N ~ ~ O O x a O O ~ ~ n ~ ~ ~ V? ~ ~ N ~ O
N O O O ~ ~O ~ N N ~D t~ ~n O ~O ~ x a ~ ~ x x M ~n oo r; N ~ oo ~n t~ x
M ~~ M ~D ~ ,-, v0 I_~ 00 ~ t_~ ~n ~ 00 ~ ~ .-~ ,-, ~ ~O N_ O vp O~ a_o O_v ~
~ O v~ O
O ~ p O ~ ~' pN N N
N N ~ N a ~ ~n ri ri N N N N ~ ,~ ~ x x ~-1 O x ~ ~ oo (W D v'i Vi ~ ~ c'~
~ T_ " ~D N N_ ~ I~ oo Q~ v1 v1 v0 _~ r.; x " Owl M t~ O N O ~n V
O N M N ~ ~ N M N N ~ N NO N O M N p~ O ~~ ~ ~ M O O N ~ N N M ~ N N N N
00~~~OO~O~ N WO~
N N ~ M a ~ v0 M M N N N N ~ 01 a a x x ~ ~ N ~' p ov oo ~ ~ ~ Vi ~ ,v, M E-~
a
Op ~ oo N ,_, ~D v0 N_ M O v0 a0 M t~ ~ r; ~' " " ~ ~ '~ OW O o0 V7 V M M_ M
~ N cn ~ ~ N ~ N O ~ O N O M N ~ ~ ~ N N N N ~ ~ N N N v0 N
" ,~ O O x O ci ci ~ O
ci ri ~ ri ''~ ~ ~D ~ M M N N N ~ ~ a a x " ,°~ x ~ N N os oo tyo so vy
~ r; x ,~
N O M t~ rr v0 ~ oo v1 lW O o0 Ov ~ V1 ~rj N r, '-' ~ ~ ~, l~ Ov O N v1 dw0 N
N N
N v0 O t~ ~ ~ ~ ~ I~ N Ov N ~ O O ~ M ~ ~ ~O o0 0o vW O oo ~ Ov ~ _
x .O O O O O O ~ ~ O ~ N ~ N ~ N O N N t~
~' ~' O
~n N ~ ~ ~ ~ O M
N N 'O~' ~ a y0 ~t M M N N N ,-i ~-, a ,~ x x ,~ V7 ~ ~ Oy o0 t~ ~O ~O V1
00 .-. ~p M '~ m t~ O O N O ~ M Os ~ M N ~' .. ,...; .~ N ~ N M ~ f~ M M ~ M ~
~ M cV
O_O l_~ O 00 ~ N O_~ ~O O_~ N ~ ~ ,~ M ~ 00 ~-rj O ,~ .. .. V' V1 ~ O G~ Ov M
l~ 00
O '~ O O O O O O . ~ ~ ~ N N N N N ~ N N ~
x a x __~~~~~~~d~~d~aa
N N ~ ~ ~ ,ri t~ ~ ri ri N N N ,-.~ N ~,~ x x ~ ~ ~ M ~O Ov ~ 00 I~ t~ v0 vW n
~ M ~
I~ ~~ V'1 Ov ~ O ~_ ~ Ov V'1 V7 Ov ~_ ~ ~ ~ N ~-~ '~ N ,-~ ~ N v0 lW0 QWO O t~
M M N
Nc~nON~N~M~N~NNN~~~N~p~ NNN~NNNNNNNO
"'~ N
O ~ ~ x ~ V7 x ,Ø.l x cV
NN ~-n~,-i ~~I~VMMNNN~~~j~j.~.-;~;~; N~,~p~00I~Iy0v1V1~M~N
t~ ~ Ow0 M N ~ ~n N Ov ~ M OW O v7 ~.j .. p M ,~ p ~ vp oo I~ N ao v0 00 ~n t~
t~ ~. s0
00 t~ 00 G~ M VWn O~ 00 O Ov 00 M ~ O~ ~ M op N ~ ~ N v0 ~ Ov oo t~ t~ Ov OW ~
Ov
N N O O M N N ~ ~ M N ~ N M N ~ ~ ~ ,~ ~ ~ N N ~ N N ~-~ ~ ~ ~ N ~
O O O O O O O O O
O 00
V7 V7 M V7
.-r .-w M
~O M
~ O
O
M
M M
148
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
.M-in ~ N ~
'~ N
ri N N N N N ~ yi ~ ri cn ri ~ M M M N N
~ p M N N N w~ N -~ Ov
~D N oo N ~i --~ ~ N t~ oo ~n ~ N ~t ~ v~ V
~-~ oo cn
i ~
~ ~
~r M O O
p t n N O O
w M M ! ~ 00
~D 00 l ~ t~ N V1 M ~
~ 00 00 O ~D O~ O O
M ,~ 1 ~O V'1 ~O l ~ Ov N l
~ l
~ ~ _ _ _
~ _ _
_ _
_
_
M G
v0 O ~
~
NO ~ cn M N N N N ~n ~ M M M M N ~ M M M N N N
~ N ~ C N N ~ N
IF
r~r OW _O ~O M O O N O 00 ~ ~ ~ 00 M_ O O Ov O 00
'~' M I~ O ,_; O~ M N_ O~ O_~ 00
O ~ ~
N N N ~ O N N WD ~ ~ ~ N N N ~ M N N
m N N N N N N N
WG p
M M N N N N N ~ ~!1 ~ ~ M M M ~ ~t M M N N
~ N N N ~ N N
.~ynvWnMOl~ooN.~ OW )~oooOVW~NOv~ NN~~OVl~~N
xx o 00 ~O 00 ~O N l~ O~ O~ M ~
~ r~ l~ V1 l~ ~ 00 -~ N l~ M .-n ~ I~ ~ M I~
~ 01 l~ 00
~
-; N N N O ~ M N ~--~~ ~ ~ N N N N ~ -~ ~ N N N
-a '~ N N N N N
_. ~ ~ O O
M
~ ~
00
~ ~ <.i cn N N N ~!yt ~ M M M M ~n ~t c!~ M N
p O N N ~ a b N N ~ N N N ~ N
~
,T,
~ ~ MNW
~ ~ NN~
N ~ ~~
~ ~ N
W ~
M~~ ~~~~
r; o o O
~ MC o OC
n 0o o
V O O N N N wn O
IO 00 N t
O V
N O N M O N N ~ N O wn N -~ N
N M ,_, N N M N
ri cn N N N N N ~O ~ ~ M M M M v~ ~ M M N N
~ N O N N ~ N N N
\ ~ ~
M M N
~
" ~ M N 00 V1 01 In O V7 ~D 00 00 ~~ ~ ~ 00 ~i
a O , ~t ~O 00 O~ O
-i O M V~ 0 lw0 Ov N N
,y 0 v~ ~D Ov oo v~ N ~D o0 0o I
N ~n M p - 00 m OW ~ ~ M
o0 O o0 w
~ O O ~ N N N ~ .-I N N N N
O ~O N N M N N N -~
O ~ ~ M M N N N N N ~D ~ V M M M M ~ ~ M M N N N
~ N a N N ~ N N -~
~''~,~n~ ONI~~DOO~OvOM~ \OMI~~D~I~O
O~sO~00vc 00
~CvN
'-: _ N ~ N ~ N ~ N _
~ _ N O N ~ N N M N N N
pN O M N N ~ N ~ NO
N N ~'~ ~
~M ~~~ ~~~'"S'"l~
M M N N N N N w~ M M M M N N ~ ~ M M N N N N
~ ~O N
O
~ , ~ ~ ~
.~ ~ W
-, v ~
~
~ N , Iw_O 00
W O W _O N_ M t~ d' O~ M t~ '~t ~n N N_ M I
V~ _~ v0 ( O O t
O O t_
~ ~ O N ~ N
~ N N N ~
N N N ~ ~
M N N N
N N N ~p N -~
N N N N
~l vi cn cn N N N ~O ~n ~ M M M v0 V M M N N
~ N N ~ ~ a M N N ~ N N N --
,..; ,~ ~, ~ I~ ~ N ci v0 ~ ~ O oo v~ OWO ~ OW v_0
~ M t~ t~ -v .-i Ov O N O l~ ~ O
~; ~ ~ N N N N N N ~ O O O ~ ~ N
~ N ~ ~ N N ~ N ~ N N N N
O
N
N ~ ~ N N
O ~ ~ ~ O -~
O O
~
~
''~ n ~ M N N N N N ~O W ct M M M oo ~ M M N N
W ~ ~ '~ M N N ~ N N N
~' oo s0 t~ ~ r cn ~i ~n oo O
.-i n o0 s0 I~ o0 c~i i OWD Ov ~ O -~ N
M '-' ~ ~n ~ ~ cW O ~
t
_ _ _
~ N N N N N ~ ~ _ _
~ ~ M O ~ ~ N ~ O ~ N N N ~ M ~
N N M N ~ N
i N M M M M N N N oo ~t M M M N
i ~ ~' N N N -
N N ~ ~ 0 ~
~ " v n V 00
'-' r cW v
N N ~ s
y s
~ 00 '
v0 W t~ oo O ~ c M v1 Q
N O t M O t~ N O
~ N ~ O vD -y O OW ~ ~
In l~ ~O C~ N l~ M ~ ~ N
00 O (~ ~ ~ 00 ~D I~ ~ M ~ ~O ~O M 01 ~
M O ~ l~ ~ O w l~ M M
N N N N M N ~ M -~ ~ N N N M N ~ N O ~ M M N
N ~-~ N M ~ N N
~
~d~ ~~~d ~~~ ~~~x ~d
d~
~xx x
~; v'7 d: M N N N vD ~n ~ cn M M 00 ~ M cn c!o
~,~ N N ~ ~ r.; M N N N --! N N N N
,_, ~n ~ .~ O~ ~O ~O ~D ~ ~ O ~ O ~ .-r M l%~ O M
p d' ~ O v7 ~ M ~_ M In M N l~ O~ ~O
~ ~ ~
~ O
~~ O
~
~
~'-' N~N~ONNN~~~ NN O
~NNN N
~ NN
NN
N
O O O
O
~
Ov O
I~ M 00
00
et O
O N M
N
U
~1 W
av o
r ~n ~n
149
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~i so
00
O v0 .-r N d~
M vD d: ~ M ri N N ~-~ ° ~ O
~ ~O ~ ~ ~ M N ~ ~D ~ ~t ~ M ri M N N N ~ '~i
v1 O r ~n ~ M oo cn N O ~ ~ ~ T ~-~ v1 ~ Ov M O~ t~ O ~n M oo O_ v'i ri o_o ~;
vD
NN~N~N~M~ ~ NNNN~N~ ~0~~~~~~''~O~NO
O N
~
N vp ep ~ M M N N ~ ~ 0 ~ ~ ~O V'1 d: ~ M N ~ I~ ~ ~h ~ M M M M N N
O_v U O o0 ~_ n l~ N N x O ~ N vo M ~n ~ ~t t~ N ~ N N ~ Own I~ GW n M ~;
N N N N M N ~ ~ v1 .-i ~ N N N N O N N ~ N N N N N N N ~ ~ N pip p
O .~ N t~ vi ~ ~ ri N N l~ vi ~ ~ M ri ri ri N N ,-~ O
'~ ~O ~ ~ M M N N
N O~ M ~_D ~ ~-~ ~ ~D N x' ~~ ~ 00 ~O OW O M ~ l~ ~ 00 V1 M t~ l~ O O~ M_ ~O
Ov ~
NONMNN~~~~ pOp ~O~NONN ~~~NNNNNNN
~~~~~~~~~x~ ~~~~~~~~~ ~~~~~~~~~~~x
N v0 V1 ~ M M N N ~ N a " ~ t~ V'7 ~ ~t M N N t~ ~ yT ~ M M M M N N
N M ~ ~ ~ cn Ov ~_' .~ a_o ,-~ N t~ IWi'i ~O ~ ,-, ~O v1 ~ ~ N M ~_n ~~ O_
NNNN~NNO~ nj NNN~NNN ONNONN~~NONNNN M
h~~~~~~~~x~ °
N y0 ~ ~ M cn N N ~ N x ~ ~ l~ v1 ~ 'd: M N N t~ V1 tn ~ d: M M M N N N ~
~~'1 V N N l~ ~n Ov M W O . ~ M M VWl1 ~O l~ 00 N \O M ~ ~ N O I~ ~ l~ ~C Cv ~
O ~ ~ O (~ O~ O~ M ~ N ~ M I~ V1 ~ ~ (~ O ~O ~ N M 00 O~ O~ O~ ~ G~ M
N N ~~ N N ~~y ~ ~~~!! O '-' M,.,~ O,y ~~ O M N ~--' N ~ N N N N N N N N
,,..,,//
~~r~rO M00 " ~ ~a O
N r wi V cn cn N N -~ ~ ',I'" ~ N t~ wi ~ ~t cn N N ~ ty0 ~n ~ ~ ri M cn N N N
~'
Ov V7 O ~ ~ s0 N ~ ~' _~ ~ Ov ~ t~ O o0 ~n ~ ~ N ~ ~ M Ov ~ ~ CWT N_ N O_
N N O ON ~ N N ~ ~ p~ M O ~ N N N ~ N r~.n N ~ N O O N N N N N ~ N N
cri
x O oo ~D
N t~ N ~ M M N N' ,-i .~ ,~'r, N N t~ ~ <t d: cn M N N tW0 V) ~ ~ M M c'i N N
N ~-i N
M M Ov ~w0 l~ v0 0o v0 ~; ~ ~ M O ~ M v0 ~ 00 .-i N oO N_ O ~n N O~ ~ ~ v~ N
~_O
OOO~NNN~M NNONN~~N ~NMNNO~NNNNNN
N t~ v~ ~ ~ ri N N .--i ...i r'r, 0 N I~ vi ~ V ~' cn N N Iy0 vi ~t ~ cn cn ri
N N N ~ M N
M m ~n O ~ Os O t~ O ~ N M O_~ M_ O O o0 ~ ~O ~1 Ow'i ~ ~ ~ ~O oo ~_O l_~ N
~NN~NONNN'-' ~~NNNNNON~ ~~~NNONNNNMNN
O ~ ,-~, ~ ~ ~ ~ x ~ ~ ~ b ~~r
t~ v1 V. ~ M N N ~i ~ '~ O ~ ~ t~, V1 V7 d' ~ M N ~ 00 v0 V7 ~ ~ M M M N N N ~
N Ov M f~ M W oo .~ N ~1 ~' O N M N_ M M ~D N M v0 ~ ~ Ov N v0 l~ oo M N oo O
t~ v0 _.. O
,~ I~ M .--m0 Ov N M N O
M N -~ O M ~ N N N ~ ~ M ~ N N N N N N ~ N O N N N O N N ON N N N
O ~ ~ ~ O y0 O ~ ~ ~ ~ ~ ~ ~ v_'i
N o0 v1 ~ ~t cn N N ~~ ~ x '~ ~ ~ I~ ~ vi et V cn N ~ 00 y0 ~ ~ ~ cn cn cn N N
N ~~ ,-i ~n
In M l0 V1 ~ 00 V1 O ~ Qv ~ ~ Ch ~ M M O~ 00 00 O\ ~O ~O M \O I~ V1 M O O~ 00
O V
O ~ O~ W O 01 O~ C~ o0 M d' ~ N M ~ ~D O~ ~O M V1 ~ N ~-~ d' 01 ~ ~ ~O oo ~ M
O ~ ~~ '-' O
M O O ~ ~ N -~ ~~ N ~ O N N N N N N N N M N ~ N N O N N N ~-~ ~'-~ N M
v1 . . ~ O~ O ~ ~ . O
N o0 ~ ~ ~ M M N ~ ~ r, ,_; ~~ -~ l~ V7 V~ ~ ~ M N ~~ OyO V7 ~ ~ M M M N N N
~r ,-i N
M ,--~ O v0 O O O N M ~t ~p ~ ~ Ov OWE d' v7 O ~ ~~ ~ ~ t~ 00 v0 M O~ ~~ M 00
vi Oyj
l~ l~ ~~ O O 00 O~ ~O M M ,~ ~ O~ O N ~ I~ ao 00 O M I~ ~ O O O~ ~ V'1 O~ 00
~O \O t~ ~~ N O
N N M N M ~ N ~-~ N N ,n ~ ~ N N N -~ N N M N ~ N N N N O N ~~ ~~ N N ~ N
O O O
M
M ~ ~7 ~'r
t/~ v0 M
U w ~ °w
N M
150
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
l0 ~ ~ M M ~ M N N N N ~ N M M N N N N N ~ M
M N ~ ~j ~~ ~ ~~ ~ ~ M
N
O t~ ~ N ~ vwp ~y ~ pv pW O ~n r O OW ~ O N Os
O ~ v1 N C N ,-~ o0 N o0 ~n
I
~ O f~ Q~ ~ v~ ~D .-. f~ O M t_~ O a_o N O v0
O ~W O v0 I Ow o oo t~ IW o
O w0 O O O m
v
_ _ _ _
b _
.. C
vD ~ ~ cn ri ~t ri N N N N N d M N N N N N ~ M
M N ~ ~ ~ ~ -~ ~ --~ ~ ri
N
O O oo ~ v0 M .-. M N O N n OW O o0 ~ N I~ Wn
O ~D v0 ~' N --~ Ow ~ ~n M tw0
M M Ov ~ Ov t~ t~ vW n O ~ o0 0o d~ M t~ ~D
d' p~ I~ N v1 I~ Ov Ov N t~ -, N
t~
~O
N N N ~ N N N N O N M N N N O ~ N N N ~ N ~ N
N p~ N ~ N N N N
N
v0 ~ ~ cn M V cri N N N N N ~ M N N N N N ~ cn
M N ~ ~ ~-v -~ ~ ~ -~ --~ ri
N
Vj ~-, 00 N M ~ I_WO O V1 f~ Ov ~~ IWO Ov ~t
O Ov N_ ~ 00 M_ vD O ~ I~ ~ M ~
~ ~ ~ O 00
~ ~O ~~O ~
~ ~
~ ~O
NMN~ N N M N
~N NNMO N N
NN NN
I~ v1 ~ M M ~ cn M N N N N ~ M N N N N N ~t
M N N ,~ .~ .~ .-; ,-.. ~ ~ M
M
N
v0 N M Ov oo Q, N oo Vi O N M v0 v0 Vi ,--~ p vp
,--~ m Ov M ~t V O~ ~t oo O oo .--i
"
~ 00 ,~ 00 O 00 ~ N I~ 00 v~ D t ~D
00 ~ O N ~ ~ M ~ ~
O l d' ~ O v0 ~D O
~ v W O
O l O ~
~ o
_ _ _ _
_ _
_ _
_ _
I~ ~ ~ M M ~ M M N N N ~ N ~' ~'~ ~'~ N ~ M
M N N .-i ~ ~ ~ N N N ~ --a M
N N
~ ~n ~D M ~ ~ v~ ~Y N cn N ~ O N v0 ~ 00 v1
w0 -~ .--~ Own -~ N v0 0o Owt N
N cn
t~
~O l~ ~D M '~ ~D ~ I~ M l~ ~ O OO .~ ~O ~ t~
Ov O ~ ~ 00 N V1 M d' Ov 00 l~ ~ M I~
~ ~D
N N N N N N N ~ M .~ N N ~ N M .-~ M N -~ O N
~ ~ N N N O ~ N N ~
O N
r~
t~ ~i ~ M cn ~ c~i M N N N M ~ M M N N N N ~ M
cn N N N ~ ~ ~-w -~ ~ ~ ri
~ N
N Ov w0 N M w0 t~ O ~ OW N N ~ Ov cn v'i o0
t~ O ~' ~ ~ ~ v1 o0 M N N o O
~ a0 t~ N N o M ~D O -~ O M Ov o0 00 ~
M t~ ~D ~ t 00 .~ ~
00 O t W O o ,~ O v
W t
~ W
_
_ _ _ _ _
_ _ _
_
_
~~~dx ~~a~
f~ ~n ~ cn ~n M M N N N cn ~ M M N N N N ~ M
ri M N N ~ ~ ~ -~ ~ N -~ M
.-i M
v1 cn oo M W ~ O ~n I~ t~ O -w0 t~ ~O ~n vD
oo v0 ~ oo ~ O ~ ~n ri I~ ~ ~t ~W
~ M O
v0
v0 v0 N OWO ~O O ~ lmn M I~ v0 -mD ~O ~ f~ Ov
N v0 v7 - v0 ~ M N ~ ~ t~ O
o0 v0
~
N N N ~ N O N M N N N N N ~ ~ N N N N ~ N O N
N N N ~ ~ -~
N M
00 tn ~ M M ~ M M N N N ~ M V7 M M N N N ~ M
M N N ~ ~ ~ N N N ~~ M
~ M
n I~ oo Ov ~O cW O N I~ o0 cn ~n M N M v0 M
~ N ~n Ov oo .-i .--~ ~ Ov
M I~ ~ ~ ,--~ O N ~
M
_ N~ ~ _ _
~ O ~ N~
~~ N
NN ~~
NNNNN N M M MOO
NN N N
O N
O
00 ~n ~t cn ~n M M N N N cn
M M N N ~ ~ ~ -~ N ~ V'7
w 0 M M N N N N d'
N M
M
Ov cn o N o0 r ~ ~ cn Ov ~ o ~ ~'~
0 ~n N l~ ~n i oo N Ov M N M O OW v0 ~t N ~
O t Ov t~ O
~
_ _ N _ N ~
_ ~ ~ N N ~
~ ~ ~ N N ~ N N ~ N
~ N N
O
N N O N
N O N N N N
N N
O
0o v1 ~ d' ~D ~ M N N N M ~O M M N N N ~O
M M N N ~ N ~ ~ N N N ~-~ ~ ~
~--~ M
M
W ~ ~n l~ ~n N N cn ri in cn N ~ M OW ~ N CW
oo O M cn oo ~t v7 v0 ~ Ov o0 N ~
N O Ov O~
N
_ ~ N N N ~ N N N ~ N O ~
~ ~ N N ~ ~ N N
~ O ~
~
~
N N O O N
y- N N
-~
N
ao v0 ~ ~ cn f~ ~ cn N N N ~O 0 M M N N N N I~
m M N -~ N ~ -~ ~ N N ~--~ ~ d;
w M
M
-~ W O ~ I~ v0 ~ ~t o0 t~ ~ O ~O oo t~ I~ ~ M
Ov ~ N oo M M O v0 t~ I~ O M Ov ~ ~
v0 t~ M N M 0o v0 t~ N ~ Ov ~O M N t~ ~ O O
v0 M M o0 oo Ov oo N N N Ov O oo ~ M 'O
--~ o0
O t~
-~ N N N N ~ ~ N N ~ ~ N N O N N N N ~ N N ~
N N N ~ N N ~ N ~ M ~
M N
O
~O ~D ~D ~O
O~ ~ N O
I~ v7 N
vO O v>
N O~ M
M 01
V7 ~' V~ V~
w w
151
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
N
.. O ~
N N ~~ ~~ ~ I~ s0 v~ ~!p V ~t cn c'i N --~ ~n ~ et M ri cn N N N ~ ',~" ",a ~O
~D v1 ~
O ~D ao 0o p~ v0 t~ ~ ~1 00 ~ Ov O Ov N !~ v'W O v0 ~ ~ N ~ ~ O _~ .b N N ~ O
O
N N N O ~ N ~ N N N ~ pN ~ ~ N ~ ~ N N N N N ~ ~ ~p ~ ~ ~ N ~ N N O
N N ~ ~ ,~ I~ ~D V'1 V7 V'7 ~ M M N ~ ~ ~ ~ M M M N N N ~ ~i ~ ~ ~O ~O ~ ~
Ov M ~ t~ ~ N ~ ~ v0 v0 ~-~ Ov M t~ O o0 0o M .--~ O I~ ~ M oo Ov N O ~~ ~ oo
Ov M N
00 ~O M ~ op 00 00 O N M ~ 00 O~ 00 ~~ l~ N M ~O M O~ M I~ O ~ ,~ ~ ~O oo O~ O
~ ~D
N N N O ~ ~-~ ~ N N ~~ N wn N N ~ N O O N N N ~ M N v0 _~ ~p ~ ~~ ~ M N N
p oo N
. a V1
N N ~ ~ .-i fy0 yD ~!1 ~ ~ d: M N N ~ ~ V c!pn m N N N ~ Iw0 v0 v'i
v1 O N_ v0 ~" W O l~ N_ M o0 v1 f~ N N v0 ~ O ~ c~i o0 I~ v1 I_~ o_0 N O O~ oo
v'i M M l~
N M M ~ N N ~ M N N N N N N N N N N N N N N N N ~ a ~j N N N N ~ N
N
N N ~ ~ " t~ ~D ~O ~n v~ ~ r1 M N N vi ~ ~ cn M M N N N --~ ~ t~ ~D W ~ V 'ct
p~ oo ~_' v1 v~i N t~ o0 M .~ cn ~i O Own N O ~D ~_D ~_t M O M N '0,T,' m o0 .-
-~ v»0 ~D
NN~N ~NONONNNMNN~ NN~NNMNONONNO,.; ~N~ONNN
N N ~-~ ~ t~ ~O vG ~n W ~ ~ M N N v1 ~ ~ M M M N N N N ~,~ O ~ I~ ~D y ~
N v'1 M I~ ~n ~t ~ I~ t~ V7 N ~n O O ~ \O v7 ~ O~ ~~ ~O Ov ~, O M et O I~ M
N oo M oo ~ 00 N O Ov N ~ N N N N ~ N ~ N ~ N ~ ~-~r N O ~ ~ N o0 ~D QW ~ Do ~-
-~
N N N N M ~' '-' ~~ ~ N ~ N M
N N N ~ ~ I~ ~ ~O ~Wn V ~ cn N N p ~ d: M M M N N N N d; O ~ l~ s0 W m ~ et
Ov ~ s0 00 O M Ov M cW O o0 ~n ~O ~ ~-~ N O l~ O v0 M vi N N Ov ~ ~ I~ OW 7 O
t~
~-~ l~ N M ~O t~ M ~ O~ ~ O O V~7 ~ 00 N O M ~ ~ 00 I~ l~ l~ ~ .~ ~ O~ t~ O O
~
N ~ N N M O ~~ N N N M N N M -~ N M N N N N N --~ N I~ ~ ~ ~ N N --i N M N
N N N ~ '~ a0 ~D vD ~n yi ~ ~ M cn N wi ~ ~ cn cn cn N N N N ~~ a N f~ ~D v-i
v-i V V
Ov M oo ~ 00 O N oo N V O oo M o0 W ~ M a Ov Ow0 v0 N M N ~ ~ N M Imn s0 M
O~ 00 O~ ~ Vl N ~~ M M 00 O 00 1n I~ V) M M (~ Q~ 00 ~ .-~ ~ '~ 00 00 O ~O WO
N M ~ ~ ~-~ N N N N N N N N ~~ O N O N N ~~ O N M M N ~ ~ ~ ~-~ N ~ N N
N ~O ~t
N N N ~ ~ ~ c0 l~ v0 vi vi ~ ~ cn ri N ~O V ~ cn ri M N N N N ~ a N I~ v0 V1
~1
'dWD M W N ~ O l~ M O~ O l~ N ~O d'0 ~O d' M ~ O ~ ~ O~ O O ~O ri ~ O~ O M O~
V7 'ch
~O O~ O~ V1 O~ O ~ M ~D I~ ~D l~ 00 G~ ~ I~ O M 00 V1 00 O~ O~ O~ ~O ~n w0 t~
G~ N lW D
N ~ N N ~ M N N N N N N N N N ~w~ ~ N N N ~ ~ N ~--~ N N ~ ~ N N N N
O
N N N ~ ~ ~ oo t~ s0 v~ y7 ~ V M cn N .~ t~ ~ ~ ri ri M N N N N ~~ a N f~ ~ vi
~n ~ V
_ ~ ~n '~ N v0 I~ Ov ~ ~n ~
O_O 00 00 ,--~ ~ ,--v U ~_O M ~ \O ~ M l~ M V~ N M O l~ 00 l~ ~ lW O
NN~ON ~NM~N~NNNONO ~ON~N~N~NNOONO~o ~~~ONON
,0~,
N N N -~ ~ M Ov t~ ~O ~n ~i yt ~ ri cn N ~~ I~ v~ ~ ri M M ri N N N ~ ~ ~:,~
oo ~D vi ~n ~ V.
~D M N O ~ ~ Ov O ~ Oi Ov N ~ ~ O et ~~ N OW ~ M .~ f~ N N ~ 00 M N N ~n ~ v0
l~ ~n
.-r 00 I~ M I~ M N OO l~ O ~-~ ~D ~n Ov Ov N ~W O N I~ 00 M o0 0o M O o0 .~ O
N t~ ~n M oo I~ M
. ~o
N N N ~~ ~~ ~"~ O~ Iy0 V7 tn d~ ~ M M N ~ I~ ~1 ~ 'Ch M M M N N N ~ ,...., M
00 ~O ~ V~7
N t~ N Ov 00 M tn t~ N o0 ,~ .--i ~ v) O ~~~~ o0 ~ ~ oo O Ov M Ov oo Ov ,_-i
~n ~O W O O t~ t~
Ov O oo dwD M t~ ~n t~ t~ Ow0 two ~ OW ~ ~D ~D oo v0 M two v0 00 ~n Ov N v0 O
M ~ ~n ~D
N N N N O ~~ O ~ N ~ N ~~ O N ~~~ ~ ~~~i N O N N ~ -~ N ~-v N ~ ~ N N N N N N
N
O
O ~ N
t~ I~ I~
N
v7 N
'-'
~p M O
N
O M N
O .~ N
152
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
M oo ,-i N ~-i <f
~M
M M N ~ ~ Oy o0 I~ ~O ~O ~ ~ M N ~ ~ M M N N ~ ~ ~t ~ ~ ,_~.,, N .~
~O N_ ~ ~ Own oo ,-i oo vG I~ Ov ~_ ~ Ov ~ ~ Os ~ oo t~ a O E-~ O
N N N ~ ~ N N ~ N N O M ~ N ~ ~ N N N N N ~ ~ C/~ ~ ~ N
p o_o ~n ~
~ M cn N ~ ~ Ov o0 t~ ~D vD Sri ~ cn N ~ M ri N N --' ~' O vD O ~
00 M ~ V1 ~p ~ N_ l~ ~ V ~~ O~ O V1 M ~ M ~-i ~ ~~ ~_D ~O I~ n.~ O r.~ O ~'
~''~ ~p
N N N ~ ~ ~ M ~ N ON N N N ON N ,M-, N N N N N N N N 'x ~-i "x
N
~ t~ ~ ~D
~ M M N ~ p Os oo l~ v0 ~D ~n ~ cn N ~ c~i c~i N N ~ ~ O ~.,~ O ~ N ~
v0 d' ~ M ~' ""~ O~ ~ l~ ~D M v1 Ov ~ -~ O~ 00 O vO ~ ~ ~O l~ ''4 M x O ,~ 00
Ov M ~..~ M ~ p~ I~ O~ ~ O~ ~D Q~ ~ ~D N pp ~ ~O M l~ ~O O~ V1 ~ ~ "~ N 00
N N M O ~ p~ ~ ~ N O N N N O N ~p N O N ~ O N N N ~ ~ N N
~t cn cn N ~ oo I~ ~D v0 ~ ~ c~i N d: cn M N N ~ ~ a ~ ~ N ~-'
ri M v~ ~ ~h O vp oo O t~ cn two N ~ O ~ oo I~ Os Ov M v1 x O W O
V7 O~ 00 t~ "'~ ~" O~ M ~O 00 M O V7 M I~ '-' l~ O~ ~ 01 t~ M V1 N x .--i r~
I~ ~_O
O ~ ~ N ~ op ~ N N N O N N N ~ ~ N ~ N ~ N " ~ ~
N~ N 0
~t cn cn N .-, Oy oo t~ ~D v0 yi ~ ~ N ~ v1 ri M N N ~~ ~ x p V~ ~ N ~'
Q1 ~p .-r Ov pp O ~ M ~ V7 t!1 ~~ M ~ ~ O~ M N ~ ~ O l~ V7 M M
M OwD ~ N ~ O ~ Owl ~ oo ~ O ~ O ~' ~ ~O I~ M t~ ~ N ~ . ~' "'~ w0
N ~ O ~ ~.' '-' ~~ N O N ~ N N N ~ ~' N ~~ ~ N ~ M ~ ~ ~j ,.; .~.'
M M N ~ Os oo ty0 v0 wi ~!'~ ~ N ~ v-i M cn N N ~--~ ~ a x '~-4' g N
00 I~ O~ N o0 ~' M ~O N o0 OW ~ v_1 -_-~ oo ~1 N vD ~_O O ~ d: ,~ T v~
N M ~ N ~ ~ O ~ ~ N N N N ~ N N N ~ N N N M ~ N ~
cn c~i c~i .~ ~.~ N Os oo ty0 v0 ~ v7 d: N N V1 cn cri N N N ~--~ ~ ~ 'T" a N
N '-'
~O O M N O ~ O~ ~D ~ O o0 N O s0 O ~ M ~--~ ~ oo ~i'i d' ~~
.-r M V7 ..r ~ N O~ I~ O~ 00 ~ O M ~ ,~ ~O ~ ~t O~ M O~ ~ ~ ~ ~ ~ O I~
M N N M N ~ ~ N N ~ N ~ N N N N ~ N ~ N N N N ~~ O ~ ~ ~ M N
NO O v0 . ~ ~' ,--i
00 ~O
~t Ki M M ~-, vD ~ p~ 00 IW O y0 v7 vp ~ N ,~ yn M cn N N N ~~ ~ "~Ii ~ ,~ N N
N ,~
N O oo N ~ v~ M Ov O M oo ~ W cn M N t~ O f~ I~ ~n p~ "'' ~ M ~ V ~t
O~ Ov O oo ~ v1 t~ v~ oo W O ~ t~ N v1 ~ 00 v0 O ~ f~ 00 00 '., N ~ .w0 N O
N ~ N ~ N N N N ~ N N N N N O ~' ~' N N N N N ~p p~ r., ~ij O ~-~ N C~
~~~~~~~~~~~~~~~~~~~~x~~~x~~~o
d: M M M ~ ~ ~ O~ Oy I~ ~O v0 v0 ~ ~ M .~ y0 ~ M N N N ~~ V1 a x a ~ M N N
.--w0 N t~ o_o ~-~ N c'~ ~--~ dv Ov oo N O M_ N ~n O N_ ~n N ~7 0o ri N t~ nj
~ .-~ .~ N l~ M ~~
O N N N ~ ~ N ~ N O N N ~ N ~ O ~ M ~ ~ ~ N O N ~ ~ ~ ~ ~ N N O
O ~ ~ ~ ~ ~ ~ O O O O O ~ ~ O N
~t ~ ri M N ~:,~ N Os OW v0 s0 v0 v~ ~ M ~ i:,~ ~ ~t M N N N ~ ~ a x ~ a ri N
~~ ~t
O Ov O Qv ~_ f~ ~t v0 N ~ ~O ~ Ov o0 v0 O v_0 t~ d' Ov ~ v'i --~ cYi ~ Ov N ~.-
~ ~~ ~O v0 ~ W
N~~ON ~N~~NNN~OMNONN~OONO~~NNO~~ ANON N
~~~~~~~~~~~~~~~~~~~~~~xaa~~~~
M cn N N ~ Oy OW o t~ s0 ~D W ~ ri N N t~ ~ M cn N N ~ -~ ~j ,~ "_; r,; M N ~
N
0o O M OW _%i c_n o0 OW ~ l~ t~ N N v7 v_0 ~t M O t~ ~t ~ --~ ~ ~ t~ N ~ ~j ,~
~;j v_0 vi N c_n
N~ONNN MNN~NN~N~MNN NN~ON~NNN~p~~NN~M
M O O O
~~ N M ~t ~ ~O
M M I~ I~ l~ l~
M M ~--i ~ ~--i
0~0 00 V1 O O
N 00 V1
M M M ~ ~ O~
00 00 ~O ~D ~ 00
O N
153
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
.~ O ~ O y d N ~~ N .-M-~
N o0 ly0 ~D V) ~' M ~ ~ ~O ~ ~ M M N N .-i ,~ ~-r ..., .-i pp" l~ t~ I~ ~O ~1
~ ~ M
~ oN0 vD O~ v~ OW i ~_O N v_0 p v1 t~ N c~i ~ oo ~ N N ~ can ~ N N_ ~' N v0 ~O
~ M ~D x''
~ O N N N M N N ~ ~ N ~ N ~ ~ ~ N N N N ~ ~ N M ~ ~ N O O N N ,.~
N oo I~ ~D v0 v1 V ri ~ yD ~ ~ cn cn N N N ~ ~ ~ ~ ~ t~ f~ IW O v1 V7 vi tri p
QW~ l~ M Ov O M ~ ~ v0 ~O ~ 01 ~D M vD ~ vp 01 O ~ ~ ~ O ~ I~ ~ O~ Ov ~ OM x
N N N N N M ~--i N N N N N N N r, ,~ ~y M ao O N N ~ O N N N N N
N O N oo I~ ~D vD v1 V ri ~ r-i v0 ~ ~ cn t~i N N N gyp" ~ ~rj .-~ 00 00 l~ (~
s0 ~y!'~ v'i M O
v1 00 0o c_W D t_~ ~' N ~ oo ~ N_ oo (~ N ,~ ~' ~" ,~ O Ov oo M N ~ M_ ~
NONNOM~NNN~N~NNM~NN p~pN~~NNON~00MN
N
N o0 00 f~ ~O vi ~ M N ~ y0 d: ~ cn cn N N N ~ 00 0o I~ IyD v0 yi ~n
N O ~ p vj oo v1 N t~ ~ M ~' M v7 N ~ f~ v~ v1 N ~ '~' M ~' O O O M dw0 M f~
d'
.~ .-r V~ Oy ~ ~ 00 N ~ N ~' l~ I~ ~D I~ O~ N l~ ,~ ,~ "-~ ~~ ,~ ~ ,~ 00 G~ 00
tn 'r O v0 O ~'1
N ~~ -~ N N N N N ~ ~ ~ N ~ N N N Vj ~y op ~ ~ M ~-~ ~ N N M N
00 00 ~ I~ ~O N v0 O~ OW
.~ .w0 N .-~ N .~ ~~ N v0
N o0 00 (~ s0 ~n ~n ~ N y0 ~ ~ M M N N N ~ ~ 00 0o f~ I~ ~D v0 v1
_~ ~ M ~-~ ~ M O M C_~ d' _~ N ~O Ov ~ t~ l~ Ov o0 ~ O ~ ~D v7 ~ 00 v0 00 M
~.j
N ~'' N N N ON N N N ~ ~' ~ ~ ~ N N N ~ N ~ ~ 'M-' ~~"' ~ ~ oo M o0 f~ -~ ~ ~n
M
~' N N N N N N N N
~_~_~_~~~~~~~~~~~~
N 00 00 l~ \O ~ ~ ~ M ~O V1 ~ M M M N N .-a ~ ~ 00 00 I~ I~ ~O ~O ~ V'1
N N v0 M ~ ~ O wD ~ Ov M O Ov ~ M ,_~ sp Ov ~~ w0 O f~ v1 O_v oo N
M N N O N O ~ N ~ ~ N N N ~ N O M N ~ ~_ ~ ~' O ~ N N N N N ~ N N
N vp O ~ ~ ~ VOJ
N N ~ 00 00 tW O ~1 v'i ~ M N (~ tn ~ M c~i cri N N .-n N '-' N '~ N o0 00 l~
Iy0 v0 ~i Vi
O~ O~ l~ ~ ~ M -r .~ ~ V1 O ~O M_ ~ \O O~ M .~ ~ ~ M M ~ l~ ~O t~ ~ In
N O N O O N O N ~ N ~ N N N O ~ N ~ N N ~ N N O N '-'
~~_°~~~~~~~~~~~~~~~~~~~NM~°~~~~~~~~~~
N N ~ Ov o0 (~ ~O ~n V7 ~ M ~ f~ V1 ~t M M M N N ~ N ~ ~ N ~ 00 00 I~ f~ ty0
V7 tn ~ M
~NN~~ONNO ~NN~~~NN~N ~~~~~N~~NONNNNNO
N
~ 01 0o tW O V1 V1 ~ M ~ oo v'i ~ cn c~i cn N N ~-~ ~ ~ ~ ~ ~. OO o0 I~ l~ I~
~O ~n ~n
00 W O ~ ~n t~ N_ f~ O ~_ M M OW O M Ov O O ~ N ~ N N M_ N ~ N ~ Ov O ~O O
~NNNN~NNON ~N~N~NONNON~~~~~NNNN~NOM~Np
M ~ O ~ ~ ~ ~ Cv ~ ~ N O
,~ '., ,~ N ~ r., .-, ,~ ..-i ,~
0o O c~ ~ 00 t~ s0 ~i ~i ~ cn M 00 ~D ~ M cn Ki N N ~~ y0 O M ~ 00 I~ t~ ty0
v~ V1
I~ l~ V'7 ~ Qv ~ 00 ~D V1 -~ N ~ O~ ~D o0 v0 v'1 00 I~ ~ ,--~ ~ ,~ I~ 'fit o0
O ~ ~ O ~ 00 ~ Ov
--~ N N t~ O O~ N M O ~ N M .-mD M M v1 ~ ~D N ~ N N ~ N O O m Own t~ t~ M f~
N
M ~ O N ~ ~ G~ ~n 'vt N O
,~ Ov o0 l~ \O V'i V'7 ~ M M OWD ~ M M M N N ,~ ,~ ,~ ,~ ~ ,--W1 00 l~ I~ I~
~D W V) ~ N
~D ~ O vD v0 cn Ov o0 0o V a0 O~ O ~ ~ ~ o0 ~n cn O N ~n N O --~ ~ ~ v'i o0 M
M QW ~ N Ov Ov
l~ O~ O Q~ ~ ~ M 00 00 N ~ M ~D ~O l~ l~ V'7 O~ O QW~ 01 (~ 00 ~ ~ O~ (~ 00
V'1 M M 00 M N ~
O M N N N N -~ N N O O ~ ~ -~ N N N ~ -~ ~~ N N M ~ N ~ N O N N N N N
N
M O
M
N
154
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0
i ~ ~ ~ ~ .-..i
.N .
~ O ~ _ ~
V ~l I~ ~ O M
O~ n
~ ~ d' ~ ~
O M x ~ c
x ~ ~ V, ri ri ci ri N N N M N N
" v~ O ~
O '
~ M
O ~ ~ O ~ N ~ ~ M_ v
f~ ~ v0 v0 M .~ tyG O v_0 ~ 1 ~D
N N ~t ~D ~
~ O N ~ ~ ~ ~ N N N
N ~ ~ N N
' ~ ~ O
cn ~l N N
N p x N N
N
r, O N
~ O M
d r ~ ~l N r
wt cr1 ., In ~ ~ ~ M M
tn ~ ~ ~t ~ M M M ('n N N N -~ M N N
o0 v1 M
~
O O ~ t~ Ov OW 1 0o v0 M ~ O O in oo N t~
M p l~ ~ p O ~ ~ --~ t~ Cv N
~
OMN~-1 NO~OVO~oMNONOM~~xx~a NO~NNM~NNN
~O~ ~ ~~~''~,'~~MM
M M M M M M N
n M N '
~ '
~ O
c wj
N N ~ ~ ~
Vj ~ n
~ ,
'
'
O ~ ~ ~I ~ '-' ~ ~ 000
O t~ M M cn N M O ~ N ~ ~ ~ Qv o~0 N
~ ~ O ~ N
a O '-'
~
' N O N N N ~ ~ ~ N N ~ N N N N N -~
_ " N N
" ~ ~ ""~ ~
~D ~ v1
~
~ p '1
~ M M M
i
. 'vt ~ M M M M N N N ~ .~: V) V
O v ~ O r
N O 0 p p ~ ~
~d N
O ~W O v1 ~t ~ O cn oo ~t ,~ M OW D
M O O x x O p cn ~ t~ Ov o0
~ ~ ~.l O vD M
; ~) Ov o0
0 ~n
oo O N
O
,_ O
~ 0
N N
y ~
N N N ~
0 n ~
M p Vi ~ ~t cn M M N N N N ~ ~ ~ ~t ~ M
~ p O x ~ a cn cn M N
~ M
Ov~,.~ vIM~NMOOONt~oOVO,~ VD~ W 000
, ",~ NN~t
.~ Ov v0 N ~O ~ I~ M Ov o0 M N o0 v0 OW O
r; " .~ N " r., ~ r" -~ ~D Ov O
N I~ --~ N M .~ N N N N N N
~ ~.j ~ ,.., ..
M
~~
~~
O
~ ~
x a a
W O Ov ~D o0 v0 OW ~ N O oo N
"'~ ~ oo w v
~ Ov N ~ ' M
' '7 O O~ Ov
O O _ _
~: _ _
~ N O N N ~ N N ~ N N N ~ N N N N N
N ~' ~' ~' ~ N
~h ~ M ~ M ~
~p
~
O
~
y n M vi ~ ~ m M M N N N N ~ ,'~ ~O vt ~t
a a x ~''., a ,~ cn ri ri ri
D O cV
~ ~,'
~ " ~ 00 ~
~1 O ~D O ~ ~
~ ~n (w0 W O N M n
r-i Ov " I f
,-i .--~ ~ O N
~; oo 00 ~ I ~ t~ o
~~ ~ O t~ ~ v'WO N O M c~i ~ t
.-i '-: .-i '~ o Imn t
~ ~n
N -~ I
m M O _ _
N p r ~ _
N _
_
0
,''I', W ~ ~i ~ ~t ri ri M N N N ~ v0 ~n ~ V M
~l N --~ ,.7 ,~ ~ ,~ ""~ cn m ri N
t
/
r.; t~ cn vD ~ N two 0o f~ v'i M O N cV Ov -~
,_.; Ov -~ . .~ " .-i cn ~ O O_ 00
i j ~ .~ ~D v0 M ~ Ov o0 rr ~
r, .. .-r ~p M ,-n ~ -~ ~: ~
~ N N ~
N
N
O N M N M N N N N ~ ~ N O Ov _,
O ~ O ~ ,~ ,
p~ ~ ~ ~ ~ ~ ~ ~ M
O N
p O ~p p 0
O ~
O '~
l
''
"
V1 Vj M '" ,.a M vD v7 ~ ~ M
~ '~ ~i <t ~ m M c~i N N N M M M N
Fj ~ N ,~ a t~ '
,
.-i N W '~ ~O oo v
""' M ~ ci Ov Owt v~ tri .~ O N N v0 N ~
,~ ~; .-i ~D O
vW n ~ ~
N O _ _
~ ~ _ ~ ~ N N ~ ~ O
N M ~ N N N ~ N ~ N O ~ N
O N ~ ~ N
~i M v-i V ~ cn cYi cn ri N N s0 p ~ ~ M
" ~ N N ~ ~ " ~ ~ r"~ M M ri N
' cn .-.
.-.a .~ ~
v7 O r,i ~ ,:-i .~ C~ in oo ~ ~ ,~ .-,
~ ~ .-r d' N O ~ y0 n N oho
oo d' oo ~O v0 v0 0o VWO t~ 00 n n O
N t~ O M .~ .-i op v0 O N
N N ~~ ~~ N N N N ~ ~ N N N ~ ~ N M N N
~ t~ N ~''~ ~~ W O ~ ~ M
O ~ a ~ ~ ~ x (O/~ ~
O a ~
N
x
,
tn r
a O M I~ ~ ~ M M M M N N N ~ --y0 V~ ~ ~ ~
.-; ~ '.., ,-, ~ .-, M M M N
~
O c~ ~-w0 00 00 ~ ~ O t~ M WD W N -~ ,-a
(T ~ ~ M N ,-, v0 l~ Ov ,-., t~ N .-.,
~ M ~ Q~ 00 O l~ l~ Ov o0 ~ Ov ~ ~D v0 vC
M ~t t~ V1 N ~ .~ OWn OW ~ O
00 N O N N M ~ ~ N ~ N O N ~ ~ N N -a N N
~ vp ~ ~p M M ~ N N N N
,n ~
O
~
O O O p O O O O
O
O
M~ Ov O
MM l~ 00 M 00
MM ~ ~ M
O,
M
O
OvOv~f' ~ v~O
V~1~ ~ 00I~
ty p ~pO
~O~ N N N N
H H H
O
155
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
c
N '~
Ov
N N ~ ~ p~ ~ t~ ~O ~!'? ~ d' ~ M M N wj p N ~ d' (n N N ~ ~ N M N N N ~--~
O1 M ~D O pp M N V1 ~~ M O t~ 00 G1 M ~ O . ~ M N M N 00 O~ M V) O~ ~ M ~ M
00 O ~n ~ ~p ~D o0 N Ov ~ ~-, v1 00 l~ O ~. O .~ ,~ N v0 ~n o0 O~ 00 O M O o0
O o0
O N N ~ ..~ ~ N N N ~ ~ N ~ ~ ~ O N N N ~ ~-~ 00 O N ~ ~ N
~~~~ ~~~~~~~~~~~xoo N
N N ~ ~ ~ ~ l~ ~O ~ ~ ~ <h M M N V1 ~ ,~, N ~t ~ M N N ~ ~ ~ M N N N
~_-WO O '~,' Cy N N v1 .-. vp l~ O~ ~i OW ~ I~ O 'O N ~ ~_~ O v0 ~ ~ t~ I~ ~_
~ I~ V
N O N ...; N N N N N N N N N ~ N ~ 'T' ~ ~ ~ ~ M N ~ N N N ~ M ~ N N
~~aMt~ ;o
N N ~ O p" 00 I~ v0 y V1 ~ ~ cn M N ~~ ~j ~ M m ~ M N N ~-~ .-i .~ M N N N .-~
O oo f~ ~,' ~' ~t v0 WO v~ ~ oo ~ ~ Ov oo O O ,;j ,-, y0 p .-.~ .--r oo N ~ ~O
v7 N
OvMN .. vjj~~~~~t~Ov10w0~--~Naa ~Q'IMf~OI~I~OW~~O l~t~~~~0
N -~ M N N N N N N N N O N N - N ~ N ~ ~~ ~--~ N N N ~ M O N
N N ~ O o0 t~ v0 W n ~ ~ M M N N ~ ~ ~ ~n ~t c'~? N N .-~ .-: .-: M N N N
M M OW"'~ O N v0 W ~O N I~ Ov O~ O vD oo a a ~ N O ~ ~D ~n l~ I~ Own o0 M ~ O
Ov .~ 00 ~; ~' ~O v0 ~ OW ~ G»D OW ~ ~n ~ " ~ oo ~O ~ 00 W ~ oo O M ,~ M O
N M ~ .. ~ ~ .~ N O N N N ~ N N ~j
M N N N ~-~
N N ~ a o0 l~ t~ ~n v~ ~ ~ cn M N N O O N ~n ~ cn N N N ~ ~
cNn N ~ ~ p ~O N ~~ l~ ~ O~ ~ I~ O M M a ~ ono ~ v0 ~ ~ ~ ~ ~ O ~ ~ ~ N
M N ~~ N N ~ N N N N "' ~--~ ~ ~ ~~ N N N M N N ~ N
N N N
N N N a ~ o0 0o t~ ~n ~n ~ wt M M N N a x yn d; M M N N ~--~ ~-~ M N N N
O n t~ ,r..; N O ~w0 OwD O O v0 ~ O " ~ ~_ ~ O ~ t~ IW O ~D ~t v_i ~n Os N
Or~iNrr,,~~Nrr,,~~~ p~~N~N~N~NNNN~ N~pMpNNNNN pNNNNN
op0
N N N ~ N o0 0o I~ V7 W ~ ~ ri cn N N ,"O~ "O",~ p ~O ~ ri ri N N ~-, -~ ri M
N N
v1 O O ~' yn ~ M O M W ~ N M t~ N ~ ~ O~ M h N ~O ~n ~ oo M N IWO v~
p~ \O ~-a ~ ~~ ~D ~W D o0 00 00 ~D l~ N M N ~' ,W O ~ ~-n ~-i f~ M 01 ~ 00 IW
O o0
,,,,~~ N,,..,,~~ N op ~ N ~ N O N ~ ~ N ~ N N,,,,~~ ~ ~ N ~ N M N N N ~-, N N
N N N
~,p~, ~~ ~~~p0 Ov
N N N .. m o0 00 l~ ~O ~n ~ ~ ri M ri N x a y0 ~ M cn N N ~ ~ ~ cn N N
O~ O~ M ~ ~ M N O~ I~ l~ M M O ~ O O ~j ,-i ~ M tn O M I~ .~ ,~ V~ ~O N ~ M
M M M O In O~ M ~ l~ ~~ 00 O ~~ O~ M ~ O~ ~t O~ 01 00 ~D l~ O~ ~D O ~ ~O
O N N ~ O ~~ O N N M ~ N N ~ N O O M ~ N -~ N ~ O ~ O ~ N
p O ~ ~ r;
N N N N ~ OW O l~ v0 vi V ~ ri cn M N a a 0 ~O ~t cn M N N ~~ ~~ O ~ M N N
In tn O_v " ~ O~ V1 ~-n o0 ~D ~ M o0 M N \O N ~' ~ p V~ N_ V O\ ~ O Qv ~ l_~ M
V1 Ov ~~
O N M ~ O ~ ~ N N ~ N N N ~ N M ~ ~ O N N N ~ N ~ N p N O ~ N O
N ~ ~ ~ p p N
~ as
N N N N M Oy oo t~ v0 W ~ ~ M M M N ~ M vO ~ M M N N ~ ~ ~ ~t M N N N
O~ M ~O ~ ~ ~ I~ ~D O l~ ~ O Qv O~ M 00 l~ V1 M In ~D M .--s M M ~ ~ ~O (~
00 ~O V1 O N N ~D 01 O~ ~~ ~ l~ I~ oo M N ~ M N O ~O ~t '~ M M O~ t~ ~ ~~ ~ ~O
O~ M
-~ O N o0 N ~ ~ ~ M N ~~ ~ ~~ N N ~''~ '-' N ~~ N N N O N ~ ~ N ~ -~ -~ N
a ~~dax
N N N ~-v a ~~ Oy 00 l~ ~D V1 V d: ~ M M N rj ,-i ~-i ~O ~ ~ M N N ~ ~ ....; ~
M N N N
~D ~ ~ 00 I~ M O~ 00 M M V7 In .-r 00 I~ ~ O ~ l~ O~ N ~ M 00 ~t 00 00 ~ M N
O~ 00 Qv
O M ~ ~ O N O O M O~ 00 V~ O ~O ~O O~ N pp l~ ~O ~O N ~ O O ~7 M ,~ ~ ~ ~O ~O
00
M ~ N N ~ N N M M O ~ N O N N N ~ ~ ~ N ~ ~ N N M N N N ~p N M N ~ O
p O O O
N ~O M l~ ct
00 M 00 M 00
M .-~ M
N o~0 0~1 O
~O ~ 0~0 00
-, ,~ 00 00
O O
H H
~~ ~x
N M
156
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~'? N .. ~~ cri
Ov ~ ~ ""~ 00 ,-i N
r
'-' ~ ~ 'i
O ~ M M
~ i
x
.-i~. ~ M tri N N N v
M . p ~ ~ ~t
U o0 Iy0 Vi V ~ N ~ p v r
~ N vi ~1 N
~ Ov N ~ cn w0 0o x n M l~ !~
O ~ f~ l~
'
Ov N O v'i
W I x O o0 V7
N w0 t~ Ov O M v1 Ov
N ,~ N .-r OWE N I~ x p .b N
M l~ ~D v'7
O t~ OWE N o0 ~
x
N ~ ~ ~ ~' ~~ N N O M ~ N N N N l~ ~ ~j N ~ N N
N N O ~ N N N
r; a ~
a ~
~
-
s
.. I
~ Cs oo ty0 v~ yt . p ~ ~ cn
M - cn ri N
~O
cn cn N N N ~ -, p
~ I~ ao ~ p ~
O .--mn O oo ~
,--i cn
OW O
00V'1~DV'1MMM OV_1QW~MOOaxoOxOO
N n ~ Ov x ri~~c
.-. M vD
oo t~ N
N ~ N ~ N N ~ N N ~ N N O N ~ ~ ~ N ~ N N O
N N N x ~~ ~ '~' N ~ N
~N
N p
oo ~t
~
-i ~ ~.,j ~; ~ Oy oo Op M ~ I~ ~ d: ~ M
ty0 v'i ~t ~t M c~i cn N N N ~ ~ a ci cri
O O v~ ~ O t~ p M
~ w0 x O O x O O O N O O
OW 'i oo ~n Ov
~
-' O
~ ao ~ ~ oho
M M W I
v
'
ax
O ..~~~~N~NNNNNN MO~~~NN "N _-"'' ~_.. ONNN~~O
N ~j ~ l~ O ~n O .:.
-i OvoOI~~O~n~~M ~n~~c1MMM
,~ O l~ M O ~O
d'c~iNNN ~ ~'~,7~'a00,.~,000
M ~ ~ ~ ~ N M N ~ Ov O v0 ~ v1 N N o0 ,~ ~ N ~ M
O~ ~~ ~ IW x " ,~ V1 ~ N ~
I~ O~ O~ ~O M M N , . V~ O~ ~
l~ O~ O~ 00 l~ ~O M O ~ M l~
~ nj 00
~ _
~' ~ N oo N '-' N '"' ~ O N ~ N N op
N ~' N N N N N
~O ~O l~ o0
N ,~ ,-, N
O~ 00 h ~O ~ 'ct V ~ M N N N ~ ~ x x O ~n ~ V M
M O C/~ O O M M M
~O m ~_n I~ oo ~ OW i ~ c_n v1 ~ dw~ t~ a t~ N ,~
O C/~ ~ a C/~ ,--~ O
NO ~ ,~ V7 N
~N N
N~N ~NNNN
N
N
N ' ,~ 0 ,~ "..,
N M N N -,
N O~ .-, M
p
'O N
m ~ cn N N N -i .-i x v'i ~ ~
Ov oo fy0 vi v1 ~ x ~ O ,.'S'., a ~ ~t cn ri
M 00 ti
0 "~ ~
O 0 ~
W ~ ~
~
Ov v0 ~ 00 t~ 0 o 00 I
M vD N ~ ~
.~ .-~ O oo M v0 Ov ,~ ., .. O~ M
M v1 O l
t O t~ I~
t~ M v0 0o
O N ~0 00 ~o ~ t~ N t~
N ,~ ~ ~
N ~ ~ ~ ~ N M N ~ N M N N N N N -~ ~ pv N N ~ N
~ ~-n N ~ ~ N ~ ~ N N
O M ~O ~ ~
,~ M O~
v~ ~O ~ ~ ~ ~ O ~ v7 M O V~
O l ~O
~ O O
O O
N _ O ~!~? d:
_ ~ M N N N ~ ~ x x a ~t ~ cn
t~ ~D ~i ~ ~ cn x x x x ri ri
a " ~ ~
N i M
~
N
n ~ .- M O
~ o , N
O ~ Ov O ~ c O ~ O ~ ~p N cV ,-,
~ ~ O o
N N ~ N N M N N N ~ ~ ~ N ~ M N W O ' ~ N N N
~ O ~ ~ N N
O ~ p
~ ~
O p
M M_ Ov ~ ~O ~ ~ ~T
~ ~ ~ ~ ~ ~ ~ ~. M ~ M M M
N ~ M N N N ~ ~~ x "'~
Ul x x x
Ov M O N d~ -~ oo s0 t~ ~ v~ Qwn ~D
oo dw~ ~ ~ M .--~ ~ N N r; ~' ,-; ,_; O oo f
OwDOv N l~ ~ N v0 O ~D O~ ~ ~ oo .r ,--~ ~ M O N ~O
~ O o0 00
~
O M
N ~ N ~ N N N N O oo ~ N M N ~
N ~ N N N M N N ~ M N N
oo
~~oooooo ~~~~~~~"~
~~~~da~
.-i'~ N Oy O~ 00 0o v0 , y0 ~ ~ ~
.-iv0 v'i ~ M ~t M N N N ~ ~ , c~i cn
j x a ~ x ~ x M
0o ON N N O oo t~ O O ~ ,~ ,~ pv
O ~ l~ oo t~ M M ,~ O oo O~ cn ~ ~t ~n ~
~ N N ~' '~ ~' ri V
~ ~ O vD v0 0o Ov
~O
~
O M
t~ O oo N ,-..~ .--~ ~ N N N
00 n , N N N
~D ~ Ov t ~
N N -~ .~ N N N ~p
~ N N O N N N ~ M ~
OM M g
O ~ N p O
N
) ~ cri ~~ d~ cn N N N ~~ ~' t~ ~ ~ ~
00 00 v0 ~O M M M
O~ V ~ cn N ,~ ~ ,-; ' o
00 v0 tYi d~ ~ ~~~~.~-,0~ ON~ WO
OMO~ONN~~~ 0~~~~vi~'OU ~
~o~ONt~N ~
_ _ _
x O O O O O O _
x _
x
.. -~ ~t N ~ x
-i N .~ .-~ ,~ Os Ov x ,~ oo vi ~
r.,oo I~ ~O ~i ~ M N x ~ M M M
~ c~i cn N N N ~ ~
~.,~ ~.j ~ ,~ ~; ~;
..-~N_ O_O V1 M M O I~ W O ~!1 ~ t~ l~ ~O ~D ~ N M
00 l~ d' ~O ~_ O l~ ~ O V_'f
O ~ O
~ M N ~ ~
~ ~
N N N N N N N N N N N N N
M N ~ ~ ~ ~ N ~ M
~i
M ~
d' ~1 O N ~ O ~
O O O O O O O
V7 ~O I
00 00 00
-,
I~ M I~
O
N
0~0 N M
N
w z
A
o O x
x x
ls~
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
O ,_;
Ov Ov M f~ N ~t N M vp ~ O
O t~ ~ M N
N N ~ ~ ~ M M N N N -~ N ~ O o0 I~ l~
.-, ,~ .~ .~ M ~O
~ M
M ~ M O M (~ O O~ l~ M M
N M V' M N ~ 00 N tn l~
Ov ,~ N ~O W ~O t~ O O ~O Ov 00
00 M M o0 M ~O
N O N N N N ~-~ ~-~ N ~ ~ M N O "' "~
~ N N N ~--~ N ~ ,-i ~' ~_'
N
r d'
N N ~ O~ M I~ N ~ N O N ~ o-.a M O
N ~ ~ ~ ,-N, O O ~' ~' v7
y ~ ~ M M N N N .. O ~ ~
V1
~~o_~o~~_:~~~~;.~x .~~Mxb ~;~~~~~M
O N N N N ~ O O
N
~ ~ N ~ ~ N N N N ~ ~ ~ ~
~ N N ~ N
O ~ O
N N p OW ~i Ov ~ ~n N N N '~ M O ~ oo
N O o0 ~i ~ N O O I~ Iy0
~' a
O f~ 0 ~t ~t M M N N N c ,~ ~ ,-a
00 ~ ~ .~ .~ n ,-, ap
vW M M M N t~
x O
O r N f~ ~ Ov N v0 O W ~ Oyp ~ .-~ N
t~ O f~ M oo " V7 t~ 00 00
~' ~ ,~ ~ ~O ~O M ~ (~ ~' ~' V
N N O~ V1 M M N .-, vp
~ N N .~ .-~ ,~ N N _~ N .-,
~ ~ .-i N N ~ ~ O
O '
x ~ ~ ~ ~ N p ~
~ M
N N p M 00 t~ IW
N N O ~ O ~ ~ N O oo N N O
Ov ~ ~ N ~ N ,-, M O ~ vp
o0 ~ x ~ I~ O
t~ O
N
~ sD v1 ~ ~ M N N N ~ ,~ ,~ N
-~ ~ .r ,-, .-~ t~ Ov ~D ~n ,-,
O O v0
. p .. ~'~ N N
M 00 '~ ""~ O
M ~'~
O M
N
~ .-i ~t O
M py N 00 N N t~
.~ O ,~ N ~
M Qv ~~ O pp ~ N M
V ~n oo N oo .~ Ov
oo OW O v0 v0 .
N O ~-~ N ~ M ~ N
N N O O N
N N ~ ~ N N Ov ~ 00 is
N O 0 typ
~ O WO N O OWl1 ~' N M v0 v0 U tW
Wn V1 O ~t "'~ D I~
s0 ~l M O
Q~ ~ ~
(~ ~ .-n pyp ,~ 00 l
l~ v0 v~ ~ M N N N ~ " M o0
Ov .-m, ~ N ,~ .~ ~ O N
.~ ~n ~ ~n O ~ T O O ~ ~. N N
~., M ~ 000 W ,_, ~ N
N ~ ~'
.~ ~
N
N N ~ N N ~ O M N O ~ N N
N N - M
N N ~ N N --a o0 l~ l~
N x a ~O
~ N t~ N sD oo
O M (~ " .-~ ,-r
~D
v0
s
_ ~ O ~t w0 f~ N O OW N N N M ~; N Ov
N N D ~ N ~ ~ N o0 v0
ON ~n et ~ M N N N ~
N ~ ~ ,~ Oy
N Ov ~ N W M N - M O ~
~ O l~ M ~
O
l~ O ~O l~ ~D t~ ~O O
-~ O o0 ~O I~ 00
N N N M N ~ ~ ~ N N N ~j ~j M N
N N N N ,~ ~ y0 v~ M
~ ~ ~ ~ O~ a ~ N
I~
Ov
~
O
~f' I~ ~D ,-., p~
O~ ,~ ~~ ,~ 00 ~O
.w0 ,-,
N N ~ O ~ ~, ~ op' N ~ ~' '~ ~.,~ ,~
M Ow0 ~ ri O N ~ N N N
N ~p ~ ~ ~ M N N N ~ N
l~ M ~ 00 M O~ C~ O O ~ ~D
N N O~ ~~ M ~D OO ~j ~j O
N v M oo Gv ~ M oo N r; ~ v ~ p~ I~
-i N N O ,~ I~ ~O
v O
I~ ~
a~OW _ ~NVO~-~ _
M ~ _ N N N ~~~d0'o~0
-n _ ~ O .-y .-r
N N N
M N ~ ~ ~
~ ~ ~ ~ ~ O p
N N ~ x ~l pyj
~t ~
v1 ~ ri ~D ~ ~O oo D
,~ N O Ov ~ ~
N N ~ ,-r N ~ ~D O v1 N N '.~ t
N w0 0o M N O~ ~ ~ ~
~ O v1 00
~ t
-~ N N N N ~ N N N N ~D v~ M N O N
v1 N N N N v~ ~' O ~ v~
M "' M t~ O l~
~1 ~~ V7 l~
O~ U ~p ~ ~ ~ N
00 ,~ N N N
~O N O ~
Q~ ~ M
-~
N
N
~
Iwt vi cn ~D N ~ ~ O O v1 N
CW ~ ~ ri ,-i
~ f~ ~ ~t ~t M M N N ~ x ~ -~ Ov
N N ~ ~ ~ ~ ~ M N '-' ~t~ cn N
N N N ~ t~ ~ --~ O Qwn ,-i ~ 00 I~
~' o0 .., O n ; s0
v7 ~ ~ .-~ et (w0 OW ~ Ov V~ l~
M ~ v7 V'1 00 l~ N Ov o0 N O M --~
O Ov ''
N '~
Gv N M M N ~ N ~--~ N ~D o0 ~ N ~ ~
Ov N -~ N N N -~ C_v
M N Gv
t~ o M ~--~
N N M N O D N
n p
~ x '~'
~
~
. o O
N N t M N - ~
N N '~ N O ~j ~ ~ - ~ Qv
~ t oo Iy0
~
N
O ~
Oyn ~ ~ M M N N -~
~ ~ ~ ~
0o v~ ~ v'7 00 ~ N W in N t~ v~ N
N vi ~n ~D two v0 ~ .-, N W O
oo O ~ C~ ~O I~ ~ I~ ' O M ~ W
v0 00 O~ O~ 00 ~O (~ O ~O O
G~ ~ ,n
M M
.~
O~
N N N N ~ ~ ~ N N ~ N N ~ M N N M ~
N N N ~ ,n ~ --~ M N
O O
00 0oOvO ~ O~ N M O
00 M M~ d'00 ~ ~ 01
M MM M ~ M M
~
00 0 N o N
~O
OvOv~ l~00 00l~
M M MM M ~ ~ N
a ~ aa a ~ ~.~
~~ ~ o o o
o x
x x xx x x x x
00 a\ O
158
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
-.. "
c!i N ,~ ~ ~'
~; ~: ,~ ~ v; ~, ~ o c~i o 0
v0 v'7 v'i ~ ~ ~ ~ ~ ~ rm., t~ ~ ~ ~ M M N N N N ~ M ~ ~ '~~'. 00 00 ly0 v0 v7
W
~ t~ Ov M v0 p O O O ~ O .~ ~t O et N ~ 00 ~ N N ~ ~D ~ ~D M v0 M N t~
l~ O~ M 00 ~O "~' ,~ f/~ x r~i a O a O ~O O l~ ~O M ~ M N N .~ ~' ~ ~~ O~ Ov M
l~ M
N N N I~ ~ ~., ~
ri N
-, N ~n V N ~n ~ " Oy
v0 '~i ~n ~ M ~ ~ p 0 O ~ ,n p ~ M M N N N N -~ ~ ~ ~ op o0 00 tyD v0 ~n p
0o QW ~ ~ t~ O O O x O O v0 a M M oo I~ cn .-, V m .~ ,~ ,_-~ O~ O N t~ v1 0o
V ~
~O O~ V~ O~ N x ~ 1/J " C/] a O ~O O~ M O O ~O ~O 00 ,..., O~ ~O "~ ~ .~ 00 l~
~O O M
N N N N ~ .~ " " ~ r; ~~ ~ N N N N ~ ~ N N ,~ ~ N M N N N N
~O v1 v1 ~t ~ ~ ~ M O N ~ N p ~t cn cn cn N N N ~ ~ ~j ,...i p ~ 00 00 tyD vD
W v1
t~ 00 O O a U7 x ',h., ° O ~r' I~ OWE O ~D Vi ,--i ~ Csj ,~ .~ ..~ ~ v~
O v0 ~ O OWE
N N N N x ~j .-i ~~ ,_; a ~ ~ N N N N O °N O ~~-~ p ~ ~ ~ ~ N
°N ~ M N ~~-~ N
v0 V1 V1 ~ V ~ O O O O ~ ~ O ~ M M M N N N ~ ~ ~ ~ o0 00 l~ I~ ~O VW ~
v0 v'i O ~W O x x x x x ,,.] O x N O~ V1 V1 ~~ M N I~ ~ N "'i O M 0O N O~ M 0O
M O~
~ ~1 Ov o0 in ~ ~ " .. ~l ~ ~O o0 Ow1 ~ ~ N ~O ~' ,-'~ ~' ~-, N o0 00 0o OW ~
t~ N
N O N ~ N ~ N ~! '-' ~ ~ ~ ~' ~~ O ~~ N M N N N ~ ~p ~ C.j ~ N N ~ ~ ~ N
NO NM~vN't ~ ~N
y0 v'1 v'7 ~t ~ p VJ C/~ ,"Ii ° C~ O "Si ~ cn c~i M N N N ~ a ~ ~ ~ p
o0 0o I~ ty0 ~D v'i
n O~ V M O\ ,~ . '~' " ~l ~" ~-' t~ vW O oo ~D N ...r ~ .., v0 Ov OW v0 Ov
~D o0 M I~ N oo ~O oo N ~' O N ~D ~ Ov ~ ~O M ~-~
°N N N ~ ~ ~ N '-' ~ ,-i ~'~ ~r ~ N N N ~ N ~ ~ ~' '-; '-' ~ N ~ N N N
N
O N ° ~ ~ ~ ~ ~ ~ O ~
V
~ vi vi ~ ~ a ~ H~ ~ y°,~ o x ~ M M M N N N ~~ "'~ ~ ~ ,~ os oo t~ ~ ~
~ vi
M ~1 N o0 N " " " a . ~ N M ~-~ ~D O~ N M '-' O N ~O ~O 01 M v7 M
M l~ l0 W M N '~ ~-~ ' ~~ " r", ~O I~ M I~ O~ O~ M oo M " N ~~ l~ O~ ~O V~ 00
00
O ~ N N N ~ N vp ~ ~ ,~ '-: ~~ N N N ~ ~ N N O M '-' O Nrr~~!! ~r~! O O
p~°OO~~p ~~Cp/7 NAM
~O yn d: <t ° H '~, ,T, ° xi a 'x, ~ c~i M M N N N ~-~ ,_; N N O
p~ 00 l~ (y0 v0 W
omoOM~O°~~N~~'~~,-i~' d~'N~~_oM_o ~~_M ~ W°OOOO°_~O_cn
-v ,~ N N ~
~O M ~ ~ ~ ~p
O O O O O C/~ O O ~ ~ ~ ~ ~ O~
s0 'v1 v~ ~ ~t ~--~ x ''~' x x ~ "~ x N v'i ~ ri M N N N ~ ,-i N N ~ ~ ~ oo t~
IWO ~D ~n
o~oNOM~~N ,~,.._,~,-"~O ~_o~_O~_~~NN~ ~~1" ~ ~0~~°Do°_o ~V~
N M N N ~ ~ ~ ~ y0 v0 ~ x ~ O M ~ O
M
p O ° o0 p
O O ° ~ O ~ ~ ,-, ,~ ~..-~ Ov
v0 ~1 Wi ~ ~ ~ x x x x " a x ~ Vj ~ cn M N N N ~ ~~ M ~ o°~O vp ~ oo l~
fy0 ~D ~n
M M M o0 ~ <Y N N ,-i .-i ~ ri ..~ '~ O o0 O O N_ O l~ M_ O N ~ N ~~ ~ ~ I~ M_
v~ Ov ~
~ ~ M O O M M '~ N N ~ ~ N M O N N ~ ~ ~ ~ N N N N M ~ ~ N
N~y N~; M N O
~~~~~~xx°°xOOx ~.-~o
~o ~o v'i ~ ~t x ~? ~ ~ ~ ~ ~o ~' M r; chi N ~i ~ ~ ~; ~ ~i ~ ~' ~ oo c~ ~o ~o
~i
~t N N ,~ ... ,~ ..~ '
M Ov OW O O . ~ ~ Ov M Ov ~ oo I~ O O t~ ~D ~ OWO ~ O ~ N ~n N Ov
~_D o_o M N M ~_O N ~ ~ ~ O oo M N O ~n M v_0 N ~t oo O Ov N N N N O_v O~ o_o
~O ~n o_O Ov
x~x~axaax
~D ~D ~i ~ ~ ~ c.i ~j ,-i ,-i ~ .-; ,-i -WO ~ ri ri N N N ' . ~D N O O ~ 00 0o
t~ ~O v0 Vi
O O ~O M N ' " l~ N Ov M s0 ~-~ 00 t~ N t~ N N N Ov N M M oo M v0
v'7 00 Ov M o0 °~ ~ ~ O t~ ~ ,~ ...r ~ ~ 00 v0 ~-~ ~-n OWE ~ Ov O I~ N
~D o0 W n ~ v1 V ~n
N ~-~ N N -~ ~ O ~ ~ ~ O ,N ~ ~p ~ N N M N ~-r ~-r N ~~ N ~ N ~ O N N N N N N
O O O O O O O O O
v~ .~ N
O
M M .~
00 M ~-~
M ~ M M
M ~ ~t N
~ ~J
a
N
159
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~i
M ~ cC
_ O_v ~ N N N .-i ,~ ,~ ~ ,-i .-.
M ~ N ~ ty0 W ~t ~ tYi M ri N N ~ ''~ ~ O y0 O ~D O N. d oo M cn ri N N N
I~ M l~ N ~D o0 M N O OW 'i
p 'p o0 OWE ~ ~O M M tn ~ ~_O O_ N 00 ~D
O '~ N oo -~-r O N M ~ N O N --~ N M ~ ,T, ,~ '~' C~ 'T' ""T~'' ~ x ~ r' .-~r
0~0 N N O
~ ~ ~ ~ ~ ~ O M N N ~ ~ ~ ~ N
N ,~ _
f~1 ~ ~ ~ I~ ~O V1 ~ V M M M N N ~ a ~ ~ ~ ~ ~ a O~ ~ ~ M M M N N N
y0 O N ,-.-~ ~j .-i ,-, v0 ~O O o0 v0 M oo ~ p ~ ~ p O O ~ O O N (~ O ~_n M ~
N O a ~ ~ N N ON N N ~ ~ N O O N M ''~ a ~-i-Q-11 C/~ '"~, "~, ~ x C/~ M N N O
N O N
N pip O~~NoOON~~O
N ~ xi t~ O Ov
N p . ~p I~ ~O V'7 ~ ~ M M M N N ~ ~ ~ ~ ~ M U1 ~ ~ N N ~'Ny' M M M M N N
N O ~ ~ ~ ~ O Ov ono ~ ~ can ~ v1 N W O ,.a ~ O ~ a a N ~ N cMn ~ ~ ~ O ~
N ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ N cn Ov ,~ O ~ 'n N M
d~ ~ O .b ~ t~ ~ V7 ~ ~ M M M N N ~-n ~ ~ ~ ~ O M O a ~ O c~i M M M cri N N
N O ~r' ~ h M M o0 ~ ~ ~ ~ ~--~ O ~ O N a ~ ~ ~ ~ ,T, '-' a f~
_ ~ v_D Ov o0 ~ M O ~ ~O N ~W p _ _ _
N N v0 op ~ ~ a N N ~ O p~ Ov
Cv ~ ~ ~ ~ ~ ~ ~ O M O M
0 O ~ ~ oo v0 vi V d: cn cn cn N N N ~ O O p M O O a ~ O ,~ ~ ri ri ri N N
M a ~ a ~ N ~ in N I~ N ~ ~ tn M M M ~ a ,..a ''~ F"' ~ ~ a M O~ ~ O O 00 tn
N~j'~~' ~~NN~ NNNNONN~~''~NN ~~ ~.~~.-i ~~ ~~~NNN
O O ~ N x O O p O O O a p O
00 ~O v1 ~t ~t M M M N N N ,~, ,~ d; M M M N N
x '~ oo f~ vi oo N N_ Ov N_ oo ~ M ~ x '~ a '~'., a ~-1 ~ ~D Own " ~.-s Cv O
O N ~ ~ ~ O N ~ N ~ N M N N N N N O M N N r3 ~ N ~ ~ N N N
00 ~~~~~~~~~~~~~x~~~o°°x~~
O ~ ~ N ~ ao v0 vi ~ ~ ri cn ri N N N ~ O O O ~ O O Z ~ O m
.. 0v V7 C/~ ~ F,~, "'~ ~ ~ cn cn M N N
M "~ ~, _ N ~ O M M cW O N Ov O ~t ~ x a ~; x ~ ~ ., ,...; O N oo ~_D O~ h iii
"N O p~ ~ ~ ~ N O N O ~ pN N O M N N ~ ~-: ~ ~ ~ N ~ N M N N N
M °~ I~ N ~ O ~D ~
MOO pO~~ O~p00~O~DOOOO
~t ~ x x N ~ 00 v0 v-i v1 ~ d; cn cn cn N N "' ...7 C/~ ''~' ~, C~J ,."L,' ~
,~ ~ N V M cn cn N N
O ~~V'O~O~O~~_OOvV7I~'_~t~MN ~~.-i""'~,-i~ ~~~~ON~-i.~
N v1 ~ O N N N N O N M N N N N p ~ ~ ~p ~ ~ M yG ~ ~ N N N N N N
O p N ~ ~ ~ ~ ~ ~ O O p O O p O
~ ~ oo ~ vi ~n ~ ~ M cn ri N N ,~,' '~ x ~ x x '~ x: a ~ ~ ~ M M M N N
00 M ~ ,-~i .-n ,~ ~ .--i p ~O d' 00 ~O M ~O ~O Ov ~ M N N ~ ,-i ,-i ~ .-i ""~
M ~ ~ l~ ~n ~O M
N ~ ~ ~ ~ ~ ~ N ~ N N N N N N O N ~ ~ O ~ ~ O "~' O ~ ~ O °~ ~ M W
~ t_~
~OoOO "~~~ ~~OOOOOOOOO
N ~ oo ~, UJ ,.~ x x ~ x ,~ x ~n
~ ~ 00 v0 'v1 ~!p ~ d: M cn cn N N ,...~ ~ " " ~ ~ ~ ~ ~ M cn cn N N
00 ~ ~ '-' ~ ~ ~n o0 00 W I~ t%'1 ~ M O~ N N ~ M N N ~ .~ ~ ~ .-a O o0 V7 00
t~ <t O~
M ~ O ~p N N 00 O_~ OO 00 V1 O M M O_~ ~ M ,~ l~ I~ O~ O~ ~ V1 O ~j~j N ~_O M
(_~ O M
~r~r~rrax~x~r
r; ,_; M ~ 00 l~ \O v1 ~ ~ M M M N N ~ ~ N N N ~ ~ r"~ ~-~ ~ ~ N ~ M M M N N
V1 M N ~ N ~D O_ W t~ 00 O M_ Ov N " t~ M O ~ M ~t .~
00 ~ vp ~ ~ N N N ~ N M N N M ~ ~ ~ ~ O ~ ~ ~ ~ ~ N N ~ Ov Ov Ov
I~ ~ t~ t~ ~ N ~ N d' O O t~ ~ .~
O O O O O O M O O O O O O O
~D M ~1'
d' O~
M ~
v~ Ov N
~N O
00 N N
~D ~ O
~N N
v~ ~ v~
~a
xx
M
00 ~ 00
160
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
ri
Vi
0
N ~ ~ ~ ~ ~1 V: ~ M M M N N ~"'~ N 0 ~ ~ V M N N N ~ M N N
t~MN ~~ f~I~t_~t~~_-,v0v0MpO vDOO~t~-~~~viv_O W N_~NWt
N O N ~ N N ~ N N N M N N ,M_, x ~_ ~ N N ~ N ~-~ N N N N ON N N
O ~O
r~r N ~ f~
N N ~ ~ ~n v7 ~t ~ M M M N N ~j ~ N v1 ~ M N N N ~ M N N
IWO N_ ~--~ Ov O ~ t~ N I~ ~ M N ~ O O t~ N O t_~ 00 l~ 00 v~ ~D v0 c_n
N N M ~ N O ~ N N ~ ~ O N ~ x x ~ ~ ~ N N ~ N ~ ~ ~ N M N
c~ .-
N N ~ ~ ~ ~n ~ fit' cn cn ri m N ~ ~ p N y ~ ri N N N ~ M N N
os~~;~ oo.ri.~~~os~~_:;~ ~x ~.-:~nsoso~M,:-. ~Ms_o~~
N~ ~~"~~N~NONMN~x,-i ~~~NNONO ONNNNN
a ~ o.
N N '~ ~ ~O ~n ~ ~ cn cn tri M N o0 0 O ~ ~ ~ M M N N -~ c~i tn N -
Ov .--~ oo ,~ N ~t t~ ~t cn N '-r cw_O l~ ~ WO Ov oo l~ -~ O~ O M N O ~_ ~-~
O ~ ~ ~ N N ~ N N ON ~ N r r.; ~! ~ ~ ~ N N ~ N ON ~ ~-~-~ N M N
N N -~ M ~O V'7 ~ ~ M M M c'n N ~ O a ~ ~n <h M M N N ~~ c'n M N
v0 N ~ N M V ~ I~ v'7 O N O Os M x " ~ ~D v0 v7 ~ Ov O N M_ O I~ v1
OMN ~~~~NNOMNNNN~~ NON~N~~ NON
N N ~ ~ ~O W ~ d' ~ M M M N ~~ O ,~ N ~n ~ M cn N N N ~ M M N N .-
cn -_-~ O_ N ~O O t'~1 N N oo O_ N_ ~ Ov 'x ~ ~ d' M ~~~ ~ Vi l~ V_ N ~~ O ~t
M o0
ONNN ~ON~N~NNMOON~ ~~NNNNN~~~~N
N N ~ N ~O wi ~ ~ ~t cn c~i M N N a a ~ ~n ~ cn M N N N ~ ~ ri N N
O vi oo N M ~ TWO ~D oo cn W Ov Ov ,~ l~ O~ N 00 M O~ l~ V~ V~ C~ V1 M ~
N ~ N ~ O N N ~ N ~ N ~ N ~ ~ N ~ N N O ~ N O N O N N
00 ~ ~ ~ O
N N ~ ~ ~D V'1 V1 ~ ~ M M M N N x x M v'i ~ ~ M N N N ~~ ~t M N N
~ vi O N ~n vW V oo M vWn ~_n cn ~ ~' cn ~ M O v7 N O Ov Os N N_ vi co
N O N ~ ~ ~ N N O N N N N N wj ~ ~ N N N OM N N O N ~ N M
N N ~ ~; y0 ~n ~n ~ ~ M M M N N ~ .. ~p ~ ~n ~ ~ M N N N ~ ~ M N N ~ N
vD v0 v0 W .-. .~ O vj vp ~D ~ ~ N_ ~ O ~j ~ M ~ M M N Ow_G O v0 v~ Ov N wO v0
N
NNN~ ~~~~N~NNNNNON_O ~~NNOMNN~ONN~M
'~' O ~ ~ ~ ~ ~ ~ O O 'b N
x~
N N -a ~ ,_; ~D tn V1 ~ ~ M M M N N '~ ~ ~ N v7 d' ~' M N N N ~ ~ M N N ~
~ f~ cn Ov ~ V~ M M O~ 01 ~O 00 ~ l~ ~' N .. ~y0 O N oo O OWO Owt t~ ~t N M
Ow0
.-.~ .-w0 ,~ N ~n l~ O o0 Ov ~~ M ~O M M N ~' t~ -~ t~ ~ I~ IW O oo Ov N OW O
~ oo Ov Ov
N N N N N --~ N N N M N N N N ,-.~ ~ t~ N M ~ ~~ -~ N N N ~ N N -~ N O
N N ~ ~ ~ t~ ~n ~n ~ ~t M M M N N ~.,~ ~; ~; ~ ~n ~n ~ M N N N ~--~ v~ M N N ~
v~ O N ~ O oo O Ov o0 t~ O ~ M O oo ,_; ,!j .~ ~ O W D ~ t~ M cn v) Gv ri ~n
Ov O
0o O N N ~ oo OW ~ ~D t~ f~ ~ ~ O ~n n ~ ~O vD W O N -~ t~ N ~ w0 Ov O Own
N N N N N ~ ~ ~ ~ ~ N N N N ~ ~ ~ ~ N N N M N N N N ~ ~ N ~~
O O O
I~ ~D [~ 00 O~
M ~ ~ M M
In ~
O
M ~ ~ O ,N
~n ~n M N N N
--~ ,~ M
161
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~o
~o
cn N iV p~ .-; wi N ~~ '-' v_p
a t? N N .r \O ~ ~ 0 ~ f~j p ~ C~j f~j ri ~j ~ p~ ~ ~D ~ ~ ~ <f'
M O ~O t~ ~ O O O O ~ ~ .-~ oo M p~ p ~ p ° ,~ O ~O N
M O v0 ~ a a x V1 x a O ~ ~ N N O ~ a V1 a x a x
x ~~~~~~~~~~~~ ~~~~°~~~_
M ~ ~ N N ~ ~ ~ 0 ~ vM1 ~ M M ~ N N ~~ ~!? ~ ~ O O ~ N O
v_0 t~ O t~ t~ O O M ~ .-3 N c_V WO ~ O x x x a p ~_i'
M°NNNaNxxxaa ~ ~MNNOa _ ~x v,ov
,'y~ ~~II~~yy N ,~ ..~ r, ~ pp ,~
x M ~ O v~I ~ '°~~ '~~' ~ ~D ~ ~ ~ "T' ~ ~ ~ ~.~r, M ~ .-r N
N ,-; ~ N N ~., ~ p O O M ~ .-r ~ ~ c~j N ,-.~ .wp ~ ~ p ~p M
O o~_Od'v_D~O~"x~COO~N OOM.~N°O°~a0
O N a N ,~ .-i a V7 ~1 ~ M N N N a 'fir ~ .-r _. x ~.j ~ ~_
x ~ ~ ~ N tn M O '~ l~ O ~ v0 ~ ~ M O Cv ~ M N M
~; vorici~~o0o0~,°;°~~' °rici.~~oNO°o'na
~o~o.''' ~M~o~.~v°~xx~~a~~ Mo~oNO~o~o-a~xx''aa
O N ~ N N ~ - - ,. ~ N N ~ N N
00 ~ M .. . ~ ~ ~ ~ ~ ~ v1 M
x x ~ M ~ ~ O O O O v0 s0 N ~ oho ~ v0 ~ ~ yp ,~
N "d vp tri N ~ p O O x H O O N ~ M N ~' ,-.~ O ~ p x O Q ~ M o_o
O~ ~ OvtnMQv,~,ax ~ ~a~O O~DNO~xax ~''~,.-~a NN
OW _D v0 ~O C~j '-i '~ '~ ~ ~ ~ O M .~ Ov
v0 x ~ M 01 ~ M N ~' '-' N M N ~ M f~ 00
N ~ ~ N
~M~ vp o~o~~ OO
" M ° O O ~ 00 ~ V1 ~ O 00
°Nx ~MN~°axxx°Mg Mv~Nr..-:ao°a,°~Oa
~,NOC,~~
ov os ~ c~i ~ - . a a v~ o N o ~ c~i a x . ~ a ~
00 ,~ ~w0 N ~n N ~; ,~ ,~ _ oo OW ~ M ivj '-'
N w N -~ N N ~ " ~"-'
Oy ~ M ~ O ~_ ~ O Wit. v0 ~ N N ~ N ~ N '-' N ~;j '-' N M
op~o ~ ~ ~. ~ O O ~ ~ vp~1 l~ O ~ oMO NO
O ~ a h cri N ,-: x ,~ ''O~"'I"'~ 'T'. ",°,a °'~, i-°-1 ~
v1 N ~-: ~' a -O-1. a x "~' a a 0O V1
O_v ~ ~ oo O ~~ ~j .. .~ ,~ " ~ " N O N v~ M ~ ,~ ~ ~ . I~ 00
N ..-~ O ~ N N ~ ~ ~' in O ~ ,~ ,-. ~ N O N oo ~''~ ~j ,~ ~~ ,~ ~ sp N
° ~p ~ ~ ~ O ~ O O ~ can ~ t~ 0 ~ ~D p O ~ t~ O N
~ x l~ cn N ~ a '~' a '~' '~'~ a V°1 a ~ v~ N N ~ x
ONO ~ ~O 00 00 l~ ~, N ~ ,~ ~~ ~~ ~-r ,~ N 00 O~0 ~D
N N O N N ~-~ M ~ cn ~ cn .. .. .. ~ ,~ "~ N N ~
O ~ ~ ~ ~ O ~p O O ~ ~ ~ pv ~ ~ ~ O p 0 O O °~p p oho ~
O N O
N ,-i a x x x x a a V7 ~ V1 N N ,-i x a V1 "~I''~ ~ a a
N ~n '-' O_O N t~ ~ ~ N ~ '~ '~ .~ .-~ ~ O M N N ~ fn N ~~ '~
M O N N N ~ N O ~ ~ ~ gyp" ri
O ~ N N N ~ ~ M O ~ ~ ~ N t~ ~ Ov ~ N v0 t~ O O ~D f~ OW O
~~ax ~~'~a~~ax~xx°aaa
~n - Cyt N ~~ ~ . ~ ~ ~ v'i N N ~~ .,
M O ~ O~ O~ M N ~ N N ~'~ ~' .~ ,~ ~ ~ 00 v0 Ov V1 M N .-.i ~
O ~O M o0 M N t~ p~ s0 ~ M ~ .-y v0 O ~ ~ O t_~ ~ O oo ~ ~ N
m v~ yn
O ~ ~ O O O O O O O O ~ ~ N ~ ° O O 0 p
O
x ~ax~xHaaa ~ xa~xxaa N
vp ~ O~ <h N N ~ M N ~--~ ~ .-i .-i .-i "~ ~ N N '~ ~ N ~ ~~ r"i ,-i ~~ O~ M
~ V7 ~ pOp ,~-, O~O 00 ~ ~ O ~ O vp l~ O Q1 N ~ O~O ~ Ov O '~ l~ ,_; ~ ~ vp
MN~ O~NN~~~~N~~~ ~~NNN~~~~~O~O~~ OM
O O O O N O O O O O O O ° O O O
~-~ N Ov M O
°M~ MM~ M°N MMN°
~D V'1 ~O
.-~ M
'~ ~ M ~' N N t~
00~ ~~ o~O~o°~O
N N N N N N ~ o0 00 pOp
U U U ~
00 ov o .-
00 00 ~ ov
162
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~i
0
~ M N ~~ '-' ~ ,-i
ON yp O ", Qv ~ ~ p _~. .-i ,-i N
N ~ l~ s0 v0 W vi ~ ~ M M N ~ ,_~~, ~ ~ O O p ~ ~ N ~ '!~ ~ cri N N N
v0 ~ ~-~ ~D v0 ~n oo N t~ O O N ~ O O v0 O O x x ~ ~ O vO ~ O O Ov O t~
v0 T O~ O~ ~O Ov o0 00 l~ l~ v7 N vp ,~ C~ O x x .. " a O O ~ ~D ~O M O N ~ N
O~ N ,-, N N ~~ .~ ~ .-, N ~O 'x,~ ~ _- ,~ r, _..~ x V7 ~ N ~ M N N N
a Ov N N y0 M pip ~ ~! '-' N
N .-i t~ y0 vi v7 ~t ~ ri cn N ~ O M r ~ O O ~ ~ Own ~ cn N N N ~~
00 t~ O N M N o0 00 t~ t~ N ~ ~ O O ~ O O x x ~ p M ~D ~D l~ ~ M M
~D v~ t~ t~ oo v0 M v»n v0 v1 t~ N a x O ,.''C'', x . " ~ O Ov ~ p~ ,-, l~ ~ M
Ov
.-r N ~ N N ~ N N N N N N ~ ~ M N ~ ~ ~ '~'! ~ ~ ~ "'~ ~.j
N a~~~~~_N~
N .-i tW O v0 ~1 ~ V V M M N l~ p O ~ O O ,,1'', x O ~ O V'1 ~ tri N N N ~~
O ~O O W O M O N ~ I~ ~~ I~ O O~ oo O~ ~n t~ M ~1
~O M (~ ~~ N 00 O ~D Ov 00 M ,-~ .~ x x ~ ~ x ~ . ,~ ~ ~ Oyp M t_~ ~ Ov O ~7
~ N ~ ~ N N ~ N O ~ ~ N N ~ wj N ,~ ,".~ ~ ~ '-; ,_, ~ ~ O
~~~~~~~~~~~xm°~~~°o
N .~ tW O ~D v'i vi ~t V cn cn N °.~ O O ~ O O ~ O p l~ ~ Vi V: M
N N N
00 ~ N O ~~ 00 t~ O~ 00 l~ O a0 ~~ ~l x O U1 x " x a O a ~ ~O M OWO o0 ~ M
!~ M ~ O N O I~ a0 Ov ~ ~D N ~ ~ ~ . ,-.y; . ~l ~ IwD oo OW ~ Ov ~~
N ~ N M N M N N ~ N N N ~ ~~'~ N '~ ~~ ~ ~ ~ -.i .~ ~~ ~ N ~ ~ N N
N O ~ N ~ ~ ~ M ~
a ~h ~~ I~ M T ,~ ,_, N N
N ,-i o0 f~ ~D wi v'i ~ ~ cn cn N ~ ,0~, O O ,_l O x x O O O ~ t~ ~ c'i N N N -
-
v1 ~n v1 N Ov ~ (~ Ov oo ~t Ov ~-~ v0 x ,~ " x .. " x
v0 ~-~ Ov oo N t~ 00 O t~ ~--~ M v0 N ,-.~ ~ ,-, ~, " '~ ~ ~ 000 ~
N ~ ~ N N N N M ~ N N O O ~ N N V.j ~ vp pp '-: .-i '.': '-' ~' N N N ~ N M
~~d ~~~~d~~~~~~~x~~~~°~~~°~~ ~~~~d~~~~
M v'i v7 N I~ O N O O ~n ~ t~ ""
N ~ ~ I~ ~O ~ V7 ~ ~t M M N '~ x ,x O x ~ x ~,, a O a ~ I~ ~ M N N N
M ~D l0 l~ M I~ V_1 O~ ~ ~D O N ~ ~ ~ .. ,~ ~ y-~~ I~ ~D M ~ ~Y Q~ M
~O ~D ~ O~ O~ ~-~ ~ 00 ~ O~ M M ~ ~ ~j N ~' ~ ~' .-~ ~ r; 0 .-i ~D ~ ~ ~ 00 M
N ~ O N N N N N N O O ~
VJ x x x V1 ~ a r~ N t~ ~ M N N N
~n O v~ Ov M d~ .-, .w0 M ~ I~ oo " ~ ,-i ri ~ 00 ,~ .--~ O t~ O d'
O o0 ~ O_W O O_ O_WO 00 M M N ~ ~ N N ~ ~"~ ~ .-i ~' ~O 00 Ov dW ~ Ov M
~ W ~ ~O ~~ N ~ N N N ~ N
p O O O O O O O M O '~ cn
(V ~ ~ a0 I~ v0 v'i v'7 ~ ~ ~ cn (V ~ x C~ x x x x x x a v~ ~ N ~ ~ cn r; N N
~-;
N 00 M 00 O ~ M O~ V7 O~ M ~O l~ ~ [.j ,~ r; ~~ '~ .~ ~ .~ ~ 00 ~ ~ I~ I~ V'1
M
~ 00 O ~n ~n ~D oo tmn N O N .. .. ,~ ~ N .. ~ ~ N N N ~ N
N N N N O N ~ ~ N N N ~ ~ O ~ ~ ~ ~ O
O O
O O 0 O ~ O ~ ~ O O 'Cf
~ 00 ty0 vi yo ~ ~ cn N N '~ '~' ~l x .-7 x x x ,~ ~ ~ -~ 0p' ~f M r; N N
N, . ..
V1 Ov ~ ~ M ~ W O_ M ~ ~ ~n ~ M ~j .~ ..~ ~~ ~-~ .~ ~; ~~ .-. N Own l~ O ~-~ ~-
~ Ov
N~~ ~ON~NNNN~NNOO~~N~~ON~O~~'~N ~~~NONOO
x ~~~~~~~~~~~~~oooo
~a,~xxxxxaxx
N ~ ~ ~ O~ I~ ~O V7 V1 V1 ~ ~ M M N ~ M .~ .~ '~ '~ ~ .~ ~~'~ ....i ~ ~ ~ M M
N N
l~ --~ WD ~ I~ v1 M v0 Os ~t O w0 0o N N ~O O ~1 N o0 m I
f~ t~ -~ ~ OW ~ Ow-v M Ov Ov M ,-, vp ~ ~ t~ cn N O WO oo ~ N N ~ t~ Ov o0 0o
O o0
~~~~~~~~~~~~xaaxxxx~~xx
.--s ,~ p~ l~ ~O ~ V1 V1 d: d: M M N ~ M ~j r-i r-i ~~ ..w r.i ~; ~-i .~ ~ 00
V ~ M N N N
O M N N_ v1 00 v0 M V7 O v0 M N p pp w ,-.; pp ~ ~~vj ,n N c~1 ~ N t~ 00 v0 N
N v0 t~ Ov -~~ oo ~O M N t~ OW ~ M t~ ~ "~ ~ ~t °~ ~ N N O Ow0 N oo tw0
~ N N t~
N ~ N -~ M N N N ~ ~ N N ~ O ~p ~ ~ N ~ ~p ~~ ~ ,n 'p N ~ -~ -~ N N N N
O O O O O O O O O O O
~O N l~ M
m O ~n O
M N M N
O ~ N ~D
~O N M ~
N M v0
DD
00 t~ O l~
d
N M
163
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~
--' .. v o .~ ~ oho
r;~-~~o~;~ ~ " M~ 0 0
vp p O W ~ G~ N ~!O N N N N ~ ~ O ~ cn ~l im!p
00 ~,,~ O M x O ,N W oo v1 I~ Ov M N t~ '~' O Ov .WO OW ~ 00
,.a O _" x O O y0 O v0 O N O~ t~ ~j x Ov ,_-i ~ c'~ t~ ~I' O
~ a ,~ N N M N .-~ .-~ N N -~ N M
d: ~n ,~ V~
N ~ ~ ~ ~ ~ ~ O
~
~ ~ O ~ oMO ~ N ri N N N N ~ ~~ a ~ cn x ~i wi Vi
M O O ~ x O ~ 0 ~ N OW i O ~i'i O M O ~ ~-~ oo ~ O~ ~
" x O ~ Ov oo v0 O t~ dw0 N x O op ~n I~ Ov Ov
" N N N M ~ ~-~ ,~ _" ~ ~ .~ ~ N
vp 00 O ,~ vp ~ ~ ~ ~ O M ~ ~O
-N, '~ ~ O O N ~ ~ cn cn N N N ,-i ,~ ~l O cn _~ v0 v1 ~!1
MMaVpIE"~~ra ~~OoNOO~ONOpoON~ o~o~ ~~TO~o
_ _ ~ ,-, .--i .-~ ~ ,-, v0 ~ O N
~ N M O ~' ~~ ~ ~ ~ ~ O p
O O ~ p ~ ~ O cn M N N N ~~ ~ "~' 0 M ,_; v0 v1 ~1
MOx~ ~xOa ~N.~~O~Oc~lOvt~N,~ N~jj ~h~tNl~
01 a ~ ~ ~ ~ 00 ~ O~ M 00 ~/1 " " 00 O ~D (~ 00 00
~ N r; " ~ _ " M N M N O O N N .~ N ~ ~ N N N N
~ ~ M v0 ~ 0 ~ O
~ O~ ~O O ~ ~ N ~ ~ " x M ~
.~ I~ O O x O O O N M M N N N .-~ ,~ O ~ ~ ~D U7 N
xx ~xaV7 ~~tooMW Dl~,--~NVl Ov0 MOOoO
" ~ t~ 00 O M
00 O~ 00 V'7 d' ~~ O \D .-,
N O ~ O ~ N -~ ~ N N N N O ~ N x ~ -~ ~~ M N
NOO~~O ~ ~~~~,~ N
x ~ '',L" a O ~ ~ ri cn N N N ~~ ~~ N ~ ~ N v0 v'i ~n ~
~ r.7 . v0 N M Ov Oi ~n oo " OW ~ Ov ~ oo U
" ~--~ ~ ~ ~ 0_O t_~ V7 OW_O I~ V'1 n ,--i o0 l~ ~ Ov 0_O l_~ o_0
~ .. ~
o ~~~~~~~~x~
0
~ ~O x x x V7 a ~ Q M tr7 N N N ,-i .-i N "x ~ fV M l
00 ,~ ~ ~ ~; ~ O~ N ~ 00 ~ N ~D ~ ~D O~ ~ M M O~ M
00 N N ' ' _ ~ . . ~ 00 ~O M I~ M ~D O ~ .-i .-~ V'1 ~O ~O 00
~ .~0. ~ ~ ~ ~ N N O N N N ~ ~ pp M N ~ O N N ~
ooOO~°O ~ ~~d~xo
~v°~x~xx,°~x Nr;ri~ic.icvr;-~~~ wici ~c~~;~i~"
~
-i ~ ,-i v0 0o v) oo O l~ d' ~n ,-i O OWn t~ O M
M ~ .. ~ ~ O ~ ~ ~O ~O ~ ~O ~ O M ~ ~ N O
O p~ N ~ ,~ W p ~ N O N ~ vp ~ M O
o'
M M C~1 N N N .-~ ~i ~ x uj y0 cn N l~ v-; V1
M N ~ ~ .-i .~ ~D O O ~n M ~n N v0 y ~ .-i ~ op ci-; ~ ..r N ~W O
O '' oo ~; ~ l~ v7 Ov O_v ,~ N o_0 ~ ~ ,~ 00 0_0 -. N .~
~OOOOOpOb ~~''~Ob
x G ~ G ~
,..] ~ ~ " x ~l x al ~ M N N N N ~~ N x ~ ~ M ' I~ V1 tn
~p~ M N ~' .-, .~ .~ ~-V M .--n ,~ '~ .
N_ _~ ~ ~~ O ~O M_ v1 ~ ~ M O O v0 v_0 ~D o0 O o0
M O O N N ~ ~ ~ Ov ~ ~ N M N ~ N N ~ ~ ~ O O . ~ O ~ N
~a~,xxx~,,~a ~ ~~axa ~ M
~ ~ M N ,-; ~ ~ ~ ,~ .-n ~ M N N N N ~~ ~-! ~ ,~ 00 M ~ N 00 ~ ~ V7
M O N ~ w f~ M ~ t~ Ov oo ~ M ~ ~ p ~O v1 f~ O Ov
N~~~~M~~~ ONONNN~NN~~ OMB ~NNONO
O O O O O O O O O O
0o Ov ~ O ~a N v1 M W O
~n v~ O ~O ~O ~O O ~ ~O O
M M N M M M N M M N
O
~ M ~ N O ~ op ~ O
d~
00 ~ N
00 00 00 00
U U ~
~,
164
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N gyp"
M rr .-i .-i
~ M ~ ~ N " yp
O ~ V ~ M O r1 O .-i ~ ~' r,
M M N ~-~ a ~ ~~ O ,~ ~ y0 ~O v1 v1 V ri ri N ~ ~ ~n ri N ~ "'~ N d~ O ~
t~ ~O O ~ ~ N O p x ~ ~ W oo ~t o0 ~D ~-~ N O ~O " yn o0 t~ tw0 ~ ~ x f
O Ov ~ O O ~ '~, ~"~ ~b M .-a M M l0 00 O ~ O~ ~ ~ .~ ~ O~ N t~ ~ ~
° O
~ p N N N N N N ~~ N N N N N ~
a N ~ ,--: O a (V .-, ~ Oy N
ri M N ~~ ~ ~"~ ~ ~ ... .~ ,;.j ~O ~D ~!p v-i ~ M M N V7 ,-, Sri ri N ~~ ~ W.
O
~ ~-i fj o_o N ~ x O ~1 ~ ,--i v~ ~~ t~ h ~ ~ N I~ ~-yi o0 ~ '-' ~' M ~ O ~ ~,
O
N N N N ~ ~O " a O ~ ~p O O_~ O~ 00 l~ Q~ l~ O N ~ ~ M O~ M O~ M ~ C/~
N
O a '~ ~ w0
N M ~ ~ ~ ~ ~ M ~ ~ N Ov
M M N N O~ N °~ ~ rj .~ t~ ~D V1 N ~ ~ m N '~' p v7 M N ~ ~
.-r M Os ~ M Ov ,'y', ~) O '-' ""' t~ M N v0 M ,~ ~ v1 M N ~' OWO ~ M p~ ~ O x
O
t~ M -~ ~ oo O " ~ ~j ~.j N Ov oo v0 w0 v0 N N v1 Ov M Vj ~ x
N~; N~; Np~ N Np; v~ ~; '., op ~p ~ ~~;~ ~ N Np~ N Np; N~; N ~ ~ N M N O ~. "
.
o ° ~ ~ ~ ~ .°-l ~ o ° t
0
M cn N N .~ O ~ v~ ~ °.~ (y0 ,n v1 ~ ~ ri N a ~ ~D M N N n ~ ~ O ~
00
t~ M v0 0o Ov N x ~ O M '-' ~ O~ M M ~ O N OW i N O O v0 v0 v0 ~ M O ,"I'~, O
I~ ,W O N o0 Ov " " ..~ '-' '-' N ~ M oo OWD ~-~ o0 Ov d' ~' v0 WO v7 M '~ xi
~ ra
N N N N N ~ ~ ~' ~ ~ op N N N N N N N ~ M ~ O N N O N ~ . _"
N a N ~~~'''!"'~MMyO
..., O ° l~ l~ O ~ I~
M M N a O ~,~ l~ s0 ~n w ~ ~ M N ~j .~ ~ ~D M N N ~
OW ~ OWD v~ O x " a ~ ~ oo N O v0 t~ t~ ,-W ~ M ~: ~p N ~ ~ Vi O
N 01 ~ ~~ ~ l~ ~ ,~ ~a ~ I~ N o0 M I~ W O ~ 00 ~ O l~ ~ .-r ~
N~NO~'-' ~~ "~''-' MNNNNN-~N,=,ij ~'~NNNMMN r,
O~n M OM ~ ~ ~ Cn x ~ l~ O O V1 M
d: ~ cYi c~i N ~ x a p ~ ~ ~ ty0 wi ~i ~ ~ cn N ~''~ ~ ~ I~ cn N N ~-~ ~ p ~ O
v0
~cn t~ _- V1 ~t ~t Ov M M Ov O t~ N ~ ~ I~ Ov ~ Ov ch
.-. 0v M M M O_v N N N ~! ,~ ~ O t_~ O ~1 00 ~ N M O ~ ~ ~ ~ N ~ Ov
~ N N N N ' N
V' ~~n O~ O
O ,~ ~ ~ ~ ~ ~D O v1 O ~ N
M M N -~ x ~ ~ N N N t~ ~D ~ ~!1 ~t ~ c~i N ~ ,~ N t~ M N N ~ x a x y0
N o0 ~ O N o0 " ~ ~ ~ y0 v0 OW D I~ oo N M sD ~~ ~ ~ ~ ~n Ov oo .~ "
00 ~O M M M ~D ,~ ~ ~ .~ N O_~ O_~ M ~O 00 N ~ ~ ~ '~ 00 00 00 V l~ M
N N N ~' y0 0o N ~ ~ ~ ~ ~ N N '~ O N N
~O O ~p N N N O
Oi ~O O l~ O N O O
M c'i N ~! x x: x p ~ Vj WD v0 W ~ ~ c'i N ~ x N o0 ~ N N ~--~ ~ ~ x ,WO
O M V'1 ~ ~ "~ ~ I~ ~ ~ ~ O~ M 00 In ~O O ,-; ~ M ~O ~O M N M
~D M O~ O~ O ~D .. 00 .. ~~ ~ M ~ O M N O 00 U oo M M " N ..
N N ~ N O p~ op op ~ ~,,..,,~~ N ~ M O N N,,~ N,,..~~ N O~ ~,,yy O N N N,,,,~~
~ p~ O
0~,~ N~~~ ~~~p N~~~~~ODOp
M M N ~ w . ~ ~ ~ N l: ~O v0 V1 ~ ~ M N ~i x ~ 00 V7 M N ~ ~ a x
v0 v0 N_ f~ t~ ~D r; ~ ,-i O ~--a ~' N OW O o0 00 ~n Ov ~~ 00 ,-i N OWn I~ O
oo M ~j ~--i .-i
N ~ N N N N oo M N ~ ~ ~ O ~ ~~-r ~ N OM N N ~ O O
M
ri Mcn N ~ " ~; ~ cn M o0 ~ ~O s0 v7 ~ ~t t~i N ~ " ~ 00 wi M N ~-;
O N oo O vD v~ ~' ~' .-~ t~ l~ M oo t~ vi ~-~ M O d' N ~W O ~ M ~ I~ ,~ ~ N .~
O
~ ~O 00 ~O ~ ~~ ~: O ~ M .~ .~ ~ O~ l_~ V7 M ~ M ,--i C_1 ~p N O~ O~ O_ WO O p
O N O
NNNNNN~xa~~ ~~~~,~x~ ~ N
O O O O O O O 'fl
M M N ~ ~ ,-i ,_; M ,..-i r, l~ ~O ~O V'i V~ <t M N ~-~ ~ ~ 00 V1 M N ~; ~1 N
,-i ,-.~ r., \O
W O V ~~ ~_ op ,-; Ov O Ov O v0 ~f ~n O N O~ t_~ ~_ O N ~ Ov c_n cn
N N N ~ N ~ ~ '~ O O N ~ ~ N N NO ~ ~ N M ~ N N N N M N ° ~ ~ ~ M
N
O O O O O O M O O
p M O M O
p
v7
d' M~ HOMO
A A
w
x xx xx
165
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
v_i ~ N
~i ~ cn M cn N N ~i ~l ~ cri ~ ~ iN ,_; ~ O~ f~ ~D W wi d: c~i N ~ N Iy0 v1 ~t
ri
N Ov V N ~ t~ N ~ d: O O O vp I~ ~ n M N t~ t~ d O N ~~-~ 00 N ~ Qy ,~ v0 0o N
cn
0o t~ Ov N Ov oo ~n t~ . ~ ,~ O O N N O ~' O t~ OW ~ oo M t~ I~ O y0 ~O f~ v~
00
N~NNNNN~~x ~_.
O M ~ ~ x a M N ~ N N ~ N .~ ,-, O ,~ ,~ ,~ N .-~
.. M
v7 ~ M cn cn N N ~ '~ ~ y0 ~ p°p ~ ~ ~ OW v0 Vi ~i ~t M N ~ N f~ Wn ~
ri
00 M ~ ~_D O~ l~ M ~ ~ O x O O l~ M N Ov ~_ ~O M OW O V1 N V_' ~ p~ ~ V1 V7 Ov
00 O
N N ~ M ~ N N N ~ x r.; a ~ n..7 N N N N N N N ~ N N N ~ p ~ ~ ~ N N
~-a1 00 yD O~ N
O v0 I~ ~ N O ~ Iy0 ~O v~ ~ M N --; ,~j tW O vi ~t M
tn ~ M M M N N
~_-m1 v_0 Ov N M o0 .~ O ,''J.~~, ~l O O ,~ ~~ ~~ ~D ~t nj o0 ~ O v0 N ~ N Os
p M V OW O
M ~ N N N O ~ O ~ a ,-i .-; '"~ '""~ ~ W N ~ v1 0o v0 v0 vD N lw0 ~j p~ ~n OW
~ M ~
~ O N ~ N ~ O N pp ~, N ~ N N N
~~~~~~~~~~~_~N
V7 ~ ri ri M N N -~ s0 ~ O O ~ ~ O~ I~ ty0 ~ ~ cn N ~ t~ ~D vi ~ ri
0o O oo O ~ M O OW O ",p,~ ~l a O O t~ N O N M ~ ~W O N ~ ~D Ov ~ O ~O ~n N
l~ l~ ~O ~ I~ O O ~ N r; r; '-~ '-~ '-' ,~ ~-, 00 V~ OWE ~ ~~ N O~ 00 N "~ n M
,~
N ~ N N N N N r0 ~ N O O N N N N N ~ M N N -~~~ ~ N ~ M N
0o O O ~p ,~ ~ ~ ~ Wo vi ~ r;
~i ~ ~~; r~ ri ci c.i -: --~ O x ,~ O O ~ ~ ~ ~ oo ri ~ ~n ~ r; ci ,-..
00 ~o o; oo O O t~ M t~ a ~ ~ ,~ ,~ ~ os O M v0 v~ N O~ ~ O ~ ~ N ~O t~
~O M o0 M ~O O~ ~ oo (~ r., .-~ oo N ~~ V~ O~ .~ ~ oo M N I~ 01 O O ~ O ~-~ ~O
M
N N ~~ N O N N N N N 0 ~ ,~ ,...; ~' ~~ ~~ N N N N ~ N N ~ ~-v M ~' N N M N N
ONNN~~~ ~O
wi ~t M M M N N N ~-~ a ''~' ~l O O ~ Os oo Iy0 v7 ~t c''~ N N ~ ~ oo v0 ~ ~t
M
O ~ v~ ~n v0 N n O o0 ~ ,-; a a Ov M_ O_~ O Ov t~ M d' ~~ N M M_ O W
o0 VO ~ I~ N v0 Ov O Vyj . . ' - ~ ~ op N ,~ ~ M N N O N N M ~ '~ ~' ~ ~ N ~ N
O N N N N M N ~~ p~ ~ ~~ ..
a~~~ Oo~
v1 ~ cn ri cn N N N ~ ~ x x y..~ ~' N N Os oo t~ ~D vi ~ M cn N '-' '-' oo t~
wi ~t cn
I~ f~ v7 I~ ~ N M QW~ ,_; ~ ~ M N Ov O t<1 M O~ O o0 ~ ~ 00 N M I~ N
~O Imn O v0 ~~ ,~ oo ~ N . . ' ' ,~ ~; v~ v~ M vW O N v0 00 0o OW ~ ~ ~O o0
N ~ N N O M M O N ,~ N O ' ~ ~ ~ ~ O N O N ~ N ~ ~ N ~~ N N N
Op O ~ ~ . ~t ~_ W Ov O
v1 ~ ~ cn ri N N N ~ x ~ x ~-.7 C/7 ~ N M ~ O~ 00 tyD ~n V cn cn N N ~ 00 I~
~!1 ~ ri
V'1 ~ 00 N I~ 00 In l0 ~ ~ ~-~ ' ~ ~ I!7 ~ [v .-r 1n M M .~r (v .-r M M O1
N O M .~ N N ~~ .-, N ~ ~' O ~ ~ v1 Ov ~ ~lwD W O Ov O o0 O ~ M v0 Ov
N M N O ~ ~ ~ N N ~ ~ N O O N N
~ O O ~ ~ x O cfi ,~ ~D t~
N ,~ ,~ ~ M ,~
~ ~t ~ cn M N N N ~ ~ a x a x ~ O ~ ~ O~ 00 I~ v0 v7 ~ ~ M N ~; t~ ~ 00 l~ ~n
V V
M ~ l~ ~~ V7 O V1 ~ M N ~ ~ .~-~ ~ .. ..
N~MMNMOO\OM ~~[~OO ~'~' NNN~~NON~~NNN NNM~~Oo~o
N N N N N N O ~ N N ~ O N ~ ~ ~ r~ M M N
~ O O M can N
x x ° ° O ri ~t -~ os o0
c~; c~; ri ~i ~i ~ x ~ ~ a Wo cu .-a ,~
'~ ,~ ~ ,~ O ~D ~ 00 f~ vp ~ ~ ~ cn N ~' v~ N
~D FWD Ov N ~ WO v0 N '-' ~' ~..' oo ,~ ~t v0 ~n ~ v~
~D M l~ M 00 V1 00 pp M V'7 00 ~~ ~ 01 ~-WO V~ 00 M ~ M V~ 00
N M N oo l~ Ow7 l~ ~_O M t_~ N M O N in ~ ~O t~ ~O
N .~~ .~ N N N N N N O v0 M O
~~d'~~a~~~'~~a~d'~xx°a°.°a
v0 vp d: M cn cn N N ~ M .-i .-i ,~ ,-i r.i N ,-~." ~ p~ 00 ty0 v1 v1 ~ tYi N
~ ~ ~ ~ f~ s0 d~
v7 M O l~ O O 'et M ~ ~p ~,j " ~ M o0 N ~ W n O v0 v0 t~ 00 00 O v0 O Gv N ~-n
N o0 Ov N ~ N O Ov N ~ 00 ~n ~ N M N N ~ p ~ N N ~ N ~ N ~ ~ O M N ~ ~ N o0
O O O O O O
l~ O
M N N
N N
O N
M O~
N ~ M
a
A
xx x
O
O O
N N
166
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N '-' ~ ~' oo t~ ~i
~ M N N N ~D O N O O
~ ~ -i ~ ,-" ~
i
n N N N
t
cri N ~ M N cn v N ~n t~
N ~ O r M ~ I
00 ~
~ ~
c
M O oo t~ OW ~
~ ~''~ ~
0
~ ~ O~
Ov N v O N 0 ~D ~D I~
~ O oo Ov o0 Ov M O~ ~O
M Iw0 M .-y~ 0 N
O .-. .w0 00 N Ov N ~ t cV -, N
~ l~ O O ~ O N N N
_ N ~~ N M _
N ~ N ~ ~ N .-~ N N N
.. .. c~ - Ov ~ I~ 00 t~ v7
m N N ~ ri N N y wt V M ri N N N ~ ~ cn ~-,
~ N .-~ .--~ ~ ~ ~ O
,~ ,...,
,~ ,~ ,.~
,~ 00
cYi r ~ ~ ~-~ v~ , Oy~ ri ~t
N t~ M t~ ri t~ N M Ov O oo ~ Cs -~ t~ t~ O
O ~ O x 0
t~ N M oo ~ v1 N ~ w0 O t~ Ov Ow0 ~ oo in o0
t~ ~ M W n N N N M ~ ~ N O N a ~ t~ O~ t~
N ~ N N M N O N ,.~ ~., O N .-r
O ,--n N
,..r "'
y0
M N N .'~~' M N N V7 V'1 d: M M N N N p~ ~ yj
~ N N ~ ~ ~ ~ M O ~ ~rj ,-i
p" 00
~ .-, o W o t~ ~i cn O O ,'1,' -~ ,~ ,~
pv .--i O ,~ Os O O ,-, .,
v oo M O Ov O oo ~t o ,-, cV
~ N
_ _ _ ~M
O~~ NNN~~N _
_
N~ON'~~
i"~
N~
O
N ~ ~MO O_O ~_p
_.- ~ M ~ [~
N N
N
N ~ M
M
M N N ~ M N N N ~ ~n ~n ~t M M N N N " 00
~ ~ ~ ~ M ~ O p
~n O Ov N N M O M M W O M ~D M O ~ O I~ v1
~ oo O M W O O x O M ~ O
r, ,~ .~
~ ~ ~D ~ UJ ,~ r,
~ M O M x x N
~O ~
~
~ ~ O
t N .. M
Ov N n O Ov N N
n N N N M N 1 l O ~W O cn
N N N N - O v0
v ~ ~ ~ N
~ O ~ M M N N N N ~' O ~
r;
~ ~
cn ri -i ~ O O ~ 00
N N ~ ri N N ~ ~O ~n ~ cn cn N N N
0 N ~ ~ 'n ~ M ~ O ~
x
~
O ~O ~ - N t~ O vD N v0 N M t~ t~ ~D O Iw0 M
d' s0 ~D ~ ~ ,~j cn ~ a " ~ O ~p
v0 N OW '7 v0 a ,
M oo o ., " v0
N ~ O (w0 O M v
N O oo Ov N ~t O W O O~
NNNN~O _ ~ ..
~~ _ O
~~~p
~ ~~ N~M
~ NN
M M N ~ M N N N '
N ~ ~ ~ ~ ~' ~O v~ ~ M M ci N N . .
~ ~ O O ~ O 'fl
' a ~
~ a
ri t M I~ ~D oo .
O ,~ O t~ O cn N OWn
~ ~n --~ ~D N v0 v
~
_ _ ~ N
_ ,--n N ~ N ~ N' N ~ N ~ N N .--n ~
_ O ~ ~ ~ O ~ ,-~-i
,n N N ~ ~ ..r ~ ~ ~ ~ n V'7 ,--i
N N N ~ ~ ~ ~ ~
N ~ p '
O , ' M v~ o0 Ov O I~
a er, M ~ ~ O t~
ri cn M N N N ~ ~O d' O ~D V~ Gv ~ ~ M
N N ~ N ~O v7 ~ M cn M N N ~O 00
~ ,'~ -~ x ~ x a a N N N N
~ N N 0p"
'
v0 ~ ~ v1 ~n t~ 00 dW ~ O ~ ~f'
~D M , oo ~ ~, " "
~' ,
~
,~ ~ oo v0
Ov ~ ~ ~
N M M M .~ O~ Ov v N ~--~ ~ M oo O y0
N ao N ~O ~rj N . ,~ ,
O N ~ O
v O
N N N ~ ~ ~ x _ c
N ~ O _ j
_ '
~ ~ ~ ~ ~ p ~ I~
,
i '~ '~ M M N Ov o0
M M N ' O Ov d
N n M a x a a
~ ~
.- ~ N N ~ ",
c "~
N N ~ ~ N p
~ ~
M ~ ~ O ~n ~D ~O N ~ O I~ O N o~O M m Ov
p oo t~ O N M N ~ ,-i ~;
O
O ~ op
~ 00 00 M -
N I~ ~t
N N N ~-~ N N N ~ N ~ N N ~ N O N ~p N
N M N N ~ G~ oo v0 ~
C , ~
, O
~ ~
n a ~ O O O p ,-,
N
cn ri ,ri ri cn ,~ ~D v7 ~ M M ri N N ~ ~ ~ y0
N N N N -~ ~ N a "x 'T' a a N
~ ~
00 vW v~ ~ O~ m W ~ O ~ ~--~
~ O t~ v_~ oo n ~n vi o0 cn O oo G_W --~ N ~n
c~ ONNN~NN~ ~ I~ ~ N ~' ~ ~i ~ ~~~N
NNNNON N~NN~~NN~N~~p~~
oo ~D O t~ t~
O O O O ~n oo t~
0o aaxaa ~Y N O
M~~-:~--
M M N ~ ti cn N ~ ~D Vi ~t cYi ci cYi p~ N OV
N -, N ~ ,~ .-r N N N ~ . ~ ~ oo cn
~ 0 ~ ~O O ~O ~ M ~O N oo
vi O M O O
N O N ~D ~: N '~ '-: "
- v0 '
~n ~ 0 W O ~ N ~
Ov o0 W - N N M
I Ov .
00 0o ~ M -~ I
M o M ~ f
o o O ~ N Ov ~ O
O ~ W ~ ~n ~ M M N M oo N
M N O o0
_ _ _
_ a _
_
O M O O
. o O
~aaaa ~~,~.~No
~
M cn ~ ~ cn N ~O ~n V ~ M M N N N ~ ~ ~ ~ ~
N N N ~ ~ --V N ~; ~; ~ ~ ~ Os
~
0o cn O N N OW d N ~t ~ f~ N OW i OWn M '~ '-'
~ O i ~n t~ ~: oo t~ cn t~ oo O ~
~O M ~ ~O lW0 00 t~ 00 M 00 N
(W O ~O OO OO 00 V~ ~ ~D O~
O~ O 00 M .--y~ (~ O O
00
--, N O ~ N M N N N ~ ~ ~ ~ O ~ N O ~ M ~ -~ .~
~--~ N N N ~ ~ ~ 0 N .~ N
~
O O O O O
N ooM
N M N N
V7M I~
M N O~
M
O O N
o0
A
x x x x
N M
O O O
N N N
167
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
. r: ~ .~ chi .. ,~ ~; os
'~ ~ ~ M oo ~' ~ ~ o r.; ~' ~~ os os c: ~o ~'' ~ os os
M rr ~ [s M c'1 M O n 00 ~ ~D M ~ O ~ n ~O V1
N .~ p, p N O O '-' p M O ~ cMn p t~ 'n ~ ~ .~ ,~ ,-, ,~ M O Os
N I~ ~ O rr ,-n O C~ ~ ~ O x O ° Ey-°.7 ~O O ° ~ ~ ~
~p ~ N N
x ~' ~D V1 ~ N x x ,~ a i-1 'r~,~ N O ~-~ M
O " ~ O~
V7 x vD M O a ~_ O M ..r l~ N y0 y0 V1
mO~DM o~oN~° M.-N~OMO~~nOO~~~ ~~N~NooO
o~,~wt oas°'i' ~~"'°x0°x,~O°° ~~~°
ov~o~
N N N N ~ ~ ~ x r., ~ ,~ ~ N x x ,~ ~ ~l x ~ O W N I~ ~ N N .~-a
.. ° ° ~001M~p,~~.;pp~j.-v.~':'! ~7v_0~~
x O ~ C~ I~ ~ ~D \O N O o0 t~ ~ ~ ~ °
t~ d: cn N ~ ~ N ,~ O °~ M O o°o O ~ ~ O ~ O N ~ ~ 00 O O
M N M t~ ~ Ov ~ O x N .~ r-~ O x 0 O x ~ O O O N t~ t~ ~D
,~ N O x ~~ ""~ N C/~ x ,~ r.. "~ '~' x 0°O ~ N O
V] ~ ~ O O O ,-..
i!j ~ Cn N ~ ° M ~ ~ N
t~ ~n M N ~' ~t ~ O N O N p ~ O p O M ~ ~ N M N ~ . . ,.
v) O N ~~ ~ oM0 N O x N .~ ~ ~ '~,~' N O U7 C/~ O ° O ~ rr ,
M ~n .~ O M° N N C/1 M ~) x r; ~-1 C/~ ~ 00 (y0
° °~ ~ M N M M ~ ~' oo Ov ~' ~! '-' dye tn M N ~t ~
d: O ~_ N O .~ ~ ~ in ~n M ~ ~ ~ ,-r'-, N O
t~ V'i V N ~ ~ ~ ~ ° ri ~ ~ Cn O O ° d' O O ~ ~ ~ N
.. ~n O x ~ x O O x H O O O ° ~ ~_ ~ ~
M ~ ~ ~ ~ ~ ~ ~ ,-i '~ 0 ~ ~ ~ x ~ ,-; ~ a a ~ ~ ~ ~ ~ N M N
N N ~ N ~-~ ~ M ~ ~ N M O M N N ,~ ~ ('rj ,-~ .-, '~ ,_, 00 fy0
O \p ~D Q l~ M Ov Oy,., --, ~ M WO ,~ .-,
O twD ~ v~ 00 ~ t_n
I~ v~ ~t N N ~ (N ~,x0 ,..°.~ b o~0 ~ ~ x ~ ~ O x x O N ~ N ~ ~ ,~
N
N N ~ ~ ~ ~ "" ~ O ~ ~ ,-i ~ a a ~ O_
-, v0 M ~ ri N N ,~ ~ ~ ,~ .~ ~' N N ~ °N ~_ 00
N O N ~~ M N ~ .. ° ~ N ~ M
pW0 ~ ~ ~ O ~ ~ ~ M O O o~0 v0 '~ v0 v0 V1
t~ vi ~ ri N '~°' cn ~ a ~ N N a In x ,.a N x ~ O O ~ O wi Own N N
.-. oo N o0 ~D O T ,~ . p ~ ~ r-~ ., ~ r.a ~l ~ N v~ N .--, M
Ov O ~ O\ .-i M ~ N ~~ ~' N M N N r; '-' ' .-a ,-i ~' N .-r ,~ ,~ p~
~ O ~ ~ ~ ° ~ ~ ~ ° O O ~ ~ ~ N N N ~
p~ ''a O 0 ° x O O O ,-i M Ov ~
t~ ~; v r; cv N ri x x W ~ o ~ x x ~ ~ x _~ ..a ~ x M ~ oo t~
0~0 O ~ N M N ~p ~ M ~ ~~'? N N ,-r ~ .-, .-, ~-! O t~ O OWE O
O N N N N O ~ pp ~ ° ~ M Vj f~ ~j ~" pp pp O ~-~ M N ~ N ~~ O
~O N ~ N .~ .r ~
p°x'O ~ .~~.xpNOp~00,~°,~0~00'd ~~~~~0~0
t~ v'7 ~ c'i N ~t ~ .. x O o0 ~ x x v-1 C/~ xi ~ ~-.] r-~ ,~Si ~ N N N N ~ O
I~ O
r,
~O t~ ~~ Ov o0 W_O N ~ ~ ~ N O ~ ~rj N .-i ~-~ "~ ,-i ,-i ,-i ~ N N °N
N Ov N ~D ~D N M ~ ~ ~ N oo nj p~ ~ l~ N c~i l~ ~t v0 ~
M ~ O V1 p1 ~ M N~ ~ l~ ~O V~ l~ O O ~~ 00 V~
O ° O ~ vi ~ O O O O O O O O O O N ~ ~M-as ~ ~ OW v0
Ov V~ x x ~ ~t p r-~ C/~ x C~ x ~'"r' ~ ..a ~ ~ cn N W ~ ,-: oo Iy0
f~ ~D ~ c~i N ~ ~ .. - ,. ~ ~ .. . . ..
N .~ ~ ~ c~i N
~ ~O M .-m.-m°D t~ r.. O Ov ~ N ~ ~ N N Ow0 oMo
Iw0 0o v0 t~ O t~ O ~ ~j N N .-. O N O O ~ n Ov N N N
~ E'i x y-.a V1 U7 M M ~O 00 ~D
O O o0 O ~O M ~ O O v0 t~
M N ~~ ~ C~j ~ ~"~ '~ ~ ~ ~ M N '~ ,~ '~ ,_; .-i ~~ ~~ M .~ .-r ~ ~--n O~ l~
\O
0o M M v1 dW 1 ~D ~ ~ N N v1 ~D Ow0 N v1
0o v0 ,~ N N ~n Ov ~ N M o0 ~ '-' ~ °~ ~ O ,Mn O~ M ~ ~ v1 ~ N v0 Own
o0 f
N N N N N O O ~ ,n p O ~~ ~ ~ ~ ~ ~p ~ ,n ~ ~ ~ 'p N N N ~ ~ N N -
O O O O O M O O O O O O O O
V1 O~ O ~O ~ N l~
N M M N M M N
~OM,M-, ~0~0~
N N N o0
x xxx xxx
O O O
N N N
168
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
.. ~ ,--i r-i ~; ~ ~ ..
N .--n ,~ ~~ ~ .-i .-
ri t~ cn oo ~' cn p~ ~ ~ ~ v~ '-' N ~n O
~n ~t M M ~-r ~ ~ 0 00 V ~ N N O ~ ~ oo ~ ~ yn N ~ N ~~ ~O v1 v'i d~ ~t
N ~ 00 ~ ~ I~ O v0 .. . . .
M ~n 0 V1 O O O M ~ V'7 ~O ~ M ~p ~ ~ 00 N IW D M W D O~
N N N O ~ x O x x x x x ,~ O O vp ~ a O a O O t_~ OwD O_v ~~ N M
a ~y x ~ .. ,~ .-~ ,-, ,~ ~? a p ~l ,-; a
N "'' n M
~n ~ can can N ~j N ~ ~' Ov Ov ~ ~ ~ O~ can ,~ ~ ~ O M N .~ ri ,-i ~O vyn
O ~ ~ ..
c~iooosoo~xo~oxax~-oao~~o 'o~,.Nao~"' ~n.D ~o~n ~~vi~o.
~ M ~ M O ~ ~l ~ x ~ ~ .. " x C~ N O ~ ra "'a N N N ~ O oo ~O v7 N
N N N O M _ _. .-. ,~ ,~ _~ ~-1 ,-, _ N
~ N M ~ N 0 N ~ O cn O M ~ r,
~ N ~' M O O O O op v0 ~ ~ ~ N
~ M 00 '~ v~ ~ O v0 ~ ~ O O O O ~ N "'~ M O ~ MO M N N M .-i v0 ~n v~
m ~ M M N N x ~n O O VJ x x v1 O O oo ~' x O p N M M .o O ~r ~n ~r O vo
.-r p .-~ M ~ O a x ~ ~ ~ ~ . x C/7 O O ~ ~ " O_v O_WO O~ rr O <t ~O
00 Ov ~ ~ N y ~ ~ l\ vp o ..t~ ~ ~ ~ N N
r, l~ '
'~ p O O O O O O O M O '~ ~ O p O M N ~ ri .~ v0 v-i vi yt ~
v7 V M M N p~ a ~l x C/~ "~i ~ CrJ x ~ a ~ O ~ ,~ x ~ ,..~_, ONO O l~ G_~ M
opo ~_ ~_
_~~~~ a _
~O M M O~ N ~ pp ~ O ~ ~ '~ N OW,
N O N ~ N V1 W ~' ~''~ O oo ~n ~ O ~,~ O ~ ~ ~. M N
x x x x O O ~ N p ,~,' O O ~'' N '~ M '-' two V1
~ ,~ "a ~ ~l x M ~: o ~ ~ cYi co as oo .o
V'7 ..~ ~ M N ~ M (V ,_.i '~ '~ '~ ~ .-a ' ~.'i O ~ a ~' r.; .-i N ~ ,-a O_
~_D O_v 00 l_~ O~
O v0 t~ M ~ "j n O m ~ Ov W _p ~ ~ ~ O O ,~ ~ O~
M N N ~ 00 O ~ ~ O O O p O ~O ~ x ~D O t~ t~ ~ ~ ~
a x ~ x x x x a a G '" o x ..7 x '.'".'' '-' ~ '" t~ ~ ~n
~ c0 Ov C/~ ~ 00 .~ M ,~ p~ ~ l~ O~ ,~ ~O
~D ~'-~ ..~ ,_.~ I_~ t_~ 00 O O~ O M O ~O M
~n t~ OW 1 t~ ~ . N ~j cn ~ 00 rt ~ ~ oo . . ~ N O~ N N
~n ~t M M N "j M O~ Os O -~ O N .y0 ~O
~O O O~ l~ V ~p ~ ~ O~ ~ ~O M ~D O l~ NO O ~ l~ l~ ~D
~O t~ ~D 00 M ~p O O V7 O O O O l~ O ~ M O O O .-r
axxaxxxxC~aV7,0~, N~r~i~,~,~MN~"t/7N t~~D~l7
M .~ .-r -~~n ,-, .--n ~ .-r N ~ ,~ ~ N '~ ~ V1 l~ I~ ~~ f~ 01 00
N N . . . . . . , , . . ,-, . . ,~ oo t.,j
N l~ N O v1 ~_D t_~ M ~O M
vi o0 U vp Ov ~ ~ ~ oo O ~ ~ "j ~ N ~ vp ~' ~ ~ ~ O
V7 ~ M M N '~ t~ ~ ~ M ~ O O ~ V1 O ~' M x
00 ~ ~D M t~ ~ O ~ O O O O O v0 M ~ t~ p p ~O b
v1 O M O M ~ a O O x x x ~l x O t~ O O ~
NNNNN~ E-~'"1 ~ ~ .. . ~a ~C/~ N~.lx'~'~x ~ ~Nr' SON IyOV'i~~
x ~' N N ~ ~ rr ~ N ~ ~ M .-, ~ .-; ~ rM,., O~ M ~ ~ ~D ~O ~D ~O I
p~ ~-' t~ ~ ~ ~ oMO ~ ~p t~ M N op ~ ~ O v0 M N N ~ O ~ ~ N O N
W V' ~ M ~ ~ O dW~ N M ~n ~ O WO ~ ~ ~ ~ ~ O
O O O O O O O ~ O 0 0 p O N O
~;~~,~:~~xx~xxxaH,~xx M~~xax
M ~ N o0 l~ N . . . ~ ~ " . ~' cV '-' ~O N tW O ~n
O N N ~ ~ N M N N ~' ~' '.'~ ~ ~ .-~ '-' ~; v1 M '~ '-' -~ ~-~ O ~O f~ oo N ~D
O~ M d' O
~ t' N O N ~ ~t N M ~ ~ oo r' ~ M o_o t_~ N v~ N t~
N
V7 l~ N ~D O M '~ ~ ~O O~ ~ l~ .-r ~ M
~oo~~ov~~,°~xxHxx,°~x~°,~ ~°,~xxaa
~ t~1 ~ M M ~
O 00 ~ ~O O~ l~ M ~j ,~ ,~ ~1 ~ .-r ~ ~ ~ M ~.' ~--s ~ ~--i ~--i ~ CV ~ \O N
00 ~D V~ ~ d;
0o v0 00 0o M N N ,~ .. . O~ O~ l~ v7 O~ .-~ o0 M O d'
--a N O N N N
O V ~ ~ N ~ oho ~ M N N ~ ~ ~n vp ~ ~ ~ ~ O oo t~ N V vp vp
t~ ~ ~ N oo O Owp ~ .-. N N N O N N N O
O M N N N N y0
O O O O O O O O O p N O O O
v0 O N t~ N l~ x ~ ~ x ~ x x x ,.,.~ x v~
~ M M ~ M N N ,~ ~~ .-i .-i .-i ,~ ~ ,~ M yj ,~ ,~ ,~ ,~ ~ N '~ 00 .N ,~ O~ ~O
~
ao M N t~ t~ tn ,~ ~ oo ~p O v0 I~ 00 'p Ov ,--~ ~ ~ ~D V Ov N O N cn N M t:'j
l~ l~ O N M
N N ~ N ~ N ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ N ~ ,~j t~ ~ ~ ~ ~ N N N ~ ~ N N
O O O p O O O O O O O N O ~ O O O
M 00 O~ O d'
N l~ N
M N N N M N
O
N
N
O ~ ~D M d' ~O
N
~O N v~ Vyp
z~ ~ v
~a
xx x x xx
00 ~ o
0 o r.
N N N N
169
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
W o
O~ ~ ~t 00 et ~ ~O M
~ M M 0 ' ~
M M M N M N N ~ ~ M N N N ~ ~ p d. ~
N ~ ~ ~ O ~r M N N N ~ --~
~--n
_
I~ ~ I~ V1 O d' '~ '~ M M 00 ~ M d' V'7 O~ M
C~7 O~ M ~D M ~ V~ M 00 ~ O v0
N t~ oo ~ ~ M v1 ~ O ~ 00 ~O
~ OW ~ O f~ oo ~ '~i "G ~ N N N ~ N
U N .~ N N N O N N N ~ ~ N
N N N N N ~--i ~ ~
N N N N M
c~i ~
~ M M cn ri N N ~ '-' ~ oo vi ~ I~ ~. cn N N N .~-a
N N -~ r-i N 'O ~; p ~ -~ .-i .-i .-~r
M N N N -~ ~ ~~ . ..
v0 V1 ~ W o0 N l~ N O~ oo v1 t~ v0 ~ N O M in
N O O M ~ 00 v0 ~' ~n r'~', ,-, t~ v~ Ov
O
00 O ~ M -- N N N ~ ~ ~ ~ ~p ,~ ~ t~ O oo M M
Ov ~ ~ M ~ ~D ,.'C ~D N ~n ,~
N M N ~ N N N N ~ N ~ N N N N "" "'~ N '~ N N
N N N N . N O N N
-i ~
~ ~
V
d: ri cn ri N N 1 ~t M N N N ~
M N N N --~ ~ .~ N vp OW 'i N oo ~ .-i .-i N
0 0o M Ov M Vi I~ N o~0 '~ a I~ in N t~ f~ ~'
v N oo v1 ~ M N N N ~ ~ O N ,~
N ~ O ~ ~
O
1 vW ~O ~n M ~ N tW D ~ ~ ~n _ _
O 00 l~ ~ ~"' N "~ _
N oo ~.-~ M oo p~ M t~ V oo M ~ ~ N N N M
O N O~ ~~ N N oo N . M N
O ,~ N N
N ~ N M ~
N ~~ ~
N
N N
cC M ~ ~ .. ~
m n N a M N N N ~ ~
n N ~ ~
N
c c ~ ~ ~
M N N O
r,
0o O t~ ~; v0 ~D N ~O ~ W N Ov v0 Ov ~ M f~ ~
l~ ~t .~ N O ~t N .~ ~ ,~ ~ ~n oo N
..
N N ~ N ~ ~ O N N
N O i
~ O
~ v
~ N
n N
M M Ov I
D
O O ~ O N N ~ N op"
O
~ cn ri c!i N ~ ~ ~ N a O ~ M N N N ~
M N N .-i N ~ ~ ~
i W D O ~ N N ,-, ~ vi M
~ O ~t r v1 ~ s0 j r-a ~ N ~n o0
~ dw
_ _ _ N N N O N N ~'
t O ~ N r N ~ ~'
N OM -r~ N N '!? ~ M M N N ~ ~'
M ~ N O N O '-'
O .~ M V~ v7 M ~ M O
V1 v0 ~ ~O ~ ~ l~
v0 M '.r vp .~ O O
,~ oo ~ M ~
~ M
N
~ M M M M N N O O M N M N N N ~ M N N N N
N N ~ ~ ~ ~ ~ -
~ ~ ~ N
~
~ 00 v N I~ v'7 N ~ N OWO o0 Ov o0
' ~ OW' t~
Ov M o Ov
O
_ _ ~ ~' ~ N ~ M Ov N OM ~ -~, N
_ ~ ~ N ~ N ~ N ~ r-, N N
N N N m ~ M M N N ~~ ~'
7
N N N N
~ N N
~ O N ~ ~ ~ T
ci
N O oo O O~ N oo
~D op"
~
~t ~t ri c!o N N N N O ~ M N N oo ~ ~rj N N N O
M N N ~ N N -~ N N ~ ~
v0 N t~ M O~ ~ ~ ~ V7 N oho
M N M Ov ~ ~ N O~ a ~ 0~0 N Ov
d' o0 ~
l~ 00
M N N N N ~ ~ ~ N ~ ~ ~ N N N -~
~ N N N ~ ~ ~ N N
~
W ~ ~
r,,
~ ~ ~ ~,
~ ~
v1 W O d v0 Ov ~ s0
"' ~n
O
O O
~ ~t ri M N N _ ~ M N N N N
M N N ~ N ~ et ~ .-
N ~!? '~
~ ~ N N N ~
N
VW O tn N M Cs M ~ M .-y0 O
o0 M O M Ov o ~_O ~ M
O N O ~ N ~ N O
[~ O~ O~ O~ M M ~ N v0 .-i N
00 M O N DO ~ ~ ~ ~ ~ N
~O N
~~ N N ~ ~ N N M
O N N N O O OWn o0 W O ~ O ~ O
~ a ~ M
W V' M M N N N ~ N
M M N N ~t M N Ov O ~ ri ri N N cn
~ N ~ ~ ~ ~ ~ ~ M ~ ~ ~ O N ~ ~ M
N ~~ a
.. . . .. ~
~O ~n t~ ~ M ~ N N M N N O N N N N N M v0 O ~D
~n M oo M M ~ ~ Ov - f~
~ O t D '-'
N N N ~ _ _ ~ ~ O N ~ N
N N O N ~ ~ ~ ~ ~ ~ ~ N ~ N N
N O N
O I~ O ~ t~ d~ ,-i ~ ~ ~ N
~ ~ O ~ ~ x ,-M.
v0 W t M N N N ~
~ d~ cn ~ M N " N ~ ~ ~n M M N N
M M N ~ N ~ ~ O t~ N Qv -~ f~ O N - O~
N .. ,_, .. .. .. N
Ov .
M N N ~ C~ ~ I~ O ~ O M 00 .~ (~ f~ O~ M ~ M M
N ~~ M ~~ V7 l~ (~ V7 t~ ~ ~O M ~D
Ov .w0 ~_ O N M N N N N N N ~7 O M ~ O_ OWO
00 .~ ~n O v7 M ~ Ov O
v0 Ov
O
. v0 00 O ~ 00 ~ W ~
O ~ M
~ ~t M M ~t M N ~O ~h ~ M N N N ~ v0 M M N N M
M N N N ~ ~ ~ M ~ ~; N ~ ~ ~,
~n N oo ~n Ov v0 ~ M Cv ~ OwD Ov ~n N ~n l~ M
O V1 ~ Ov v0 ~ W M o0 00 t~ ~' N
O N oo N p~
~n ,~ M N v0 00 oo ~ t~ N Qv o0 -~ ~ t~ O two ~
I~ Ov O Iw0 ~ 00 ~ -~ Ov N ~ t~ O ~O
~ N ~ N ~ N N N O M N N N N N N N N N M
O M N ~ -~ N ~ ~ N ~ M
~ ~ N N
O O
N M
N N
N N
,w p oo O
t~ ~0 O
., N o
.- 0
N M ~O ~O
Oy o0
00 ~ v~ 00
,~ D pv
N
x
x x
x x
N M
N N N N
17~
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ r: --~ ,~
c'rj CV ~' .. O .-; '_'.' ,-i r; N M N
00 t~ ~O V) ~ ~ M ~ p V1 ~ ~ ~ ~O 0 ~D 'm-'' ~, Ov pW v0 ~D ~ V ~ M ~t O
v1 l~ O t~ ,-, W ~_ y0 ~ ~ M p O p ~ ~ p ~ N ~ ~' M r' ~ ~D s0 ~ M ~-V x O O
NNNNOONNMMO~ ~xx~lO~O NN~~N~NNN~NN
M ~ N ~ ~ M M a ~ ~ ~ ~ ~ x ~ ~ ~O
00 I~ ~D v0 ~ ~ M vp ~ ~ O O ~ ~ ~ ~ N N M "'' O O W O
-, M ~ y~ O ~ yp ,~ ,~ ~ Oy~ ~O vp v1 <t ~ M ~ x p N
00 N M O --m0 cn o0 0 O f~ p O p p ~ O M ,~ r., ,~ N N ~7 ~O f~ Ov O v'7 ~ O O
r.~ a O O ~ l~ d' V1 N O~ ~D V~ O trj Cn x
N ~ pN N N N N ~ a x ,~ ~ x ~ ~ ~ a ~ N N N M N N N N N N O
00 N ~ ~ ~j ~ Ov
0o ty0 ',p vi V m ~ ~ ~ ~ ~ O p p ~ ~ ~ ri N O ~ l~ I~ s0 vi et ~ M N x
~~ Oi p .--~ 00 0o M v'i N N O p ~ ~ p ,"~' ~l p p O ~' ,~ ~~ ~n ~O oo n ~ O
Qv ~ 00 p p
~O ~O ~O O_O ~O O M ~ ,,.a ra a C/~ x " " a x ~...~ ~ p M O ~ 'n O~ M M oo O N
~O x x
,.a ~. N N v1 ~D pc~'p ~ 'p p ~ ~ ~ N N N '--' N N ~ N N ~ ~,,~ N
v7 ~D ~ ~
0o r ly0 v1 ~t M ~ t~ p ~ N ~ ~ O p ~ p p p
.~ O_ ~ M U1 Ov V1 N ~ Ov a x O "~,~ y-l r~ O x a ~h N O M M_ ~? ~ M N ~ l' M
gyp'
~ O O N N ~ N mV a " "~' ~ a ~ ~ ~ ~ ~ ~ M N N N N N N O
N ~ ~ ,~ N ~O ~ N ~ ~ ~ ~~ ,~ N l~ d' M ~.j
~" ~.~ Oyj Ov Ov N N ~ ~ ~ opo N
. oo t~ y0 v1 V M ~ N ~ O ~ p p p M ~ ~ '~ O
O p VJ ~l O O O ~ ~ ~ oo f~ s0 ~ ~ ~ V N x O p
N v0 M o0 00 M d' O UJ ,~., ~ ~ x " ~ ,~ x a O~ O \O N IW O ~!1 ~ N t~ x ,~
~ N M oo O~ ~ '--~ t~ ~ " r.. .~ " ~ N O p ~ ,-. ~ O t~ twO o0
"' N N O N ~~ N N --i M ~j ~-i r; ~; .-r ~, ~~ ~' M N M N N ~ ~ O ~ ~ ~ N
m0 pp NripOO~~~ NNN~~~ ~~~O~r
0o t~ t~ ~D vi ~ ri N p O O p O l~ x p O O Ov o0 t~ ~D ni vi ~ ~ N a O O
~~d~~;~~;MM~~~H~~x~ ~a~a ~a~d~;M~~~~o~,~~ax
t~ 00 M ~~ ~~ 00 ~D ~ rj .~ ~ ~~ " ~ ~ M Ov ~ ~ 00 ..r o0 00 O Q1
~ ~~ N N N N O N N N '~ ~ ~: ':'~ '~ V1 N O N N N N ~~ N ~~ O N M N
M v0 ~. N v0 ~ Ov M ~ N ~ ~n ~n ~n O
00 ~ so vi ~ ni N ,°~ x a p ~ x x a x x ~ ~ ~,~" o~ oo yo ~i ~i ~ ~ r;
~ a o
O N ~ r N lmn N ,~ .~ .~ M oo M v0 N ~ ~ ~ O w
O -~ WO ~ N ~ N M cn N -r ~ .~ '-, ~-, M ~ M Q~ l~ ~ QWO O
N M N N N N ~ N ,-; ~ ~ ~ ~ ~ N ~ ~ M ~_ N O N N O N -~ ~ ~ ~ O O
~ O ~ ~ ~ ~ ~ ~ p p O O ~ ~ ~ . N Cv
~O o0 op" oo fy0 v1 ~t ri N x a ,.,pa x v°~ x x ,°~ v~ ~l ~ N N
o' oo ~ ~ y ~n v ~; M ~
~' N v0 ao s0 v~ oo I~ M cn
vW O ~ ~ O ~ ~ O~ M cn tV ~ '-' p ~ ~'~ ..i '..-~ O ~ N p~ N Qv o~0 N N ON ~
.~0. N
N N N N N N t~ ,~ ~ ijj ~ N O ~ O V1
O O O p O p p O 0 0 b ~ '.-; '~-' ~ ~ '~ p p0
~ oo ty0 y ~ M N '-a a a "'~ C~ "~'" "'~ ,~ ,~ ,~ y0 M 00 ~ 00 f~ VO v1 N ~ ~
M ~
N N ~O ~G ~~ ~O v1 N ~ Ov M M N '~ ~ ~ ~ ~ ~ ~ ~ O N N O~ ~D N oo O oo M N O ~
~ N
~ N N N ~ l~ N v0 ,~ Qv vp ~ f~ ,~ ~ l~ O vW D ~ ~ ~ N N N ~ N N ~ N
000
x~xx
os oo t~ ~ vi ~t d~ ty x ''4 .a " " ~ ~ ~ ~ a ~ ~ ~ os oo tWo vi vi ~ v cfi ~'
x ~
O '~ ~ 00 00 00 O~ ~ ~. M N '~ ~-' .. -.r .-~ .-~ --V ~, I~ ~ .~ ,n O l~ M ~t
O 01 O N ~t N
N N ~O O M N v0 O oo N M yD O O ~ ~' ~ Gv O ~ N ~ w0 ~ d' M t~ n ~ N O N
O ~ N N ~ M N N O vi ~D ~ ~ p ~ ~O O ~ ~ ~ N N N --~ ~ ~ N N
~~~~~d~~~~~°aaxxxxa°a~~~~~~~~~~~~~~~~
p~ 00 l~ ~O ~ ~ ~ M " ,-i ,-i ,.~ ,-i ,--i .--n N '~ '~ T Qy~ \O \O ~ V: ~Y M
.-a V N
V~ wj N N r~
O~ oo ~t ~ t~ N Ov O ~~ ~ "~ ~, M .--i .-, pp M ~t M ~ oo t~ ~_-~ ao M oo O
tmn O~ O_ 'p N N
N N N N ~ ~ N -~ M °~ ~ O vp °~ ~ M oo ~t ~ N ~ N M ~ N N N
~ ~ O N ~ N O
l~ M l~ ~O M ~ ~ ~ p p p O O O
O O O O O
N
N
M
M
N
x
N
171
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
_~ ~ _ O
_ ~ ~;
p N ~ I~ ~ oo ~ ~-~ .-i ~ Ow0 v~ ~t cn N -~ ~ N N
O ,.-, Ov M Ov N ~ M N ~ ~--n .-r .--n .~ ,~ ~ I~ ~ O~ ~t
O ~ O 0 ~ O ~ N N cn ~ Ow0 v0 00 0o p; M ~ ~ O ~ N ~i I~ N t~ ~
.-1 0 ° x x x ~ O O ~ N O ~ O M N ~ ~ ~' N N G~ x_ x ~ N N ~ N O ~ ~
O,N; N ~ ~ O ~ ,_, ~ a ~ ~ ~ ~l ~ N
N r, Gv O N
Ow0 vp ~ ~ ~ .~ OW ~ 'a O oo p ct M M N M
x O O x " F'' O O ~n ,-n ,~ OWn .-, ,~ pw0 ~ ~ M N x M . M W I~ -~ ~ O
x x " .~ ~ ~ ~ a N N ~ OW ~ ~D l~ O ~ ~ ~ M oo ~ ,~ ~~ ~ M o0 v0 O~ ~ ,~ x
" N N N N N N M N oo N N ,~ ~, O ~ N N O
N Ov ~ ~ ~ ~_ ~ N ~ ~ ~ M M
N V 'n
O O O O O ~ O M v-i OW O v0 ~t ri N N ~ ~ ~.j O N ~l M yt cn cn N ~~ ~O
O C~ x a ~ O O M N ,~ ~ .-~ ..r ~ ,~ .~ O~ M ~ ~., N .b O~ O~ M O~
" " .--~ " x ~l ~ l~ O Owt N O O N M Ov M M N " a ~ ~ OWO M f~ ~~ ''~ x
.~ .-r ~' ,~ ~ ~ .-n .~ o_o v_0 v_0 OWO v0 O M O N .~ " c~ N N N .WO
r., ~ N
O N ~ ,~ v~ O~ N ..
M rr .~ O M ~ Ov M V7 ~ ~ ~ ~.,~ ~ ~ ~ x
O O ''°~'' ~ 0 ~ ~ Oy~ M O ~ ~ ~ ~ M M N ~~ p O
x O (/~ ''~,[,~'' " x Cn O ~ m f~ O Iw0 ~t M N N O ~ ~p p x a O M O v0 O N x x
,~ ~ " ,.~ " " a M N N ,~ ~ ,--, ,~ ~ .-~ ,-~ O l~ I~ ~ Vj 00 ~ ~O l~ .~
~ ~-r ~! "'" " .~ N O N_ N_ M ~ ~i o0 Ov N ~' ~' '-' ~ " N N N N M ~ M
vp v0 ~ ~ ~~ ~ 00 M N ~ N M ~ N ~ N N N ~ ~ ~ ~°O N ~ ~ v ~
O~nOOxOOMO.-, ...
,~, O ,~, x O ,.~, ~ O ~ ' Oy~ ~ ~ N ~ ~ ~ M M N ~-! O O
"~..4x.fl ~tc~ot~~viriNNO~M~o.-:a"~ r~o~o~~xa
~" ~ '..; O M N N ~-! --! --~ ~ ~ ~ ~ N N N ~ ~' ,~ ~ ~ N N O N ~? ~.'?
O I~ v1 ~ ~ O M y0 O ~' V o0 .-~ .-~ p ,~ nj ~D O ~ ~ o0
~ ~O oo ~p N O 'n ~ M ~ t~ t
M O ~ x N N N ~ ~ ~ M N ~ N M v'7 ~ l~
~'axxx~'x°ax ~ ~~~~~~~~~~~~~'~"a,-°a °~~~o~xa
ci ~; ~ r, " ~ _" ~ ~
00 00 00 v0 W ~ N_ N_ O_ N N N ~p ~- ~' ~ N N N ~ N ~n M
M vp ~ N m ao O .-WV cn M N N ,~ .~ ~! ~ cn O t~ ~ ~ ~ O v~ ~~" ~ ~ N
O O N N O ,~ ~ oo M d' Ov Ov M ~n M ~~
O 00 O O O O O M M ~ O~ ~O ~ 00 ~ ~ l~ ~ O l~ O M l~ O
v~O ~xx OOO ~N~M -~ MN~oo,~;x o ~o,r;~~.,;N~;O
~d~~da~~~~~~M~~~~~ p~~~~M~x
N ~ t~ oo NO can N N °w0 v1 ~ N N O
x ° rn x x ° ° ° .--~ ~r o, r r M oo vo O ~n x ~l
° ~ °
x O O O x ~-1 x Ul N N .--i ,.., ,-r N ,~ O N Oy oo ~D O ,~ O V1 ~ M N N ,~ ~i
N ~ ~ ~ ~ ,-i ,-i .-i ~ ~ O N ~ ~ N '~ ~ O ~ ~ ~ N
N ~ N ,.:., ~ i:'j N N N oo N M N oo O~
~,°~ O O O ~,°~ O ~ O O O ~ N N ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ O ~ 0
axx x ~lvJ~l ~nM~D~Nt~ri00V1 x O
O N ~t Ov Ov O~ oo v~ l~ v1 ~ 00 v0 ~ " a ~ ~i ~ ri N N
N ,-i ~~ ,-i ,~ ~; .~ ,~ N N N O ~~ ,~ ,~ N ~ M t~ ~' ~ ,-, N t~ OWO o0 00 0o
M
00 N M ~D M Ov ,-, ~ v0 00 Ov N ~p T ~ ~ v7 M ~D ,_,~ W
~ M ~ ~ ~ ~ ~ M N N ~ ~ ~ ~ N N N N N ~.,~ M
O
r~~iOxxO'O~'C!1 ~~NW__O~_~_c_nN_~_~~~,0~,00 O_~~~~~00
N r.; x ,_; ,-i a ~ .-i ~_ 00 t~ Ov O_w~ N o0 t~ cn ~ oo ~O ~ x~ a ~ Ui ~ cri
N N a x
ao Ov ~ oo t~ N ~'vj ~n N ~ N O N ~ N N N N ~ ~O oho ~ '~ .--~ N ~ ~ ~_ ~ oho
0o Ov
O O O
~O~p~ ~ ~~O'',h'~ ~ ~Q~QOO
x,°~~°-lxxv°~E-~,~v~x NOcnoOVO~n~MN~
N N N ~ .-.i ~-..i ,--i .-.i ..-s .~ ~ M N .~ .~ ,~ .~ .~ .~ .~ ~ 00 ~O ,--i
.~ ,-; '~ I!1 V M N N
v0 ~~ W 00 ~ v0 O W 00 O M O v0 O_O ~_ ~ M_ Ov
N ~ ~ ~ M O ~ ~ p p N ~' ~' ~ ~' ~ N N ~ ~ N N N ~ ~ ~ N M N M O N
O O O O O O O p O O. O O O O O
l~ N t~ N
M N M N
M ~ 00 V1
M
0 0~0
O,
Q
x x ~r
I~ 00
rr
N N
172
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
--'
N ..r ,--~ ,-i ~ -i N
Ov N N v0 N vp ~ N ~ ~ ~ v_'i c_n O
N ~ ~ O ~ ~ M ~ N V7 Ov o0 N ~ 00 fy0 v0 v~ v7 M ~ n N N ~
O O O O '~,'~ O ~ O V~ "V '-" ~ ~O O ~h ~ O~ v7 M O~ ~ 00 .~ ~ O O O~ V1 ~ 00
(~
a ~ x x ~ a O ~7 O ~ ~ ~' '-' M N O N N ~ N N ~ N ~ x "~ N N N ~ N
N ,-i .-i rr ~ ,-i a ~ ~ ~ ~ N ~
~ M WO ~~ ~ 00 ~ O ~ M .~ ~'~ ~ ~ ~ ~
N M O IWO v0 00 N ""' ,~', ,~ ,~ .~ Ov o0 t~ s0 s0 V7 V'i <f O t~ N N ~~ ,~ .-
r
O O p O x O ~O O V7 V~ 00 ~ 00 W N ~ lw0 ~ M ~ v~ N ~D O O ~ vW0 vD N
"a~j xx ~a°xp ~~~ .oNC~....o.o,c~a.O~nMNxa ~ooQ..ovo
~ a ~ a N ~ ,~ N ,~ p~ ~ O ~ ~"~ N N N N ~ _~ N N N
N N ~-' ~ ~ O M N
N ~ M o0
~ N ~ O ~ ~ ~ M N ~ x v~ M ,~ ~ 00 t~ y0 v1 ~n ~ 0 p N N ~-~
t0 O '~' a O O p M ~: ~ ~ ,-, ,-, .-. 01 O OWD O o0 <t N M x x .~ 01 M ~ N
x '~ ~ a x ~ O_~ N ~" O v0 M oo O M M Ov o_o O~ v~ y0 O ~ t~ f~
N M ~ . ~ ~ y0 O~ d
v1 ,-..~ N .--~ ,-~ -
O ~ p N O 0 ~ ~ M ~j ~; x "'~ Ov o0 Iy0 ~D V7 y ~ O O M N N ~ ,-i
xox~xao ~ ~~:~ G ~~'-'OIwOMONOWMax t~c~ivOt~~
x ~ ~ ~ a x ~ l~ ~O ~ ~-~ .-~ ,~ ,~ ~ O~ ~ I~ ~D I~ I~ M ~ ~D ~ M ~ M
.-, r; '-' ~ ~ ~ ~ N v0 ~ ,-i ,jj nj nj ~-~ N O N N ~ N N ~'1 .-, N N N N N
~O M ~ ~ lp 00 M I~ ~ ~ M N ~ M
~ ~ O I~ l~ Ov V'7 O M '~ M ~O ~ ~ ~ ON
~ 0 0 o Fp,, a p 0 ~ N ~ x ~ ~ ~ ~ ~ ~ oo t~ vo ~o v-i vi ~ a o ri ri N .-.r
~.;
axx ~ ~axa M~~x ~ ~~oN~~~~ x
~ ~ vD V'7 ~ vD M ~., O ~ V o0 IWO M .~ N ~j ~ M N Ov o0 ~D
~ r, N N O ,~ ~' ~' ~'! ""' N N ~ N N N N N ~' N N N N N
N O~ ~ O N ~_ N
O f~ O N O p c~ f~ r
x O V7 C/~ "~' Cn O N O N ~ O ~ oo t~ t~ ~O ~n v»t ,~ O M N N
a ~ ~ a a a N p~ N a N V N M O~ 00 ~ I~ a v7 ~ f~ N ~O
~ ~ ~ O ~ ~ oo O -~ O oo .-, v7 N N .-i N oo f
N ~,~ O .~ t_~ ~_ N O_ N ,~ N .~ N N N N N -., ,~ M O~
,~ N ~ y0 M W O ~ ~ ~ O o~0 N ~ ~ t~ ~O O
O ~ O M O O ~O N I~ ~ (/~ t~ N ~D ~D O~ O p ~ ~
x a x UJ O N O ~.,j ,.~ O N ~' ~' N O~ 00 l~ l~ s0 ~ ~ <t a ,~ M N N
a a ~ ~ ,~N,, ~ ~ .-r M Ov oo M O Ov N ~ ~a o0 ,~ ~p M
N .-i . ,~ ,~ ,~ ~ ~D ,--, O o0 0o Own two N OWD t~ ~t M
~O .. ~~ ~~ NNI~ .~ N,-~N~N,~ NO N.--~,~NN
v7 O V Ov ~ ~ ~ ~ ~ a ~ ~ ~ ~ ~ M
N oo ~ M O O two t~ ~ ~ ~ O ~
O O M O O x O p O ~ ~ O ~ V'7 V~ 00 ~ O
xaaxx ~aaa M~'Na N~~~OvoOt~l~~~Vl~ a MNN.-i,-i
N .-i ,~ ,-, ~ ~ ~ p ~O O\ ~ O \O ~ Os N ,-i O Ov Ov Ov a0
p '-' '-' ,-, ~W p ,~ O O O ~O W v0 w o0 ~O M t~ ~D
O~~NO~~m NNpOO MMNN~NNOM~ ~NN~N
~n oo ~n o ~' p t~ ~~ o . ~ ~ x °° °~ ~ ~ ° ~ ~ ~
~ ~ ~ ~ ~ ~°,~ o~
pop~~xooor, o .. a
x a x ~ a a ~ ~ M N ri a N ~ ~ ~ a' oo ~ ~ vo ~i ~i Vi i.,; ~ ri N N ,~ ,-
N N N ~' ~' ~ .-: ,~ mn ~ O O .~ N N N ~-~ O ~D t~ ~O O W O O ,!j '-' ~ ~n M
t~ N
Ow0 N °~ ~ ~ ~ oo O p N ~ N et ~~'1 ~ O N N ~ N O N ~ ~ ~ N ~ N N
p~ O O
~n o0 ~ N M ~ ~ ~ ~ ~ x O Ov ~ N O
00opp°o00-o t'
~xx a
xa xaaa~ a ~~~~ ~_
~ ~ ~ N ~ ~ ~:,~ ~ ,~ N Oy o0 I~ I~ s0 v0 v1 ~n ~t ~ M N N
N ri .~ ,--n ,-.~ ,-, .~ ~ ~ ~ ~ ~p v0 N Ov l~ M M O~ ~ l~ t~ M ~' Ov t~ O O ~-
~
l~ O_O O1 ~ M ~p V'7 M ~_D O_O ~ 00 N ~ N ~ l~ ~n ~ ~O M W ~O M Vl ~ ~p V1 M
O~ ~D
M o0 ~ d' O W O ~O ~n ~O
°ax~°xaax°a a ~~MO ~~
N N N ~,~ ~-~ ~~ .~ .-~ ~--i .~ ~ N '-' ~-r ~~ '~ '~ p~ 00 l~ t~ ~O \O V1 ~n N
,--i ,_; V1 N N
O N ~_n ~_ ~t -~ v~ O ~_O M Cv t~ vi N v~ O ~.j ' w0 O f~ O O
000 ~ O ~ ~ ~-~ N ~ N N "~ N ~ M ~ N N ~ 00 t~ v1 t~ t~ ~ U ~n
N N N N N
O O O O O O p O ~ O O O O
41 (~ 00 O
N (~ I~ M M
N M M N N
O v~
O~ .~ N M ~O
N ~ "~ ~ M
00 00 M
N
W W W ~ U
av o
N N
N N N
173
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
c~i
c''i N N -i .-r .-s .~0. "~ " "'~ ~w
O M M M 00 00 ,~ ~ ~O O " O I~ V7 O
O ~ ~ ~_ Np N ~ x O ~D O ~ '~ 00 ty0 y ~t V '~ cn M M N N p ~ a'no x N
t~ O N p O O O p p (~ O ~ M ~ N ~n 00 v1 M O~ M V1 O M x O
~;xxxx~ax~~'axx ,...,oO~DV~OvNO~N~n~oooN,.a ~~~°
~ ~ ~ O N N N N N O N N N
V7 M ~j .--n .. . ap Vj N ~ ~ ~ ~ Ov
_ V7 M M O M C~ O
0o O ~ O O p p p ~ ~ p ~ oo Iy0 ~n ~n V ~ M M M N N ~ ~ ~ ~ ti7 N
O p x O ,~ ~., VJ p Vj ~ N ~ ~ M N oo ~' cn Ov O M p M 'b O
"~x..~ axx . ~ ~axa ~.~0~~,~,.~M~.~,M~~,Na
" .~ ,-, .--~ ~ ~ ~ ...~ N N N ~ ~ N N N N O N N
N ,-; "~ .. .. .. O
O M M .. N .. .. [~ M f~ .~ l~ M Vj O
~ O~ ~ N ~ ~n omo ~ O ~ x M
O N ~ O
p O O O O x ~., ~-~, ~ O O WD N N ~ m f~ t~ ~ ~ 00 00 .-
.ox~xxxx ~ _ ~axx o~~oooooM~nooNvo~n~NN~..7 N~~~
_ _~ ~~ ~~ ~-; " r, ~, op N .--~ .~ N O N N N O N ~ N O .~ ~ ~ N
M .. N "~ .. lp Op .-~ .~ .. .. ,~ M
~ ~ 00 v0 ~' Ov N v0 N ~''~ M O
M oo ~ O p
M ~ 00 O v0 .~ ~~ In pp
M ~ O O O ~ ~ M op ~ ~ tn y~ ~t eh ~ M M N N ~ O ~ ..; ~ N
vD ,~ ,~ x ~l x °x x x x O x ~ O lW O I~ v0 ~ N Ov oo Ov O~ ~ ao N ""~
O M ~ c%i
~ r, .-i ,-i ~"~ " ~ "~ l~ ~O ~O M O t~ 00 01 01 ~ t~ .~ ~ ,~ V~ ~ v0
O ~ M N N '.; ..a ~ ,~ yp ..~ ,~ N N ,~ N O N ~ N ~ N ~ N ~' N
~;x~~
O N ~ '~ ~ ~ ~n O ~
v0 Ul ~l x x x x x ~ x ,~ x x ~ O d' ~ ~ O N ch o0 ~ N tn ~t N a N ~ a N
" .-.~ .-, ,--~ ~ " O ~ 00 O ~ OW ~ N o0 v0 Ov O ~ ~ ~~ 00
M N nj ,-i ~ r; ~~ ~~ ~'' N ~~ N N N ~~ N N N N N N M ~ ~ N
M O ~_1 ~ N_ 00 .~ oo O vp O~ O~
M " 00 ~ O .. " ~ ~ ~ x O 'p x l0
~ ~' M N N O O O ~ ~ ~ N O
O O O O O O x x x O O O Oy v0 v0 V1 ~ V V M M N N ~j ~ ~ M x M
vD ~ ",$,' F-~ V~ V1 V1 ~ " " ,~ x a o0 00 M M vW D O OW ~ ~ N N ~; N M ., 00
N N .-i .-i ~' ,~ ~ ~ ~ ~ I~ O~ IW O v1 ~ O M Cv N ~ N ~ ~-, ..y0
M M .. .. ~ op ~ ~--~ ~' .~ .~ .~ N O N M N N N ~ M M .-.
O ~ p~ Ov ~ ~D '~r o0
O ~ .~ O N
x M v~ M ~ ~' ~' O O O ~ '~ ~ 00 ~ ~ ~ x O ~D
t~ ~ ~l x ,~, CO/~ x E"' x H a a ~"O"~ '~ OW v0 ~D V7 ~ ~ d: M M N N 'ch x ~ M
a M
~ ,~ ,~ .~ ~ ~ ~ ~ ~ U v~ O~ v1 N O N Ov ~ Ov V ,--~ N ~O " 00
Ov ~ cv~j N N '-' ~ . . . ,_, ,~ ~ ~ ~O o0 l~ t~ 00 v1 v1 ~ ~ . M v0 Ov Ov '~
v~
N v~ M ~ ~ " ~ N ~~ N N ~ N N N M N N ~ t~ ~ O r. N
t~ O O~ M o0 ~ O o0 t~ ~D t~ ~ ~ .WO
O ~ O ~ .-Wn ~ O N O v0 ~ N _ ~ ~ ~ ''.'] O v0
~D .~ O , v0
00 'n ~p-1 x ~°l x ~ H x ''px ~-p-1 ,°'x ~ ci N os t~ so vO vi ~
~ ~ r; c~; r; chi ,~ x M d." ~p-) ri
" ~ .-i .~ ~ ~ r, v~ ~ I~ l~ 00 ~ O ~n ~W O ~ O N O ~' O ~O ~ N
M N N ~ ,-.~ ~ .. ,~ .~ i,w0 ~ Qv oo OW ~ OwD oo ,-, v0 M .~ .~ 00
t~ ~ ~ N d' O ~p p~ ~ ~ ~ pv ~ O N N ~ ~ N ~ ~ N N N N N M ~ ~ M ~ N
O O O N I~ M t~ V7 .-r .~ ~ ~ O x .~ O t~ ~ O
0o vp ~
~~:~~~~~~~MMMN~x
M N N ."~ .~ ~ '.', ~' .-i .-i '~ ..~ ~ O in V1 V7 I~ ~D ..r f~ t~ ,y0 VO l_~
~_: O N
M N O ~ t~ ~ n ,~ N M N O ~ N ~ N ~ N ~ N N pN M N O N ~ ~ N ~ N
p N l\ N ~ N M O O p ~ ~ O ~ _ ~ p ,~ N_
Ox~lC~~l~',r,xx~l~°x° N ~x x
-; Ov 00 l~ ~D V7 d: d: ~ M M M N ~~ ~ ~ ~ V ~ M
M N N .~ ~~ ,--~ . ~-~ W O dw0 Ov ~n ~ 00 vD ~ O N ~ ~O ~ ~ M M
M I~ ~t ~ ,-, ~p ~~ nj ~, l~ I~ ~ O M 0 0 0~ .-.mO oo M ,~ ~ ~o "~
vD W O .~ ~ °~ N N O O O o0
~ O y0 N N ~' -~ N N M N N M N M O N N N N M N
xap~Oxoxxx°°x° ~~~~~~~~d~~~~~x~~~x~d
x x ~ as x N _~
~,,~ (vj N .~ ,~ .-i .-.i .-i .-; ,~ ,~ ~ ~'~ ~ 00 I~ ~O ~ V ~ V M M M N ~ .-,
~ .-a ~ .~ M
~ ~O N N 00 ~ ~ ~"~ ~''~ ~ ~ O M ~_ 00 I~ M_ Ov M_ ~: O ~ p N
~ can M N ~ ~' N ~ O ~ ~ ~ ~~ N ~ pN N N N N N N M N N ~
O pp O Op O p O O O M p O Np O Q O
O~ O N M
(~ 00 M M M
M M N N N
00 M O ~p v~
U U
l~ O~ M
(~ ~ ~O M
I~ ~O O ~ 00
00 ~O N ~ M
w ~n N
U U ~
N M ~t
N N N
N N N
174
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
r; " " "
W!1 ~ C~i M N N N N ~ ~-~ ~ N N ~ oo v0 d' ~ ~ ~ .-~'y ~ p ~ ~ M M M N
N M O ~ ~O N Ov ~ ~ N
vW ~ O ~O ~ O ~O ~ o~DO ~ ~ O vp N ~' v0 v0 Ov Ov O~ ao Ov oo N ~ O ~ --~ N
c~i Qv
~D ~D 00 O~ M
N ~ N N N N N N N N a ""' N M ~~ O N N ~ N ~ ~ M ,~ N ~~ N N
~a ~~~~~~a~a~~~~ ~~~~~~~~~a~~~~°o~~_ ~~~~a
r-i vi ~ c~i cn N N N N ~ ~ ~ N N ~ 00 vD ~ ~ N ~ ~ O ~ C.j ~' ~ ri cri c~i N
N Ov M ~ t~ O ~ N ~~ M ~ p " N ~ O Ov ~ N ~_O M
N oo .--~ M ~ I~ ~D t~ M O O N ~_ 'n '~ O M_ O N Ov .-~ cn
N M N N -~ ~ N N N N '~' N M ~ N N M N N N N ~ ~ ~ x N N ~ N N
"
.-m1 vi d: cri tri N N N N ~-i ~ ~ t~ N p~ op" gyp" ~n c~i N N ~ p ~ ~''~ N ~
M M M M
Ov o0 O ~ WO M O O N O N N ~~ ~~ ~~ ,~ .--i .~ .~ ,~ .r ,~ pp O M l~ ~ t~ N
~ ~D O ~O O~ M N O~ ~O M ~ 00 ,~ N M I~ ~-~ ~ M ~ O V7 V1 x ~O ~~ Ov 00 Ov
N a N N M N ~-~ N O ~ N N _" O l~ 00 M t~ 00 Ov oo I~ ~ O ~ ~ ~; ~' N N N
M .~ N O ~ ~ N ~ N N ~
N vp ~ M cn c!7 N N N "
00 ~ 00 ,~ v~ s0 v0 t~ ~ (w0 ~ O I~ N Ov o0 v0 v1 ri N N ~ O N N C/~ "-' M v0
l~ --~ cri
t~ M N o0 00 v0 ~~ ~ ~ ~ N N a N N .~ .~ ,~ .~ .~ ~ .~ ,.-~ ,~ ~ " M V7 M Ov
O~ M
,~ O N ~~ ~ ~ N N M N N ,~ M M O1 00 O~ O O ~7 0o N ~ ~ N ~' '~ O N N -~ N
~ .~ .~ .~ ~ O ~ ~t Two O
N N N N N N N N N N ~ O
N .--m'i ~ ~ M M N N N ,~ ,~ p ~ ~ ~ p v0 O .b ~ cn cn cn cn
M --~ M f~ 00 OWE ~ V v1 O N ~ ~ N ~-~ x ~ v1 N v1 O ao
00 00 00 0o v0 ~D tw0 ~-W ~ M N - O~ c~i Ov oo vD v1 cn N N ~ O ~ n " ~ ~p oo
v1 ~ M
N N ~ N N N N N N ~' N N '-' '-' '-' '-' '-: '~ '-' '.': '-' N ~' ~ -~ N N N N
MO N~p~NON~~ON~
v0 t~ O v0 ~-i ~--i ,--s N OW t v~ ~D 'T' ~ ,--i ~ ~r C~j I~ ,-i Ov O
t~ (W O IWO t~ \O o0 l~ h o0 V1 " ~ ~ O ,--, ~ O\ V~ 00 l~ 00
,~ N O ~, .~ ,~ O ~ ~ r, N N "' Ov M O o0 l~ ~n ~ N N ~-, O N ~ ,~ N .-.~
N N N ,~ ,-..n ,~ .~ .H ~ .-r .-r ~ M
N ~ M O WO OWO M f~ I~ Ov ~ ~p Ov
M NV1I_~~_O~_O~OOOM~~O_~ MV1
N ~ ~i ~ ~ M cn N N N N ~-! x ~ M ,.a a ~ ~ cn ri
n ~ <t v0 N l~ O ~ ~i M ~ ~ ,~ N V7 ~
v7 O O ~ ~O V7 ~t M Qv V1 ~ M .~ ~ .-i ~O N l~ DO O~
N N ~ M .~ N N N N N N N ~ p M O ~ ~ ~ ~ M N ~ O ~ N ~ pv '~ N N N
cn N N rr .~ .~ .~ ,~ rr r, ~ ~ M ~
Ov N Ov wD O N l~ v1 v~ N
N ~ ~D ~ ~ M M N N N N ~ M - O ~' oo v0 M O t~ Ov I_~ ~n ~_ ~ ~ ',.C, O ~ ~ cn
M M
~0~0 ~~N~MO~OM~NO~oNyO vO~IW D
N O N ~ N ~ O N N ~ N ~ p~ O N ~ p~ ~ ~ -~ O M
O OWE ~ ~ M N ~ O ~ l~ O
M N N ~ ~ ~ ~ ~ ~ ~ ~ Os O
N -.i vD ~t ~ cri c~i N N N N ~-r a yt f~ IW O v0 v0 ~ ~ l~ t~ O oo ~ a a vj ~
cn M cn
.-n [v ~ ~ O~ ~O 00 M 00 ~O 00 M
t~ ~D Ov Ov N t~ oo Vi Vi c0 0o O N ~ N N O N ~ N ~ M .-~ N ~O O in v1
.~ ~D o0 M 00 I~ l~ l~ Ov M o0 O " ~ .~ ~ ~O I~ V~ N
N ~ O O N ~ ~ ~ N N ~~ N ~ M ~ ~ ~ N pip N ~~ N O N
O O N V1 ~~ Ow0 v~ ~ M N ~ ~ O ~ O O
" ra ~ M N N .~ ~ ,~ ,~ ~ .~ .-n .-n ,-n ,~, ,,.a
N .~ l~ ~ ~ M M N N N N ~~ N ~ ri N ,-, ~ ~ op cn r ~ O~ op N l~ N ~ ~O ~ M M
M
~-~ WO Ov M ~ O W O M w0 N two N O oo ~ N N Iw0 M r~ .. .. n o0 0o v0 M
N Ov Ov N M O OWE ~ l~ Cv Q~ O O ~ N ~ N N N N ~ N N ~ Wn ~ Do l~ Ov o0
N N O N M N N ~ ~ ~ t~ 00 ~ ~ ~ N ~ O N N --~ N -~
cn vi ,-i Gv o0 v~ ~_ tn N ~ ~ p ~ ''~ ' a
N ,~ oo vi <t cn M N N N N -~ ~ ,-; M N N ~ .-r ,~ ,~ ,~ ,~ ,~ ,~ l~ N ~; s0
~t ri ri ri
N V v1 cn Os vW ~ cn N oo Ov m ~ ~ ri vi ,~ N two 00 ~n O t~ v~ o0 v0 op ~ wi -
~ ~D ~n v~
Iw0 v1 Ov Ov N N o0 -~ O ~D O~ ~D M ~ ~D O OW ~ 00 M M t~ N ~ ~.r, M Ov Ov OW
O N N N N --~ M M ~ ~ ~ n N N M ~ N ~--~ ~ N N N N N N O ~ N N ~ N
O O O O
V7 ~ N ~D I~
M 00 00 M M
N M M N N
~N O
N ~ ~ O O
N 00 .~ ~D ('
00 M
M ~O M 00 00
M M M ~ O
~r
W f~ W w W
x
N N N
175
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N
O ~ ~
~n N O ~ ~ M O
N N N ~! ,-, ,-Wp~ I~ N y0 Sri ~n ~ d: d M x ~
N' -; s0 ~n ~t ~ N cn cfi ri N N O O
~ O N t~ M ~ M O --, ~n ~ v0 W ~ t~ O o0 V nj
Ov ~ ~ ~ M ~ ~ 0 O
v0 ~n N Ov M N O f~ Ov M t~ ~
N OWO .~ .r o0 ~ O v0 ~D M V7 x
v0 v0 V7 .rr
N N N N N N N O O O --~ N N N N ~ N N
N ~ N N N
~
N ~' vi O
~ ~ fV
i
~ ~ ~
N
N N N oo t N v0 W n ~ ~ ~ M cn M O p
N ~ v0 vi ~ V. N M N N
00 M Ov ~ ~ ~ M ~O I~ M Ov O vD
M ~ 00 Qv M ~ N l~ ~ Gv ~ O ~ N
Ov N ~ (~
00 01 V1 N O~ ~' M O~ ~ l~ ~t O O O Ov 00 Vl
00 ~ O~ O~ ~ O Qv ~ ~O O
M ~i
~
O N N N N N pp" M N N M -~ N N M M N N M o
N - N N N
~~~
~ ~aoo
N N N W N O N oo ty0 V~ ~ ~O yi vi V ~ ~ ri
N ~ ~ ~t N ~; ri M N N .~
0o I~ '-' ,~ --Wp v0 00 v1 Ov o0 N v0 .--~
v1 v0 O I~ N ~ ~''~ N oo ,~ ~ ,-.'
Ov M M ~O n O~ O l~ ~ ~ ~O ~O O~ O ~O x x
~O ~D ~r M ,-W!1 V1 ~O l~ ~~ ~ .--~ x
00 N
M
N N ~ 'p M M ~ ~ O M ~ --' N ~ ~ N N O N ~ ,~
N O N N ~ ~ N N ~ ~ r;
~ '
~O r
N N N oo I~ s0 vi ~ ~ N v0 Vi ~n ~ ~ ~ M ~r ~
N -~ cn ,-. cn ri N N ~' C
O M .W . . . O
p v'i N O y0 ~ N cn vi oo O ~ N Ov O w0 yi O
Ov ~ O v~ N O v0 O O
r 'T'
C/~ ~-~,'
M O oo ~' ,-, ,~ p~ I~ ~ ~ r
v0 v1 -~ WD N ~n N N O l~ l~ 00 IwD <Y ,
O N : -r M ~ V7 ~ ~ ~
; ~ N N ~ O N N N N i
N N N ~ ~ N N N N
N M
N M N V-j ,. . ~ .-
. ~ t~
p ~
t~ 00 O ..
-..n ,-r N ~n
N N N ~ N ~ l~ ~O ~ vi ~ v0 y ~n ~ ~t V M N v0
N -~ V cn ~ ri cn N N -~ O O
M ~' ~ ~ ~ ~ I~ M N ~O ~ ~ ~ V~ N V1 O V1 O
N M M N ~O 1n ~D I~ '--~ M ~ 00
~O (~ ~ M '~ O~ ~D ~ 00 00 O~ d' ~~ l~ V 00 x x
M ~ O ~ ~ I~ ~ 00 N M ~D 00 x
M ~ ~
~
N ~-n ~" ~' ~' N N O N ~ ~ N M ~ N N ~ N
N M N M N ~ N N O N
a O
cn Vi
O ~
N N N ~ oo t~ v0 ~n Vi ~ ~O W vi ~t ~ ~t ~ N x
N ~ ~ ri N ri M ri N N ~ t~ ~
O ~D s0 ~ ~O M V'1 v1 Os ~ O ~ 00 M o0 N ~
~ N Ov ~ ~ N l~ ~n ~t
D t~
_ ~ O N N ~ N N
N N O ~ M ~' N O N N ~ N ~ ~ ~ ~ N
N N
~
M N N N ~ O
O 0 '~
~ ~ ~
~ O r ~ O
~
N N N
N '-' M '-' N oo tw0 N !~ ~n ~i ~ d: ~
~i ~n ~t cn N cn ri ri N N ~ N ~ ~
~ O O Wn O I~ OW ~ --~ ~ oo V M v~ O O O
N v1 ~ OW i dv N
r '
~D (~ o0 M O~ 00 I~ t~ V1 M O M O~ N ~ 00 00 N
00 O~ O O O~ N
O ~ ~ N ~ O N ~ N l~ l~ d
N N N ~ ~ ~ N O N N N N N
~ M vp t~ ~ O O N N
~
N N N ~ N N ~ oo f~ s0 ~ f~ ~n ~n ~ ~ ~ M N ~t
N ~ ~ ~O wi ~t M N cn ri N N ~ ~l '~,
E-~
--~ O M Ov oo ~ Ov V Ov ~ Ov --~ ~t oo ~ O
~1 v0 N ~n o0 M Ov -~ ~ N
~ O oMO ~
~ ~ ~ ~
' O O o0
~ ~
M N N N N N - N N N N N N N N
N N N ~ N N N - t
x, ~ ,.., ,--i O~ O ~ p
~ ~
~
O~''
N N N ~ oo cn ri ri ri N ''
~ cn N 0 ~n x
0 ~O vi d ~ vi
~
N ~ ~ ~ ty ~
N Iy ~ ~ ~
:
00 M .-~ N ,~ t~ oo ,~ ,~ ,_~ oo v7 ~_n ~ O~
~ ~ O ~O Ov O_ t~ .--~ oo ~-. t~ O t_~ O~ N
" M ~ ~O~
N~ONON~ r ~ONMN~;NN~;NN~NNO~
~~~N~N~;OMNp;NMN
~
a ~~~~~~ o~~~~~~~~~~~~ ~
~~~~~ o ~
o~
~~ ~
i o a
N n ~
i D
i
N N N N r ~ ~
N ~~ nj vp t~ Ov ~ I~ r .-.,
c'i Qv ~O vD v1 ~ c N o p N
o0 00 v0 ~D ~t v0 0o Ow1 v0 v1 ~ ~t ~t ~t c
,WO v0 ~ cn ~ N N N
~D ri t~ N N N cW
D o0 cri OwG o
o
N N OM N "'' N N ~ N N _ N O ~
~ ~ N N N N N ~ ~ N N ~ N N ~ N
N N N N
r~r C/7
N N N N ~ -~ ~ oo l~ l~ --~ 00 v0 ~n ~ ~ ~ -w0 N
N N ~ yG W ~ ~ N ~ cn cn cn N N ,-;
,-;
00 M O M ~ M 01 ~ M 01 ~~ M I~ Ov M N ~1 Ov Ov
v~ ~ 00 Ov ~ N o0 M M ~ ~O ~O ~O ~ 00
N l~ ~O 00 O~ ~O O ~O O~ ~ 00 N ~ O ~ N O
N M M o0 ~ M O l~ ~O M O~ ~ 01 ~O
I~ O ~ ~ ~ ~ N N ~ N ~ ~ N -~ N N N N N
M N N N ~ N M O N
N O N
N ~ N
p O O
00 O~ O
M M d'
N N N
N v7
00 I~ Ov
M ~O ~!1
N
U
00 0, o
N N M
N N N
176
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
-i N ~ ~i ~
vp ~' Ov ~,
O
m M N N N ~-, ~ ~ V~i ~t ~t M M M M N N ~~ ~ N
O I~ 00 .--~ .--~ ~t N ~ N ~n O ~O ~_D OWn vW_O Ov oo N_ cn .~ N O_ v0 p M O
t~
N ~ N N ~ ~ M ~ N N N N N M O ~ M O ~ N N ~ ''~ ~ x ~l
v_yt M M N N N ~~ ~ ~ ~n v-i ~ cn ri ri ri N N ~-! .b M N ~ M ~' O 'n
a O ~' O\ V7 V1 t~ T ~ C~ ~ M ,--i OWE .-i O ~n ~ ~ ~ WO o0 ~ V7 O C/7 O
00 N ~~ V'1 00 a0 M o0 " N QW~ 00 Ov OW1
~ N N N N ~ N O .~ N ~ ~ N N N O M N N ,~ ~ ~~ N N
O o0 ~_ f
O v~1 ~ M ri N N N N ~ O ~ V1 ~ ~ M cn cn N N ~ O ~,'? ~1 -~ ~ ~ O r
O~ l~ ~ ~~ ~O l~ V'1 M x 00 O ~ ~ M ~D O I~ ~-w V~1 a .-r .~ p x O V7 O
~O ~ M O~ O~ <h l~ ~~ ~ N ~ ~ ~O O~ O~ M ~ O ~-r ~ OWO I~
N N N ~-~ ~ N N M .--~ N N N ~ N N N N N N ~' N N ~ _ ~' ~
O ~ ~ N ..
O ~Y cn ri N N N N ~ ~ wi ~n ~ ~ M cn M N N -~ O M N ~ Op t~ O ~n
~O.-; r.;ooooasoo~s_ox.-: c~ir;o.~ _''a._:r:is_ovyxO
NON-~O~~MN NNNOM~O~~N ~~ N~-ANN ,...,
x ~~~~~~~~~s ~~~~~~~~~~o
x O '~ ~ cn M c'i N N N ~ a .b s0 vi d: ~ cn M ri N N ~-~ ,~ M N .-i O ~
C M ~ M O ~ N N v0 G v0 Ov Ov I~ M -~ M M N Ov ~ O oo N "~" t/~
~ o_0 M v_0 Ov Ov N ~D V1 N ~ l_~ O N M o_0 N ~ ~ N w~~ ~~' ~n ~_D N .~ _~
"' ~~~~~~~~~o
~ M M cn N N N ~ ° °° ~ o
~ O v0 ~n ~ ~ M M M N N -~ x cn N ~ a
_ t~ 00 Ov OW _O W O C~ ~ V'i -~ ~t ~ ~O O oo ~ N ~D "~ c~i N_ ~n _ ~_
pv ~' ~; N N N ~ N N N O ~ ':'! N N ~ N ~ ~ N N ~ N M ~ M ~ pp N N
°°o
x O 0 V M M M N N N ~-v a O I~ ~ ~ ~ M M M N N N x M N .-i ~ a r~-~ x
'~ M v1 ~~ ~ N O ~-W~ N ~ N r~~~ oo OW t OW1 N N O~ ~ l~ M O M
N N N l~ oo O ~ OW.r o0 00 ~O oo I~ Ov o0 I~ M Ov Ov N l~ ~ ~ N . .
M w ~ ~ N N N ~ N N M N ~ ~ ~ ~ w~ N O ~--~ N ~ ~ N ~ ~ N N O
o ~~~~~~~~ao ~~~~~~~~~~a~~~~ooo
~ "~~ ,~ ~1 M M M N N N ~w ,~ t~ V'1 <f ~ M M M N N N ~ M N ~ ~ x x
~ N O~ t~ ~O O ~n O M M _~ M OWO M ~ O t~ O N ~ ~ Ov ~~ r ~'' .-: ~;
~ ~ N N N N N O O ~ ~ N N N N oN N N N ~ ~ ~ N N ~ ~O ~ N
,.0~., a a ,.o.~ n0 ~ ~ ~ ,.o..a p O p ,...;
V7 ~ t'~i M N N N ~ M a t~ ~!1 ~ d: M M M M N N ,_; M N .~ ~
"~ ,-i ,-i \O ~ M V1 I~ V~ O ~O .~ N o0 I~ lW0 00 V1 IWO O~ OW_~ V) N ~' ,-i N
yD N OW ~ ~-~ oo O oo ~ ~ ~ ,.~~ N N O ~ ~ N N N O oM N oN M ~ °~ ~ O
pv ~ ~ N N N ~ N N M N M ~ O
O O O ~ ~ ~ ~ Co/~ O ~ ~ O v0
v~ y M M N N N ~ ~ ~ l~ W ~t ~t ri ri cn cn N N ~' ~ N ~~ ~t
O V) I~ O ~ 00 00 00 N '~ ~ ~ .~ 00 l~ O N ~O M M ~ ~ ~ V1 M
'n O O ~ ~ n l~ ~D t~ 00 v7 N ~ ~O N M oo I~ O ~O o0 O Ov ~ ~ ~ N O ~ O N
-~~n N ~ ~ O ~ ~ N ~ t~ ~ N N N ~ M N N N ~-~i O N N o0 ~ Do M O
~~~~~~~~~~x~~a~°x~a~
V~1 ~t M M N N N '~-~ ~~ ,~ l~ Wi ~t ~t M M M M N N ~ V, N ~~ ~ N ,-i ,
v0 v0 N oo d' M M I~ f~ O O f~ ~n O M ~ M t~ 00 0o N m t~ cn
~ l~ M ~D 00 M I~ O N (~ M t~ 00 V1 ~D 'ch l~ O\ 00 I~ V7 ~ V'7 M Cv ~~ ~ ~ ~
V'7
~ N ~--~ N N ~ N N ~ ~ ~ N ~-v N w-~ N N N N N O ~ N
O O O O O O O O
M ~ ~ V'1 N M
00 ~ 00 00 d'
M N M M N N
M ~ ~t 00 Ov
00 ~ N o0 I~ N
O~ O O ~n I
~O Wn oo O l~
~O ~ O~ O~ ~ M
v~ Qv o0 00 ~W O
N M M M ~
H
~~ N M
M M M
N N N
177
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
v~ . os
° ...:~~'r.; ..,~o
cn N N .~ 00 ~ ~' M M
., O ~ O~ N ~ oo N O ~' ,w0
(V ~~ M N ~ ~ ,~ ~ N N ~p ~ ~ ~ l~ ~ M l~ ~O v0 V1 ~ ~ cn M M ~ ~ V1 ~
I~ ~!-? O O O x x x a N O b ~ ~ M o0 ~ N ~~ ~ 00 Ov vp N Ov M M
N O N N ~ ~-~ ~--~ ~ x x _~ ''~ ~ N N N N N M M N ~ ~ ~ ~ O N
~ M N N ~- ~ p ~ a '-: .~ N ~ ~ ~ vD
O V ~ N ~ O ~'~ p~ ~ oo
N ,-..~ M N ~-i -..i x ~ ~ ~ ~ O O ~ ~ O ~ ~ y0 v0 Vi ~t d: cn cn c(i ~ ~ ~O
~n vi
V1 M_ M o0 M_ N ~D O O O O x O O O M v_0 o0 ~ .--i I~ ~ Ov ~ ~ v1 --~ OWE l~
N M ~ N M ~ ~ ''~ "~ x x x r; a ~ ~ a ~ N ~ N N N N O ~ N N ~ ~ N N
~ M N N ~ ~p O i:rj ,_, ~ .~ N v0
M ~ ~ ~ ~O l~ ~
N .-; cn N N ,-i a ~ Np ~ ~ p 00 ~ ~ 0 OW VO v0 ~i ~ ~ ~ cn cn .~ ~ ~D v'i v'i
._--W~ ~D ~ ~ 00 ~ O ~D O ,"~'['~", x ".~ O O O~ V1 O V1 ~ O M ~ ~_~ O_O N M O
~D
M N N N ~ N ~ a ~ '~ x .-i ~--~ ,-i ''~ x" ~ nj N O N ~ N ~ N N M N ~ ~ OM N
N ,-i cn N N ~ a ~ ~ ~ ~ O O p Own ~ Iy0 ~O ~n ~ r1 ~ cn cn N W O ~n vi
Ov W_ v0 O~ M x a O x x x r.a O ,0~, O fyD ,--~ N ~t N ~O OWD M N C~ ~O .~
N N N N N ~ ~ ~.,.j ~j N r.; ~,-; '~ "' ~ ,-i x ~ ON ~ N N ~ N N ~ O ~ ~ O
~O d. o0 ~ O ~ ~.j N p~ ON v0
M o0 ~ V'7 pp O l~ N y
N ~ cn N N ~ I~ O O p O a Cp/1 ,~ ~ O O WO v0 ~i ~ ~ ~ ri cn N y0 ~ ~n
~D N N O O v0 nj x x ,~ ~ _ _. ~ ,~ x ,~ M N o0 t~ M N ~n t~ v~ .-~ N O ~ vi
N N ON N N ~ M N ~j '-: ~ ~ ~ r; ~-! ,-i ,O~', ~ N ~ N N N N N N ~ ~ ~ ~ N
Do~o~~~0
N ,-i M N N -~ ~ O M O C~ x x t~ O O O 00 ~O VO ~n V1 ~ ~ M M N ~ ~D ~mn
~ ~n M s0 Ov o0 ~ V7 ra C~ ~ ~ ., ~ ,~ x ~l ~ 00 Ov o0 O Owt M ~n ~ 00 O N O I
N O ~ ~ N N ~ M N N '-: _'~ ~ .--i ~ ,-i ~ N M M v0 t_~ O_ ~ f_~ o_o W _D OwD
O M
~' $ °o o ~ ~ ~ ~
ri .~ ri N N ~ ~ ~ ~ a ~ x x x a ~ a '~ oo t~ so ~n vi ~ d" ri ri ri
'~° ~ Vi wi
~_ f~ ~_ ~_ O v_0 ~ ~ N N "" ~'i ~ ,-i ,-i .~ ~ ~ ~ ~ O M O ~ O N ~ v0 oMO ~
,~ N N N ,-, N N ~ ,~ ,~ N
r;,~ r;cic~i,~°oooNr~nxxooo~'
axx~_..a~x~~~~~~~~MMN
~ N ~ V7 01 ~ ~ ~ ~~ ~ ~~ ~ ~ tn N ~ V7 V) M ~O O 00 M M M 00 ~O
~D ~O Ov ~ ~ ri N ~ t' O o0 ,~ ~-V ,~ .~ 00 00 ~ Ov M o0 W O N ~n l~ ~O
O ~ ~ ~ ~n M .--~ M ~n O ,~ N -~ ~ N --~ O N N ~--~ N ~ O ~ N
~O O O O ~ ~ O ~ ~ ~ 00
~oppoxx~,xoop .
M N M N N .-~ ,~ a rn a . . . ~-a x v~ ~ oo c~ W o vi ~ ~ ri ri ri ~ ~ vi vi
O~ N N M ~ vi M ~t cn N '-' "~ ~ ~_ -~ ~ ~ ~~ O t~ O v0 l_~ O O t~ O~ t~ N t~
v1 M
N~ ~ONNO~~~M~TOv~~'~ ~~NNNNpMNNNN ~ ~ON
N
'-.~ O O O ~ rN-1 x x O ~ O O
~ N M N N ,--~ .~ ""~ a ~ ~ ,-i "...; '~ ~l ~ ~j o0 Iy0 v0 ~ ~ ~ c~i m N ~ N
v0 W v)
N O O ~D v~ O ~ ~ cn N O M M oo ~ ~ ~ f~ I~ ~ ri N N o0 OwD oo N W O O Ov
v7 I~ oo Ov Ov O~ I~ ~ ~ ~i ~n ~t M ~' ~ M v0 ~t --~ ~ 00 M Ov oo O N t~ ~ N
N M N ~n O ~ ~ '-' N O N N M N O ~-n ~ ,~, N N
~~~~~~~.~N~..~~.
O O O O ~ M ~ 2f
xxxx,~VJaO ~c~ M
~ N <t M N ,-..v ~~ uj M N ~' ,-i .-i -i .-i .-H ,-i ~' Oy v0 v0 V~ V ~ M M M
,~ ..-n \O ~
N o0 N O ~n Ov Ov ,n p~ N N ~D ~h ~n O M v0 O M oo Ov N ,jj M_ O O ~
N ~ N ~ ~ N N ~ ~ ~ ~ ~ M n ~ O ~ N ~ ~ O N ~ N pM ~ N ~ M N ~r-~ N
t~ I~ I~ N ~D O O M N I~ N
O O O O O O O O N O O
~O I~ VW O o0 t~
00 00 d' d' 00
N M M N N M N
o~O N oMO ~ M
O d' Ov
O M
.-Na O
M M M M
N N N N
178
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N ~
N ~~ ~i ~
i
~ ri oo ~ -~ ao
O ~ ~ ~1' OW ~ ri Ov
O ~ '-' ~D ci ~n W t ~fi M M
M M M N ~ r 1 N N N --~
M
~ ~
~ v M O ~ v7 Ov ~
M V7 V1 OO ~ ~ O O O N Ov
O d' M M N N N N ~ I ~ O tn Op p~
' O O pOp ~ N
<T Q~ ~t M O -~ O (WO ~
N ~ ~
~ O O O
=f O_ vD v0 00 0o O O Ov .
t~ oo ~ 00 o0 V1 '- -, N
M t~ ~n .-i N ~ N -~ N M N N N x N N M N ,~ N
N N N N N N a x
G N
~ l~
~
M M M N ~ I~ v1 ~ V M M N N N N ~
' x O ~ ~ ~ ~ ~ ~'~
~ O O ~ M N N N
v0 M ~ ~ l~ ~ .. N N M ~ 00 t~
~D N ~ O ~ N ~O ~n OW
-a V ~ O O N --~ N ~ .--~ O t~ Gv N N I~ Ov O t~
~n M ~' Cv N ,...] O O O 00 ~O v0 Iw0
~ ~, 00 00 ~D (~ M ~ Ov
o0 v0 x ,~ a
M N N N N p~ M ~ ~ ~ N N ~ ~ N N ~ N ~ ~ M ~ N ~
'- ~ ~ ~ N
O ~ I~
M M M N N x ~ ~ ~ M M N N N N ~ O p t/j Op tn N
r ~ op ,y op v1 O OO ~
~ O Ov
I~ N 01 v0 v0 00 ~ N l~ O O ~ V1 vp ~ ~Y ~ ~ M
V ~ ~ ,-; ~O "' M M N N -~
O ~ O Cv M 00 ,-.W ~
O~ ~ N Ov O U ~O ~O .-n M Ov Ow ~ M N N v0 t
n.a ~ x i--~
N N N N N ~ O -n N N N N ~ M N N ,-, ~p c_p t~
-~ ~D ~ ~ ~ ~ ~ f~
~ ~ ~
p ~N ,~j ~
~ M M N N ~ v1 ~t ~ M M N N N N
~7 x O O
00 00 00 ~1 N v0 ~ N cn ~, f~ -~ f~ ~D OW i N OW
t~ l~ Os ~' ~D v0 i O oo d' O
O 00 W O t~ Ov ~ l~ Ov pp ~ d' ~ ~ M
00 O M oo t~ M ~n ~.j x a "~ M M N N N
N ~ 'p "'~
-~ M N ~ N N N ~"' N N O .~ -~ N ~ p ~n ,-~ ,~
N N ,~ ~; N ~ ~ ,-, ,_, p~ p~ ~t N O
O M " Ov
O N O ~ 00 00
~n Cv O~ 00
N N N N ~ N N
-~ N O
~i n
i i '
x p M
N
~
p O O
r v
~t V ~t c c
N N d: ~
" N N
N
,.~
a
. ,~ M oo ~ O Ov O O~ Ov ~ N
~1 vW O N ~7 ~ ',.I'., t~ l~ OWn N CWO
00 .-~ '- ~l O oo ~ O
I~ N o0 tmn ~D O N l~ M -n O~ M OWO
--W~ ~1 ~ N ~ ~
N N ~ O N -m0 ~ M N N N N N O N N vp N V? ~ ~ ~t M
~ r; ".". ~ M M N N N
O ~p m ~ d' ~ ~ mV ~i W
N ~
O
~ ~
x~ n _
M i _
i n N _
O i ~
x ~
p'~
~~~~~a~d
r Sr d~~
N N ~ r
~t ~t ~ c
~ a ~t ~ c
N N ~
O
-
O~ O ~ M Ov ~ ~D O 00
~ V1 ~ M M O ~O . d'
Iw0 Ov o0 00 v0 00 Ov dw0 M N O oo
I~ t~ ~' ~; M ~ .~ ~;
-~ O N N N --a .~ .--~ N N N N N ~ ~ ~ ~ m c~ ~
-~ N O .NO. ~ N ~ ~ O N N
~~~ ~~~ ~
~
M
O
0
01
xO OMOOO N,-
,
~~O
-~,-
o
o
O
O
_
M M N N wj v1 ~ ~ M (n M N N N ~ _
~ x ~ ,~ O
00 M O~ 00 N V1 '~ N V'1 O~ M M
00 O ~O M N I~ N ~
~
N ~ 00 O~ V) ~O ~!1 I~ ~' M 00 N M
O~ ~ ,-, ~ M 00 ~
N N --~ ~ N ~ O N N N O O N N ~ " ~ ~ N ~O ci OW
~ N M O O -, Oi vi .~
N O ~ ~ tn V7 ~ ~ M M
O ~ ~ M N N N
~ ~ ~ ~ ~
x ~ v1 ~ (~ O~ oo O~
O O M N O
O O O ~O M O~ M
~ M M M N Vi x _
~ v7 ~ <t ~ M M N N N N N ~ ~ ~ N N ~
M ~ I~ M N x ''~ x ~ O O
--~ M ~O W O O vi ~O Ov N t~ N l~
<t d:
N
N N N N O O ~ ~ ~ ~ N N N
~ ~
~ O
N'
M
h M
N
~O V
cn cn M N ~ v0 ~ ~ ~ cn M N N N N t
a ~ x 7 ~ ~
N
N
I~ ~w0 O t~ ~
v0 t~ M ~ 00
~ .. . .. .. .. ~!) ,-, ~ Q1 M ~O 00 O~
N ~ N t~ v1 ~ ~t O ~O M
M ~n N ~'' oo v1 M o0 M_ W_ O ~n N N N N N N N
O M ~_ N ~ N ~ N
O
N~N ~~NNMN~N
NNNN~ NN~
O ~ O O O '-' ~ ~O N ~D ~ O
I~ N O~ I~ N
M M M , n ~ ~ ~ ~ ~ M
~ M M M N N N
D
N N
a x '~ ~
N ~ ~ ~ O~ M V7 ~--WD
~ o0 ~ V7 M M t/~
yt ~t ~ ~O
.. N N ,~ pv C' N oo
~ WO O Ov WO Ov oo ~
~ O .. ..
O 0v --n N M v1 M ~ I~
00 00 ~ N '-' ~
Ov M O n Ov --W ~ t~ O W oo ~ N N N N ~ N
v - M ~ ~ W O O ~ O
l M N ~ N N -1 N N N N
O Ov OwD M I~ ~ N v0 ,."T'.,
N ~ ~ g
M N -~ N N
N N
~~~d .~'
~~d~ ~,~~
x x o ~
~i
O M
~
s
~
'
~ cn ri M N ~O ~!1 ~ ~ M M N N N c
~ r.; N ~ N r; ~; ..~ t
O o
O
t
O ~
d
w0 v~ ~t d' ~t
M M N N N
~O I~ O Ov ~D M O1 ~_O M Ov M v0 V7 ~ ~ 00 I_~
~_ 00 O ~_ ~ O ~ M 00 N Ov o0
~N NON ~
N~O NNNNNN ~N
N ~~N
M M NN
N ~~p~~ ON
N~
O O O O O O
00
N M N
M 00
N d'N
d'00
O~ M M
00 0000
,nN
x z
~ x
M M
N N
179
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
00
M M
Ow! ~' N ~p
N ~~p~D~~~p,N_,N
~D vi ~ ~ M M cn M N N N ~ ~ .-: -i p oo ~ N ~-T, .a: ~ ty0 ~D p Vi ~ ~ ri ri
N ~i
~oMO000~~~N~~.-i0 M~a~,T,'-' ~ ~ ~NI~~o~OMO~N~o~OOMo
N .-,~NNNNN~~NNN ~~~ N Nx O ~ ~NNNNNN~NNNN
M ~ ~ ~ ~ 00 ~ ~ 0~0
yD vi ~ ~ ri cn ri ri N N N x ~ N ,-i O ~ p ~ "~ ~ IW O v0 v1 v~ ~ ~t M cn N
N .~ 'n N v0 Ov O oo v1 ~h M t~ o_o p Ov cn ''~ O O t~ O ~p t~ t~ oo ~ ~n OW ~
O v'i oo O
t_~ ~_D ~~ ,-~ O M O_v O_v Ov o0
M N N N ~ N N ~ N N N N N "'~ N N N 'T' x_
M M ~ ~ ~ ~ ~ vp
,ri N v0 v1 ~t ~t m cn cn ri N N N ',h, ~ N ri a ~ ~ p O N ~ WO ~D v~ ~ ~ ~ cn
M N .~
~D O~ M N 01 O ~O I~ 00 l~ ~-~ O I~ l~ O O ~ O '~ O ~ M ~D ~D M d' ~ ~O N ~'
,~ 00 ~ ~_O v0 VW O ~ t_~ N I~ N a ~~ V1 ,N, x '~' O ~ cn ~ M Gv Ov Ov ~~ Ov
Ow0 O o0
N .. I~ .. p~ , .. ~ .. M 1~
O~~O ~O~WO~ ~N~
N vD v7 ~ ~ M M M M N N N a ~ N ~ xi ~1 0 ~ O ~ ~ t~ I~ ~O v7 V'1 ~ ~t M M N
~n N N O N ~D M f~ Ov O~ N nj ,~ N v1 x ,~ O ,...] ~''~ ~~ a0 ~D O Ov N o0 v~
~ N '~t
M N I~ ~ 00 O~ M 00 00 00 M 00 N N ~ ~ ~" ~~ OO l_~ O O~ N ~O O~ ~ M 00
N N ~ N ~ ~ O N N ~~ N ~ ,-i
N o0 a; ~ ~ ~ ~ O n p O M ~n o°~O ~ 0~0
vD vi ~ ~ ri M cn ri N N N a O N ~-. x p O ~ O ~ ~ t~ t~ v0 ~n vi ~ et cn cn N
-~
N oo N -~ ~ M O wD ao Ov N a v7 ~ N V1 x O ''~ V1 v~ v1 0o M oo M ~ ~D
0o CW v0 00 t~ oo M Ov o0 M v0 ~; v0 O ~ . a ~ d' t~ ~O v~ Ov N N m O oo ,~ ~O
~' N r, N ,~ N .~ ,-, N O ~-r O vp . . .--n N M .~ ~' ~ '-' ~' Ov N N N ~ N N
O .~ ,~ M O
N~ ~~ aopo ~~OMNOt~
sG ~n ~ ~ M M tr1 M N N N M a fV '-' "~ O O O a ~ ~ f~ ty0 ~yn ~ V V M N N
M v0 M_ ~D ~_O V7 Ov O d' O oo IW O N x "x C/~ p~ pv O M v0 W O O_ I_~ ~n ~O
N ~ M ~ M O ~ N ~ NO N ~ ~ ON ~ ~' ~ ~ ~' O ~ ~ N N N N N M N N N
N N f~
,O~,~O~NO ~tOv
N O gyp' v,j ~ ~ ~ cn cn cn N N N r ,~ N ~! N ~ vp7 ~l N ~ t~ tW O v0 ~!1 ~t
'fit ~ cri N N
O a0 ~ ~ t~ O M o0 O~ M ,--i ~ ~ oo .-, " ~ ~ ~ ~ ,-, t~ N Os ~ m t~ WO v7
two ~~ ~ O~ M oo v0 t~ OWD I~ '-'. v0 v0 v0 .-.~ ~' ,.; ~..' tW O O O~ M O t~
1~ l~ O O
.-~ .~ N N N N N N ~ N O t~ N ~p; Np; CWp ~ ~ ~ N N N ~ Op; Np~ N~; Np; p~~ N
N
t~ o
-~ .-i ~ ~ O O O M O N Ov
N N ~ ~ ~ ~ ~ M M M N N N ~-~ "a ~ N ~--~ N F-~ ~ CO/~ ~l ~O Ov op" I~ vD v0
~n ~ ~ ~ cn cn N
N ~n ~ oo l~ ~~ N O o0 ~n M O ~ O O ~ " " .-~ ~ ~. 0v N a0 W O~ N N t~ O --a
O~
Ov ~ N M ~ ,~ ~~ O N o0 v1 ,~ ,n oo v0 ~' ~' .. .-~ .. N .~ ~n o0 ~ 00 ~n ~D
Ov O v~
~~ N N N N M M M N ~~ O N O O ~~ ~~ M d' ~ N ~ ~ ~ N N N ~ N ~ N N N N N
b O ~ O O ~ d~
x O O O O
M omo ~ vo ~ ~t ~t cn cn ri N N N N a ~ M ~; irj x x E" yo M °°
tW o vo vmn ~t ~ ri M N
N N ~_n V M ~O ~ O ~ ~D t~ s0 d' l~ ~ ~ ~t v1 ~ N ~' ,~ '-' ~ N O o0 N O N oo
O_ o_o l~ N V
N ~ ~ N N O ~ N N N ~ N ~ ~ N ~ ~' ~ M N c'~n ~ ON ~ N N N N N N N O N
~~~~~~~~~~~~~~xa~~°~x~~~~~~~~~~~~~~~
Cv O ~ ~O ~ ~ ~ (''~ M M N N N N ~ ~ c'n .-.~ M . ~ ,_; M ~ 00 t~ ~O 'O V'1 ~
~ ~ M M N
N ~O l~ -~ ~ V~ M l~ ~ N ~~ V~ Ov O ~ W O "'y N ~ ~ ~ l~ ~O ~ V~ l~ Ov o0 Ov M
M vG N v0
N O O I_~ N OW_D O_v M v0 ~ ~n M O_v ~ ~ l_~ Ov ~ OW1 ~ ~ ~~ N o_O l_~ 00 t_~
M o0 M ~ --~ ~ v1
~~~xa~~dxa~~x~~~
O~ ~ ~ " ~ ~ ~ ~ N
py0 tn ~ ~ M M M M N N N r, ,~ M ~ ~ N ,-, ,-, ,~ .~-n .-r 00 l~ ~O ~D V1 V7 ~
d' M M N
c%i -I~ OWn Gv M oo M t~ vW O M O ~'vj ~,~ M t~ M ~ 'p ~p y0 N M N_ ~ dv M O O
N N OW _i
ONN N~~NN~~~NNNONM~ON~~pp~ ~NONM~N~NO~NNM
O O O O O O
O ~ N
vmn tn
N N N
N O ~O
O O N
N v0
M I~ M
V7 00
O M M
U W
O ~-~ N
d'
N N N
Ig
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~
.p = r; o ~ wo r; ,-,
o
"' ~ ~t ri cn N .~ .-~ ,~ op" fyD M N ~' ,~ ,~
N N N ,-i v~ ~ cn N .~ oo h ~O
~ N
N
ov0 ~ O~
~~M~ OVNhn~O~ o
o -~N NN~NNN~
O~~
_ _
_
_
O ~t ~ M M N N ,h-, ~ ~ N oo t~ M N ~ ~ ~,~
N N -a ~D v'i ~t M N 00 h ~D
v1 ,~ oo ~ V1 O ~ M Ov 00 ~ 00 v0 ~rj
N d' ~~ ~ ~ yj 00 O M
M h o0 00
Ov ~ O ~ oo O o0 ~ N ,
N v0 v0 N Ov N M ~O Ov ~ N O h o0
M M N ~ N -i N Ov o0 ~ ~ h ~ M O
O ,-, ~y r, N N ~ N N N ~ ~ --~
N N N N N N M
'-' ~ ~ M M N N pp ~ .~ 0 00 h s0 ~ M h ~ N O
N N -~ v1 ~ M N M N ~' ,~ ,~
~ O v~ N Os N h ~' ,~ ,~ pp N O ~n O h
~O Ov vi O v0 h ~
h O h ~Y M ~O h V'1 V~ O~ '~ 00 ~ cV OO O~
M h M Cw0 W O ~ N N ~ O~ V1
N M N N O N N N op vp h N N N N ,~ h op ~ ~
-~ N N ,-, ~ N N
'-' d: ~ cn ri ~ ~: oo ty0 ~ ~t Os oo v0
N N N N ~ cn N O M o0 ~ N
M O~ O M 00 ~ ~ '~ ~ '~ O ~D N M O .~ op p~
~D ~ ~O (~ O M
O o N .~ .~ ,~ M o ~ N .~ ..~
~t v O ~ t .~ ,~ O O
D ~ o ~ N ~ N v O
o O~ h ~ M
_ _ _
_ _ ~NONN
_ MN~~~
'-' ~ ~ cn m N ~ ~:,~ 00 t~ ~O ~ OW O y0
N N N ~ v7 ~ M N
M ~ Ov O N oo ~ ~ Ov o0 h h N --~ ~ ~ O ~O N
oo h v7 00 ~~ ~ 00 ~ N
~O ~ O h N ~D O M ~ '~ N o0 Ov M -~ ~ M h
V'1 h h O O ~
N N M N N N N N N ~' '~ -~ ~ N N ~ N '-' '-'
~ N N ~ '~ '~ N N
~ N
N ~ ~ N
~ N ~ ~
N V1 ~ M M M N ~ ~ 00 h ~O V7 <t M
N N -~ ~' M N ~ N
~~ ~ Ov o0 ~p
M h
M ~ O N a0 M M h M v1 h v1 O ~ h Ov
~ N O ~ 00 M O~
~O O~ h h h h O ~ ~ ~ 00 O~ v'7 ~~~_~_N_~_'N
O~ M ~ Q~ ~ M N
NNN~ N~~ ON ONNN"x 00
~ ~ ~ c
~ i
N vp op ~ ~ ~D
, r
, vD -~ Ov
00 O~ ~ h ~ ~D ~ ~ V~ ~O
N .y ~ cn cn ri O N ~ o0
N N N N r., op" (y0 v7 p ri "' N N N N
N "'' O p~ oo t
M M ~l1 ~ M h 00 N ~ ~ ~ ~ ~ N
O M N ~ ~ ~ ~ h M N O \O M
~ 00 ~O M O~ 00 M M ~ O ~
M M M 00 ~~ h M ~ 00 ~ O 00 M
N V'
~' V~ . 1 _
O N ~ ~ ~ ~ ~ 'T' ~ N ~ ~
O N vi ~ ri cn ri ~ ~ N Oyo ty0 ~n O N N O N ,-h~
N N N N ~ v7 ~ M r-! Ov o0 h
~ ~
O O N h v1 O v0 Ov M OW- ~t .-. ~ .~
,0~, O OWE ~ ~ ~ ~ ~ ~ ~ N
~~1 ~ oo ,-~ ~n ~ ~ N 0 N ~ N ~ M
h Ov ~ N N oo N N O
M N ~ -~ N N N
N
N ~
,,,,~~ N ~ ~ ~ ~ vN
~ ~ ~ ~ ~ ~ N pN ~
N 7.
M ~O h U1 0o f~ s0 M N t~ O ~
~ ~ cn ri N N N vyn ~t cn .-i ~O ~ ao f
N ~i
y p~ h h M .. . . N N ~ t~ h
.. . . .. . .. ~ N ~ O h
N ~ O~ h O~ v7 v ~ M ~ 00 0o M N N N N N ~
0o N d' oo ~ v1 N N v0 M
O _
xi pW D vD N ~O ~ O v~ M
N ~ M .~ .-~ p~ v~ M N -~
vi ~ ~ m cn N N c0 t~ vO v0 v1 ~ 0y ao h
N N ~ M N .
p Ov O O o0 . . .. OWO v0 M h
. . N
V'7 N ~D M \O h M ~ ~O M ~D N ~ ~O ~O ~ 00
h M ~ OW O h O~ O h ~ O~ O~ M h
N ~_D OW _~ ~ 00 O N O N ~_D ~ O N
~ oo W M N o0 M O_~ O ~ ~ N N N ~ ~
~_O O
Ov ~ ~ h N O ~ N O ~O M
N ~n ~ ~ M M N ~ ,~ --n ,~ OWE v0 M N ,~ ,--~
N N N ~ IW O v'i dwn N --~ ~ oo h
v7 N ~O M N N OWD cn N h N h ~O ~ ~ d' M W O
V7 ~ Ov O ~ ~O ~ v'7 ~ ~ O N
~ ~ ~-r OWE Ov W O ~ OWE ~ M o0 N v1 tn Ov
o0 O o0 OW ) ~D V'7 ~ h OW O a0 O
O
O N N M .-r N -~ M ~ N ~ ~ N N N N N N N O N
N .~ ~ - O N N M ~ -~ N
O ~ M ~ N V1
ovO W ~ ~n ~ ~n
M M N N M N
p~~ ~p N h N
00h O 00 h O
O 00V1 M
M M O~ ~O ~DO~
M O~Ov
OOh h 00 v0O~
M ~ N
N N N
Igl
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
ri b
c
~ N '._' -; ~ .-~ N .-i ~ ~ ., '_" -i
y0 0~0 t~ '~ ;O ~ ~ pp ,--, ~r N N ~ c'i
wi d: N ,-1 ~ ~ ~ ~ M '-' ~ p ~ O ~ ~ ~ ~D vi M M N ~ ~ p ~ ~ cn ri N
O t~ .~ ~.,~ O x O ~ ~ M ~ O O x ~ ~ ~ ~ M M t~ 00 I~ ~ ~ x O tn tn 00 in
O f~ V1 ~ x C/~ O O N pp v0 !w0 M M f_~ O ~ N v_D v0 V7
a V1 t~ l~ ~ O 00 N
v1 ~ M x l~ ~ ~ ~ N ~ ~ ~ O N yp ~ ~ M N N N p 0 ~ M M N
O ~ ~ M r~ x a N x M ~ x x x a O ~ vp ~_ ~ ~ O WO ~ x r.a pNp M N ~_
~ M M ~ ~ ~ ~ M VMl
wi ~ M x M O p ~ ~ N ~' ~ p O ~ N M vp ~!1 ~ M N N N O O ~ cn cn N
Ov o0 t~ ~ r.~ x a O ,~ I~ t~ ~ C~ x O O ~' ~ O 'ct W d' v0 M O x ~l N ~ ~ Ov
o_0 o_0 N ~.,~ ., .. ~"' " V1 t~ . r; n.a '"~' N Oy 00 ~' t~ o_0 o_o V7 ~ ~ ~
v'7 ~ t_~ Ov
O can ~ N ,n v1 WO O oo .
~p M V1 ~ M
M x O M O ~ p (V '~ O O x O ~ . vD V1 <h M M N ~ O O '~ M M N
O°'N~x~'x~a~' ~'~xx,~"~~1~
~°~o'r'oo'''oo~oM°m°~lxx o'~o~o°°o~
M N N N ~ '~ ~ '~ N N,~ N ~' r.; ~ ~ ~ p~ N N~; ~ Np; N N ~' ~ ~ N
O N Ov N oo M
~~~~OM~~~ ~~~NO~~%~
x O O O ~ O N N O t~ ~ x N
V7 ~f M ~ x x ~ O ~ N ,-.i O x x O 0 'G ~ l~ V1 ~ M M N ~ x x _. ~ M M N
~ ~ O ~'~ N .~ .~ ''~ .-i ~ ~ x ,-i ~' a a ~ v1 O p o~0 ~ N ~ v~1 a .-i ~ M ~
~
N N °~ ~ ~ ,~ ~ ~ N N N . . N ~! ~, ,~ ~' ~' M N N N N N vi ~ ~.;~
O
O ~ ~ vi V ~ N O ~ ~ ~ OM ~
00
wi ~ ~ d.' x x v~ O ,~ ri ~ ,°.~ ~ x a '°o ~ r~ 0.j ~ vi ~ ri ri
ci o ~ ,,~° ~ ~ ri ri ri
OM ~ M N ~ ~' a p pp ,-; ~~ ~ '~ ~ ~: ~ ~ Ov N O N M ~ ~ ~ N v~ ~t Vi
'n ~ ~ "" ~j ,..., ~ O a0 M I~ v) M N ~' t~ t~ ~D v1
N ~ N ~~ " l_~ ~' ~ N ~--~ ~ ~' 'n O N N N O N ~ ,-, ~' N N ~~ O
x ~ ~ ~ ~ ~~ ~ ~ ~ WO N O vp
O O O t~ O ~ ~ N ~ O I~ ~p W O C~ ~ O~ NO
~i ~ ~ ~n x x x a x ~.'! r' x x x ,~ ~p-1 x ° ° ~ '!? ~ ri cri N
~°,~ ~ x a vi ri ri r;
M ~ 00 .~ ~ .-, ~ ,_, ~ 'ch ~ ~ ~ ~ ~ ~~" M I~ N 00 ~ ~D ,_, O~ ~~ M ~O
\p 00 .~ pp N ~ N ~ M N ~' ,-~ ...H ~ ~ 00 01 I~ V7 ~ N .. ,-; O OO M M
N ~ N v~ Ov ~ p w N N N p _~ N N ~~ N N N y0 -~ ~ ~ M .~ N N
~ M O ~ O ~ ~ ~ O N
O O
p <t ~ ~ x '-a "r": ,~ '~' N ~-~ ~l a '~' ~ a a N o 00 m ~ ri ri N rd x x yo
cri M M
~t OWO ~ ~j ~ '~ ~ ~ N O ~.,j ~j '~ .-i ~ ~ ~ ~ ~D M_ 00 ~ 00 ~ ~j -i ~ ,--~
p~ 00 ~D
N N N '~ Ov '~ ~ .. ~ 00 t~ ~ O Oy ~ ~ ~ N N N N N ~ 00 O N N N N
O OWt ~ M N N N ~O ~' ~ N
'~' N O O ~p O ~ ~ O O O O ~ ~ ,~ ,~ ~ ~ ~ O O O ~
V~ V'1 ~' ~-r a x ~ "a x N ~ ,~ a x vy-~ ~..yo 0 0o vi ~t r; c~i ~.i x ....7 .-
7 vyp ri ri ri
t~ 00 ~O N N '~ ~ ~ '~ ,--n p~ M N ""'' "-' .-i ,--n M N V'1 00 O N I~ N 00 N
"~ .-i M o0 l~ V
t~ ~n Ov M p vD O O t~ Oyj ~n N .. . .--~ Ov .-r .~ N Oy0 O~ ,_,.; v0 t~ in ~-
.
~~ N ,~ N in v~ ~ N t~ N ,~
O ~ ~ ~ ~ ~ O O ~ ~ M ~ M M N N ~ ~ M ~ ~-~ ~~ N N
O O O ~ O O O O O ~ f~ ' Q~ ~ ~ ~ ~ ~ O O N
tn V1 ~ N x x x ~ x. ~j .-i x x x x '"~ ,",7 ~ ~ oo v'i d: cn tri N x N ~ WO ~
M M
M ~ ~'~ M M ~ '~ O~ O~ ~ N .~ ,~ pp O~ M H ~-a l~ M ~D ~ ~ ~~ O N V1
~ f~ ~_ M N O W p O O t_~ t~ O v0 N ~ N O ~ ~ t~ OW_ nn N ~j ~t ~D OW_O I_~ 00
f_~
N O ~ N ~ ~ ~ O O
~xxax axxx.°aa~~ axx
~O V1 V: N ~"1 N ~~' ,-i ,~ ~i M '~ ~ N ".~ ~' ,~ ,~ ~: '-: 00 ~O ~; M M N ~ N
rr" ,-; ~O ~ M M
~' ~'~ ~~j oo ~ ,-.i v_0 ~' ~ O ~t cn ~' v1 ~ ~O M v1 ~ .-. ~ N oo vW O
N ~ O O n n ~ ~ ~ N '-' N opo ~ ~ N ~ O N N O N N O ~ N ~ O ~ y0 v0 N vp
O O O O N O O O O O O O O O O ~
M ~ ~O (~ 00
O, O' ~ ~ N
M M N N N
O M t~ N 00
00 I~ N
W v~ ~ N v~
v0 (~ Ov ~ O
O (~ O~ 00 ~O
00 00
..a ~ M V7 00
N
N N N
182
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
N N N ~ ~
O~ O t~ M
N ~ N -1 ~t
ra
N N N ~
I~ N C~ M
M ~' O ~O M
N N N N O
N N N N ~~
O t~ ~~ Ov
l0 M ~ O O~
O N N N
N N N N
00 M ~ Ov O
M .~ M 00 V) ~j
M N ~ N v~
0
N N N N ~ .b
l~ M ~ M O
M OWE N O
N ~ N N M ,~
. I~
N N N N ~ O
~n ~ oo .-: vo ~
~ N N ..
M
N N N N ~
l~ l~ O t~ 00
00 l~ O N V1 .~
N N N N N
~O
N N N N ~
OW O l~ N ~t ,-;
M ~ Ov ~ O~
N M N M N o0
N N N N ~
~ O O N
00 ~O OWE O
O O N ~ N
N N N N
~ M Cv O ~O
N 01 00 O~ ~ '-'
N N N -~ O
N N N N ~
O O~ -~ N
~ I~ ~O ~O O
N ~ N N
183
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
Table 1C summarizes additional polynucleotides encompassed by the invention
(including cDNA clones related to the sequences (Clone ID:), contig sequences
(contig identifier
(Contig ID:) contig nucleotide sequence identifiers (SEQ )D NO:X)), and
genomic sequences
(SEQ ID NO:B). The first column provides a unique clone identifier, "Clone
~:", for a cDNA
S clone related to each contig sequence. The second column provides the
sequence identifier, "SEQ
ID NO:X", for each contig sequence. The third column provides a unique contig
identifier,
"Contig ID:" for each contig sequence. The fourth column, provides a BAC
identifier "BAC >D
NO:A" for the BAC clone referenced in the corresponding row of the table. The
fifth column
provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of
the BAC clone
identified in column four of the corresponding row of the table. The sixth
column, "Exon From-
To", provides the location (i.e., nucleotide position numbers) within the
polynucleotide sequence
of SEQ ID NO:B which delineate certain polynucleotides of the invention that
are also exemplary
members of polynucleotide sequences that encode polypeptides of the invention
(e.g., polypeptides
containing amino acid sequences encoded by the polynucleotide sequences
delineated in column
six, and fragments and variants thereof).
Table 1C
cDNA CloneSEQ ID CONTIG BAC ID: SEQ ID EXON
ID NO:X ID: A NO:B From-To
HAUAI83 30 639009 AC010422 781 1-326
1552-2084
2162-2261
2300-2427
4485-5868
5948-6362
7914-8017
8569-8681
8765-8875
8968-9037
9284-9499
9742-9910
10837-11187
11271-11321
11554-11707
11783-12766
12866-13225
13256-13827
14284-14367
14890-15090
HAUAI83 30 639009 AC018761 782 1-326
1176-1284
1552-2084
2162-2261
2300-2426
4485-5868
5948-6362
8569-8681
184
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
8765-8875
8968-9037
9284-9499
9742-9910
10317-10501
10837-11187
11271-11321
11554-11707
11783-12766
12866-13225
13256-13827
14284-14367
14890-15090
HAUAI83 30 639009 AC010422 783 1-315
2004-2289
2650-2741
3554-3830
HAUAI83 30 639009 AC010422 784 1-202
938-1047
1219-1395
1758-1956
2907-3429
3792-3935
5366-5485
6391-6688
6899-7269
7890-8316
8400-8524
8607-8682
8824-8999
9190-9302
9691-9796
10106-10177
10571-11051
11164-11490
12565-12696
13364-13501
13964-14592
14740-15540
15610-15798
15947-16642
16717-16832
16968-17408
17521-17612
18331-18579
19120-19303
19358-19514
19599-19702
20003-20245
HAUAI83 30 639009 AC018761 785 1-202
938-1047
1219-1395
1758-1956
2907-3429
3792-3935
185
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
5366-5485
6391-6688
6899-7269
7591-7711
7890-8316
8400-8524
8607-8682
8749-9073
9190-9302
9691-9796
HAUAI83 30 639009 AC018761 786 1-82
128-293
1178-1447
1986-2278
2457-2711
3543-3844
HBINS58 35 1352386 AL096774 787 1-1023
2010-2239
2581-2962
3153-3223
3324-3493
3973-4126
HBINS58 35 1352386 AL096774 788 1-341
HB1NS58 35 1352386 AL096774 789 1-142
HCE3G69 40 728432 AC068946 790 1-108
1186-1324
1746-1835
2138-2284
2448-2545
2718-2861
3091-5889
HCE3G69 40 728432 AC068946 791 1-191
HCE3G69 40 728432 AC068946 792 1-686
HCEFB80 42 1143407 AL022327 793 1-2271
3506-3658
4643-4810
9039-9164
9382-9509
10587-10720
11135-11195
11265-11716
14644-15466
17451-17526
18012-18114
20530-20632
20957-21009
23696-23785
25338-25575
25969-26166
HCNDR47 47 1016919 AL122003 794 1-236
531-696
787-817
863-4508
5158-5744
186
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
6949-7029
HCNDR47 47 1016919 AL122003 795 1-888
1304-2003
2830-3284
3719571
4618-5268
6131-6557
8947-9033
9058-9726
14176-14480
18456-18915
18960-19871
22365-22454
23082-23248
28058-28215
HDPGTO1 61 771583 AC020978 796 1-180
2776-2899
3916-4077
4296335
4436-4632
4895-5181
8153-8246
9547-9666
9907-10007
10370-10618
10788-11046
11926-13423
13465-13494
13764-15689
HDPGTO1 61 771583 AC020978 797 1-384
HDPSB 18 67 1043263 AL355512 798 1-2572
3049-3871
HDPSB 18 67 1043263 AC006176 799 1-2571
3048-3872
HDPSB 18 67 1043263 AL355512 800 1-280
HDPXY01 74 879048 AL354000 801 1-1319
4848-4975
5229-5600
6561-6654
HDPXY01 74 879048 AL035362 802 1-1316
4844-4971
5225-5596
6557-6650
HDPXY01 74 879048 AL354000 803 1-460
HDPXY01 74 879048 AL354000 804 1-400
HDPXY01 74 879048 AL035362 805 1-400
HDPXY01 74 879048 AL035362 806 1-460
HFIIN69 93 1011487 AC027797 807 1-1438
HFIIN69 93 1011487 AC027797 808 1-329
HHBCS39 104 1003028 AL390960 809 1-2979
HHBCS39 104 1003028 AL358992 810 1-2983
HHBCS39 104 1003028 AL358992 811 1-207
HHGCG53 110 340818 AC024037 812 1-518
HHGCM76 111 ~ 662329 ~ AC003665~ 813 1-70
187
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
304-609
900-1090
1240-1835
2272-2490
2581-3598
HHGCM76 111 662329 AC003665 814 1-580
851-995
1224-1296
1314-1663
1930-1975
2724-2905
2968-3098
3283-3328
5121-5230
5331-5689
HJACG30 116 895505 AC018512 815 1-776
HJACG30 116 895505 AC022305 816 1-878
HJACG30 116 895505 AC002518 817 1-150
HLTIP94 137 1087335 AC007431 818 1-1299
HLTIP94 137 1087335 AC007431 819 1-330
HMSDL37 154 973996 AC012086 820 1-3328
HMSDL37 154 973996 AC018811 821 1-3051
HMSDL37 154 973996 AC018494 822 1-3029
HMSDL37 154 973996 AC012086 823 1-224
HMSDL37 154 973996 AC012086 824 1-468
HMSDL37 154 973996 AC018811 825 1-222
HMSDL37 154 973996 AC018811 826 1-468
HMSDL37 154 973996 AC018494 827 1-224
HMSDL37 154 973996 AC018494 828 1-1854
HNGOI12 172 1041375 AC003675 829 1-2128
HNGOI12 172 1041375 AC001228 830 1-2129
HNGOI12 172 1041375 AC013791 831 1-2132
HIVHFM14 174 664507 AC020552 832 1-290
HINI~M14 174 664507 AC020552 833 1-96
HNTSY18 183 1041383 AC004877 834 1-175
34274
573-1883
2536-2632
2831-2894
2999-3231
5032-5164
6664-6820
7288-7881
HNTSY18 183 1041383 AC004877 835 1-42
1197-1333
1575-1698
1936-1984
2246-2304
HOHBY44 189 873264 AC074201 836 1-5280
5527-5989
7392-7421
HOHBY44 189 873264 AC074201 837 1-298
HPJBK12 197 1011467 AC022033 838 1-2649
HPJBK12 197 1011467 AC013541 839 1-2649
188
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
HPJBK12 197 1011467 AC022033 840 1-190
HPJBK12 197 1011467 AC013541 841 1-190
HPJCL22 198 1146674 AC037447 842 1-102
373-826
995-1315
1450-1567
2189-2515
2599-2778
3138-4132
4537-4681
4864-4998
5144-5324
5394-6211
6816-6941
7472-7647
7791-8885
9056-9368
9506-9733
9799-10100
10277-10988
11213-11751
11783-11838
11875-12474
12592-13077
HPJCL22 198 1146674 AC022400 843 1-102
373-826
995-1315
1450-1567
2189-2515
2599-2778
3138-4132
4537-4681
4864-4998
5144-5324
5394-6211
6816-6941
7472-7647
7791-8885
9056-9368
9506-9733
9799-10100
10277-10988
11213-11751
11783-11837
11874-12473
12591-13076
HPJCL22 198 1146674 AC037447 844 1-207
HPJCL22 198 1146674 AC037447 845 1-2124
HPJCL22 198 1146674 AC022400 846 1-207
HPJCL22 198 1146674 AC022400 847 1-2124
2470-2567
2865-2971
HPRAL78 200 1352342 AC007783 848 1-2334
2508-3084
189
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
3578-3890
4198-4294
4376-4623
4712-5349
5369-6088
6527-7107
7298-7392
7730-7846
9147-9476
10487-10575
10791-11298
11485-11601
11783-13009
13207-13501
13540-13772
14439-14800
14923-14983
15133-15355
15485-15653
16750-16805
16894-17078
17162-17219
18003-18089
21085-21146
21358-21501
HPRAL78 200 1352342 AC007783 849 1-308
HPRAL78 200 1352342 AC007783 850 1-1024
HRGBL78 204 910133 AL359541 851 1-254
2777-3307
3670-3823
4113-4385
4844-5381
5995-7365
HSAWD74 207 460527 AC004951 852 1-1651
1740-2593
HSAWD74 207 460527 AC004951 853 1-149
HSAWD74 207 460527 AC004951 854 1-5057
5082-8353
8404-8996
HTPCS72 240 854941 AL008639 855 1-106
1457-1595
1666-2484
2910-3006
3705-4147
4768-5141
5304-5536
5746-5
874
7114-7241
7468-7711
7963-8746
9438-12408
12884-14976
HTPCS72 240 854941 AL008639 856 1-720
HTPIH83 241 919916 AL158821 ~ 857 1-1862
190
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
1880 3126
Table 1D: The polynucleotides or polypeptides, or agonists or antagonists of
the
present invention can be used in assays to test for one or more biological
activities. If these
polynucleotides and polypeptides do exhibit activity in a particular assay, it
is likely that these
molecules may be involved in the diseases associated with the biological
activity. Thus, the
polynucleotides or polypeptides, or agonists or antagonists could be used to
treat the associated
disease.
The present invention encompasses methods of detecting, preventing,
diagnosing,
prognosticating, treating, and/or ameliorating a disease or disorder. In
preferred embodiments, the
present invention encompasses a method of treating diabetes mellitus
comprising administering to
a patient in which such detection, treatment, prevention, and/or amelioration
is desired a protein,
nucleic acid, or antibody of the invention (or fragment or variant thereof) in
an amount effective to
detect, prevent, diagnose, prognosticate, treat, and/or ameliorate diabetes
mellitus.
In another embodiment, the present invention also encompasses methods of
detecting,
preventing, diagnosing, prognosticating, treating, and/or ameliorating
diabetes mellitus;
comprising administering to a patient combinations of the proteins, nucleic
acids, or antibodies of
the invention (or fragments or variants thereof), sharing similar indications
as shown in the
corresponding rows in Column 3 of Table 1D.
Table 1D provides information related to biological activities for
polynucleotides and
polypeptides of the invention (including antibodies, agonists, and/or
antagonists thereof). Table
1D also provides information related to assays which may be used to test
polynucleotides and
polypeptides of the invention (including antibodies, agonists, and/or
antagonists thereof) for the
corresponding biological activities. The first column ("Gene No.") provides
the gene number in
the application for each clone identifier. The second column ("cDNA Clone m:")
provides the
unique clone identifier for each clone as previously described and indicated
in Table 1A through
Table 1D. The third column ("AA SEQ ID NO:Y") indicates the Sequence Listing
SEQ >Z7
Number for polypeptide sequences encoded by the corresponding cDNA clones
(also as indicated
in Tables 1A, Table 1B, and Table 2). The fourth column ("Biological
Activity") indicates a
biological activity corresponding to the indicated polypeptides (or
polynucleotides encoding said
polypeptides). The fifth column ("Exemplary Activity Assay") further describes
the corresponding
biological activity and also provides information pertaining to the various
types of assays which
may be performed to test, demonstrate, or quantify the corresponding
biological activity.
Table 1D describes the use of, inter alia, FMAT technology for testing or
demonstrating various biological activities. Fluorometric microvolume assay
technology (FMAT)
191
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
is a fluorescence-based system which provides a means to perform
nonradioactive cell- and bead-
based assays to detect activation of cell signal transduction pathways. This
technology was
designed specifically for ligand binding and immunological assays. Using this
technology,
fluorescent cells or beads at the bottom of the well are detected as localized
areas of concentrated
fluorescence using a data processing system. Unbound flurophore comprising the
background
signal is ignored, allowing for a wide variety of homogeneous assays. FMAT
technology may be
used for peptide ligand binding assays, immunofluorescence, apoptosis,
cytotoxicity, and bead-
based immunocapture assays. See, Miraglia S et. al., "Homogeneous cell and
bead based assays
for highthroughput screening using flourometric microvolume assay technology,"
Journal of
Biomolecular Screening; 4:193-204 (1999). In particular, FMAT technology may
be used to test,
confirm, and/or identify the ability of polypeptides (including polypeptide
fragments and variants)
to activate signal transduction pathways. For example, FMAT technology may be
used to test,
confirm, and/or identify the ability of polypeptides to upregulate production
of immunomodulatory
proteins (such as, for example, interleukins, GM-CSF, Rantes, and Tumor
Necrosis factors, as well
as other cellular regulators (e.g. insulin)).
Table 1D also describes the use of kinase assays for testing, demonstrating,
or
quantifying biological activity. In this regard, the phosphorylation and de-
phosphorylation of
specific amino acid residues (e.g. Tyrosine, Serine, Threonine) on cell-signal
transduction proteins
provides a fast, reversible means for activation and de-activation of cellular
signal transduction
pathways. Moreover, cell signal transduction via phosphorylation/de-
phosphorylation is crucial to
the regulation of a wide variety of cellular processes (e.g. proliferation,
differentiation, migration,
apoptosis, etc.). Accordingly, kinase assays provide a powerful tool useful
for testing, confirming,
and/or identifying polypeptides (including polypeptide fragments and variants)
that mediate cell
signal transduction events via protein phosphorylation. See e.g., Forrer, P.,
Tamaskovic R., and
Jaussi, R. "Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and
p38 Kinase
Activities" Biol. Chem. 379(8-9): 1101-1110 (1998).
192
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ 'v~ c~ '~ .~ ,~ c~ U ~ U O '~"' ~~ V .~ U ~ ~ O O
° ~ ~ ~ y v ~ ~ j,.~ .~ ~ N ~C O '~~, .~ N ,"'~" 'G ~N N O
~~>,.C ~Uc~i;-G~v O~Ny.>NO'.'
o°n~ ~ ~ "~° ~ b
0
.y ~ °U ~ ._~ .~ ~ ~ .s: ~ ~ ~ by ~ ..O ~ Or ~
O c~ >> ~ ~ U C .r ,1 U U ~ ~ O .C O yy .~ .~ y.., ..-, O~ O
° 'b ~ ~'~ ~ ~ ~ 3 o ar ~ ~ '~ ~ ° ~ o 'U ~
O cd a.~ N U ,~ a O~ U .~'~r iC O U O ° ~ N ~ ° ,~ U >> cd
°o °~ ~ ~ j ~ o ~ M ~ 'b W v ' ~ -d ,~'r' o
b ~ ~ ~ ~ ~ N w ~ -d ~"~ ~ , .f~' ~' fy'...'' c,,~,~C y-.. > b s..~ ~
>,~~.p.,~p~~~N~'~c'-'dV7'~'~ 7N,~UO~p~~.~,.a
~ °' v: o v i ~ 'b '~ ~ ~ ° 3 ~ ~ ~ U c
w: ~ ~ ~ awo ~ ~; ~ c ~., ~ ~ ~a~ o ~ N ~° w W ~ o a~~,
b :~ y,U4 ' ;.~ O ~ ~O M ~ O N vwn ~ ,~ p" O N ,~ ° p ~ U cC
NO"O~U~-"~ OOONa'b-0~ .t"r
'''s..' >>0,~~~ .>~nc~ Ns.N,~ "fir
N ~UN~O~VJ~~~,~5.._O ~b~>,~v~~ ~Uc~d
~ v~ ~ p O .'n N C~4 ~ .~ p '~ 'b U
~~ 0 .C c~ v .~ ~ ~ ~D ~ ~ ~ 4, >, > 'v~ ~ ~ ~ O~O
° ~ ~ >~ O ~' l\ Y O U ~ ~ >> U ~ G CL ~ .~ V ~ ~ N ~
GY~t~.xp N ~i U~'Uw jOypO.~~p,0~~~+, .~.
r: O U a cC O N o_ ',~,' M ~~' ~p ,C ~ ~~ ~ N >, N > 3 ~ ~" "' ~ ° 'b
U O o ...~'.~ _CC 'b 'a ~ U ~ ~ x ~ N -y.' ~-' ~ ~ >, U ~ "C o
3 N ° O >, ~, s~ O ~ '.~ N _~ ~ O U y ~~ > N ~ U U
tU-~Cw~°O'~~~,, ~~W n Np~o~~,~'NG.~~~,~UC~
~a~ o .~ ~~ ~~ ~ "' ~ ~ p; U s o ~ ~ ~ ~ o ~ a.. ~~ .c w ~ Wv
p -d , .~-.~. .'~~" "O Y U ,~ ~ ~ O a~..~ ~ O s '~,' .~.. cad ~N ,~ '~ ~ '~ O
°U a!
Q~~~~°~~~0~'bD.'~~'vl°,b ~°~"~°OUU'G°
C~ .tUr~.N~vi~.yG~M.y..~.~.OOU~SW~+.~ON.:'O°7,~t=00.5"..
Vi U ~ v~ ~d ~ l~ O U ~ U ~ , O ~ ~ c~ r/p U
~L,~~yQUUM~U ~~~p"~OOt".,[-~
>> 'y ~ ~ >~ . G~ 00 4-a 4~ ~ V~ 'b ..U. . O _~1 y G) O ~Y ,~
S"r~~MOy.NON~' dQNL;UO'ViyU ,~a..~
V ~~~ft1'U.~4"i~ ~>>~~~~'rf~/l4""a~ri.r~O~Uv_~'l~i.Nr
CC ° .t"'..'y~-~G°bm ,ro,',~'~c~~G~~V o~p
'r ~"' ~ U c~ GL 'b " s..i ~ ~ U l." ~, 4.,
>wn~i.~.~U~G~,~~0'~~...U. ~C~>'~c~N~"'a~..' .~~.~l~N
y ~ ' U .y U O >, c~ -d a.: O ~ .~ ~ ~ cd w tin O .b ~"", ~ ~ ~ ' O N . ~
W d ° ,~ ~ >, a~ o ~ a °' ~ a a~ ~ ~ ~ d ~ ~ w° ~ W
a, y x ° ~
a~ ~ c~ ~ .D p. c~ W V1 . CL U U s~
° ~ o-d a.~
0
O w U O ~ O cad
CC .,~ v~ O '~ y cJ
V ~ _cd o ~ ~ ~~ y
~O ~~ O ~~ .N LU, U O .~ '~'~. ~ U
O ~ .~ ~ U O ~ ~ ~~N ~O Q" ~
C~.~ ~ O.~ ~~> O.,O~
M M
z
~"r M
O 00
~ U ~W
A x x
v
a>
c~ z ~ N
193
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
0
bD ° ~ ~ 4, 'O M m, M 'vW.~. Ll. c~ ~. TJ M ~ ~ (-i
N ~ ~ .r O '~ ~ '~ U ~ ~ M V cNC '~,.;' V cd ~ '~ ~ p~
~" Clm: y "C . p" ~ .3 ~ ~ i'Vi ~ ~ p~ °~ ~ w .S-'.n ~ ~ ~ ~ ,~ ~ ~ i'
~"
y, ~ V ~ ~ C3. ~ ~ ~D I~ 'b ° c~ p ~ ~ U ,.~"', ~ ° O D ~ N
voy~~ 3'.'_~,a~on °-due.~°o~°~'~~b 3'-' ~'o .~°o
° o pa o v i W s+.: ~ ~ d .~ a'' Cj ~ ~ i ° o ~ ~ w ~ o d
d .~ W ~ fz, ~ >, b ~ ~_ ~ U >, U .~ ~ o ~ 'Y U W :n ~ ~
-°~~~ a~>U~'~~a.a~~~'-''VOa~E-'oa"o a~7~~~.~'-''U~
v 3 .~ a; ,o p", b o ,~ o ° v~ W ~~ ~ ao ~ '~ 3 .c ~ o ~ o o v~ ~ -c W
V V V V....U ~ø,Vy.~cl~~Ua,'r"'.'~~'~ i-.UNUV~~a3 UU
,s," N ,~-' w ~ w ~,~ 's'~~ C~~. .~ ~~ vp d ~ '" ti4 O O ~, ~' w 'b ~ .~ -~ ~
~, _~~
.~i.V.,~I N~u.~N~,:-pO~bDVirN~~~V VU U°~,~Ob-0Va:..c~
N ~ b U '~ ~ O U ~r V ~ .r ~ -d U O ~d U 'z V V G7
V U U .~ N ~ ~ ~ ,~ ~ .b ~ U~ V ~ ~ ~ ".., ~ N y O .b .~ ~ U ~. N
U ~, V Or d au ~ V U ~ O _N t-n ctS i V a d y U ~ O vW .r ,L",
~.N, 'i' p., U ~ '..~~ ~ ~ .~ c~'C ~ x '~-'' ~ p x sV.W' p" V ~,~, m ~ ~ ~" 3
4~
p~NU O,~~vVNUNV''' ;.b s.. ~Nf3' O,~cVnVN ''' :.'~p,y,U,O
Cl. O ~ cad a~ w ~ .fl O t-~ cd ~ >, ,~ >, . .~S", c~ O~ O c~ .~ ~ p ~ c~ N
:.V.' ~ U V y b ~ c~ C ~D ~ ~ .b ~ ~ ~0 tV, O V y c~ ~ .t", bD ~ G~
p p., ~ b ~ .~ .~.~ V V O N ' ~ N ~'..~ pr . "f~' .b ~ b ~
'~'~~ o ~ ~ ~~0 3 o-d ~ ~ ~C~1 00 ~ >.~ ~ ~ ~~ ~ 0-3 ~ ~~ o ~
~ w p ~' bay ~ ~ ~ .~ N ° ~ .~ ~ '~ ~ .~ ~ ~ ~ N ~
x V c~ ~ a~ '~ w x ~ U
W~~N'b .f'a'y~ v~._° ~O~~~~~c~~p'3S:"Nj
'bNC~p ~G7..~.~~'b'b~''V'b~0l~.~y~U~~~ ~N.'~~'~N'C;~~ .~ai
Y V C ~ ° ~ V ~ p U ii P. ~ ~ ~ N ~ Q, N O m O ~ N ~ ~ p, ~
~ c~ O ~ cd ,~ ' ~ ~ ~ m .f., V ~., '~ i~. ,~ m :yn .~. C '~ c~ ,.~..~ ~ C V
>, ''i Q
a~V~A.~ Owa~-C.~~°A''c~ooMy~~,~~,~0 Ow,N
.fai.'O~Ntn~Cl,,~~~Owr ~ O~~~~~Opp.,_>wn~p
N Gbp °~CNNmN~~O~MOynrVn'~" .~.~:b~~'b~N~O~r;~j
by c~ ''' V ~. b.0 ~ ~J V t-~ f~. N ,s' c~ ~~ ..~ O N ,~ b1D a,, C~ ~y ~ .L".
N
~, ~ '~'' .~.~, . ~'' ~ ..Nr ~+. V ~ ,,,~, A"i w .b ~ p ~ a) O .~". V p . Q.
4=r . 'n w w .yp ~n .V, c~~'
b V 'b ~ ° ~ O ~. ° ~ M -C ~ ~ w .C V U 'O ~ O O ~ M ~
,.,V~b c~.~ecip.'w ~°~w.~C~',~~0 °°°pd.~~
°N
~ N U 7 ~ N ~ p O ,.~ ~ ° '~' ~ ~ Wn U > ~ N ~
Q ~ U .~ ~ ay ~ m U ~~; ~ ~ c~ ~' T ~ m ',=, ~ .-,
~. C/~ ~ '~ w ~ c~ N >, O ~ V V ~", p U ~C pn GL ~, 'y w c~ N V U ~
O°pp~~~V ~~Y.~~O~~~~'G~°Cs'.'~y'~c~f.0~'~
U~ Q~~cn~~Q~~~GN ~~~~_'~"O.~pO~ON~p't''.'lV
N~i NQ~7i..~Gc~*,~'O~ N.'S"~'Wc~yV~d ~ j'~>i.~l:ciS N..~t'.'W
C ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ N yn V :~ ~ ~ M b cad ~ ~ c~ ~ ~",' N ~ cn ~ :u C""
Nv'~d ~"~c~ .O~v'4-.bUG~'N ,_~~~a)~~d ~'nwb ~b
(n '~" ~ O ,~., a ~ '~~' ~n p ø, O ° ,L" ~ ~ p ~ .~ N O '.~".~ ~ ~ ~ Qr
O ° ,S". V
i ~ ,~ ~ .~ ~ CO
'bø''~' mc~b~~i ~C i ~'' ~~c~~~,~c~v~cdbN~ i 'f ~~'b
a~ o >, O v.., ~-1 f~ ~ ,.~. an ~ ~ ~ ,~ ~ .a ~.. >, O ,.. c~ 0.~ ° 00
00 °~
7 'b ~ .O O M ~ a, a, ~ ~ 00 U ~, i, M O N N ~ O y ~ ~ ~ pp p~
.~ .~ ~ c~ .t". ~ ~ ~~ ~ H p, ~ d ,'''f.' ~ Ov O~ ~ O ~ ~ ~ N ~ ~ ~ O ~ ~ ~ O~
O~ V
au ~ ~ fr W d cCi c~ w M U U w U cct wr ~ ~ it M 4;, ~ d c~ cC w w U cW r wr ~
O ~~ y.~" O ~~ ~'
p .° C1. v, p ~O ~ ~ i
y U N .v V . ~ U E'i
.~ ~P.~ ,s' ~ ~ ~ ~, 'o W .C ~ ~ C cad
'~ C, O t3, ~ ~ f~ .~ ~ ~ O V ~ ,~ n
i ~ U 'b ° ~ .~ i ~'
.J ., ~. a~ '~ ~t d .~ .~ w a~ . '. v
a\ a\
M M
U U
M M
194
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
c
°n o~ .b~~~_~ .~~ ~ooWy~~>,~C)c~~
~O ~~s~~UN~ bU~_ccSN ~Wn~~p~>,.av
U~OO'b~y .r.~:r'-iU~'pp~~ O'bbJ]U v~.~p~~yU"~
C' ~ ~ ~ b ~ ~ ~ c~ cat .b ~. N N w ~ s"r ~'
W n y :b ° ~ U ;3 ,~ ~ O ° M v~ ~ y~ D ~ N '~ ~", ~ ''~"' O
'y ~ O ~ ~.~.
~ ~, N
~ s ~ ~ ° ,~ ~ O ° ~ ~ O .'~ ~ ~ ~ i ~ ~ ~ ~ ~ ~' Gin in b ~ ~U
~ ~
y0
N ~an ~ ~ ~ .o ~ ~ ~ ~~ a, ~ op ~ > ~ ~o ~ ~ ~ .~ ~ ~ ~ °
.° ~ yo 3 ,~
~b ~. ~ N ...~C7~ a~
~ VJ b ~ a.U.. N ~ y ~3".n F'~-i V .y.~r ~ t-..' ~' a y " ;~ '~" O .~
U Q~ w ~ y.., i'. c~ f~'~' p O~~ U ~a~ .S', ~ ~ O ~ ~ ~.r~.' ~ p ~.C. U ~~'O
o0 N U' V G
O ~ O Q' :b ~,= Q' H m C~ Er ~ ~',' ~, ~ " y :~ V ~ Ow .~.' ~ Oy
cnV ,~~~~.'Oy~C/~OOU~'UN ,~~~'~~yN~_~
c~,~SU,'~U,' .S_''~~~bdrCO.~~~';~" 'r"'r.~.' ~C~~[1a~f-'~NyO°U
~" ,.-Vi. fir"' 'Wn ., y .... a-U. ,~ ° O '.' ~» ~' ' .~"" 3 U ~, ~.r W
° '~ U Vi U
.~ ~ , ~ ~' U " ~ ~~ ~ ~ U O ~aj N ,b O O '-~ ~ ~ . by O~ 4~" ~ ~ of
U.~_~~y~G.pV_'.'b0~4"'~,~~NaSNU ~°N~p.,~~~I~'~~..U.'N
3 3 ~'~ ~ ~ o ~ °oo.~ ~-o 0
NO~'CU~~~U~~~ Uyc~ !+.~00,~'N~~~c~
~U., y4"'.,, ~ .C ~ O 3 y ~~ ~.. c~ W .r. .~ y 3 O~1D x p p ,~.., ~ ~ G1. fan
O ~ N
N Gn GO ' ~i ~ .(".~ b-0 " c~ ~ U ~'
y G7 ~ 4-~ it f~' O ~ cC at ~ O c~
N GO ~ ~~ N ~ ° 'b 4~ O ~ t~ y ~.' ~ 'b ~ yf.'.' ~ ° ~, .O-
~ b c~ ~
-d .f.~ y,~~ ' ~r v~ p O '.' C~ ~.v , 0 U U O O N ~ N O~ tn "T'" C 'Ly -f. .~
" a~
N . ~ ~ .f-W.n " .--1 v~
OQ~c~Nb y~°~'~UVx~ WTJ~~, Y~~U O
~y
_~ ~ U O Q N ° tan C ~ .~ ~ j ~ ~ V .b ~~ ~ .U, ~ V ~ .b N O U p ~ 00
m c~ ,~ , s~ b4 ~ ~ ~~.., ,~ ~ ~ .~ ,.. O ~ U ~ ~~ a! p., ~' ~ G '..~.n ~ 0 W
O O N
O ~n ~ ~ O 7, yn N N N ~ a v~ ~ 3 > ,~, ~' ~ ...y. ~ O O "p ~ ~ cC
~ G Lln ~ ~ cV b ~ . ~ ,'~., ~ ,x., , .f""'. c~ ~ N V '+.
~O ~ ~ ~~O C~ N ~ G~'O ~p~lp ~MNx
U '~ c~ ~' cn v~ ~,., ° v_' N ~ .O pn tn C~ i.U.~ ~ cci ~ ~
,L" U ~ ~ ~~" V l.~.i ~ Wp ~ b ~ U U ~ ~3 S'.' ~~ øn ~ bD N ~' Q~ it ~O y ~1 ~
° U
'.'~~~c~ ~~ ._. ~r-.Nlr,~'~4"'3au~U~y..,yNy
~ ~ "d ~ ~ ~ .'~.U.~ V ~ w cti 0 p ~ ° N ~ v~ ~ .~.," N N
U U G7 "T~ N ~ N c~ c~ Q' ~ l~ ~ ° ~~ ~ V ~ O. 'C V '_'~ ~ fn
.T~.' b L~", s"' t-.,' ~' y ~"'~, -.t"" iC v~ '~' ~' w O~ S.-n ..L'i ~ .5.."
,f'., ;~ U ,f, a, ~ ~r ~p ~ W ..y.
;.d E-~ y . N yn y O W ,~ v~ ~ c~ N ~ ~ O 3 ~ ~ ~' O N O O ~ ~; M U
7.. ~ U ~ C 3 ~ . U c~ ~ ,_, U ca.., w . G x ~ .~ O U '~ .f.,".
Qb~dy~'''bD~NC'nUOUO~n~y~~i-'~~~N~_i ~U.~~O~b~N
.b ~ Gn O U ~ fsn vi ~ t=~', ~~ N f~ ,.~, ~ p., ~ ~b ,~,U.. _'_' W -~ ~ .~~' ~
~ O~'~w 7 ,,~"'., ~ ~ ,~ .f»
N .~n..~UN~..~NO. U~ ~Nt~ ~'G,~O. O~r O.~C/~OO~Ns.U.~
~.~' y V ~ vi .'~ U ~ p 'b U y N 7 c~ N
D ~ ~ ~ ,~ T7 'a.~~ w O .:~ U '_~ r-a ~ b ~ ~ ~ p~~p'b '~ .~ ~ >, ~ ,~ .G O ~
. ~ .b ~ 7G vi 4-, 7, ~'' O ~ U > ~ ~ ~ N cad ~ ~ ~p LU.~ t,., p ~.~.. ~ ~ ~ v-
. ~ V U
c~ N ~ W _O ~.n .O 7, ° ~ ~ ° U ~~ O ~ tn D 'b G, ~ '~ °
v ~ N .~ O O .b " N b
!7D ?a ~ C~ ~ .f. .~ .f.' ,_r .~ U p ..-1 x N v~ U y., t~.-, '>' y p ~J .b U
G' ~' ~ y
'b ~ U V y ~ ?y ~ .~ ~ y~', ~ 'L7 ~ ~ ~ ."' 4~ ,~ °~ f.N.', ~ ~. ~ ~a='
;.~ _W ~D ~ i.~"
~N ~N~~~~yW ~'~' c~C"y'O"-T'~.~ N~U,.~"'.~ONN°~ .f,"0
a '° ~ ~ ~ ~ ~ ~o ~ y o ~ w ~ o o y ~ .a a~ ~ ~o ~ .~ 3 ~ °~~' o
~ ~ c.
U O ~ . . t~. 'O s~ w. O C. O. w 'b O Cdr ~ N ~ U U ~ ~. O ~ y ~ ~ C1 cd cd i--
i'-' U -~
W W
O O t-..'
O O ~~ ' N
GL y
O
o vo .~ .~ ~ ~ ~a.
G: I~ R! b o W
r' r'
o\ a\
M M
U U
M M
195
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
w .a ~ Wo ~ b b
N O ,~ ~n O ~ ~ ~ :j ~ -d M ~
cj y~~MOV~,~_yNUU~_~~~N°O~N~c~~GQ~O ''' ~_>>U
Wn~~~._~ ~CDi~WU~O~~~N'i'~~'''y0~~>,~Ca, ~ppOpO
VUJUCC'~, .S~'.'U-~-~OU~U y~'C '~",W"d~OO~~,t~~CC .r.~r~CU
w -~~' ~ '~ y 3 ~ a> ~ ~. w a> ~ ~ w
_~~w,y~°°~~>Wx~~a'~c~~°c'°~,>,~~rdr~~~~-d~ o~~oc
~ i: ~ ~ >, U O ~-~ N .~~.~' .C'~. ~ ~ ~ ~ U y N U ~, C,' U 'b b
N N ~ 'S~'" w b N c0 ~ a, U N > . .y U v -U N ~ O ~ ~_=, ° i.,
iC U a''0 ° j~ ~C ,~ ~ Gp ~ ~ ~c~ ~ U 3 ~'r~' O~ O O D C/7 ~' w ~ N p
~C y O C:
W ~ U ~ y tin ~ ~ ~L cd ~ N ,~ w G N W n ~"' p .-1 c~ O Q ~ ~4 3 >
° .O '~
Fr xr V~
U ~ ~ ~ ~ a ..O ~ U U y G ~ ~ y U ° y U c~ y TJ ccS ~ U ~ 'L1 ~ C
~ ~C7U~.~ ~e.b.n a o c~.'b ~~d i ~ o ~
oho ~~p o ~ v ~ W ~ > ~ ~ ~ ~ ~ .~ G ~ ~ O
M pp Ov ~ ~ .~ ~ ~ O ~ U ~b N U .b U Z ~ U -~y ~'
~.~". o p b ~ ... ~ M ~ ~ > .~ ai a~ ~ ~ >, ~ ~ ° i~ ~ ~ N a~ ~ ~ p a~
O ~ W ~ ~ O ~ ~ W cti ~.N, ~ ~ (3. ~ c~ ~ ~ l~ ~ N U U N
_N~~~,Dp~~O.~~O~~~~c~~~~ ~O..byn
N w ~ ~ ~C O_ ~ ~ .~ ~ ~ ~ ~ ~ ~ .~ ~ ~0 U N v ~ ~ ~ N O °
.p"~rb>,~O°yG0'~C'°NpCN~N~ON>C~p~~,~'~~ r'~p
>~ U ~ a5 ~ GL p c~ ~ ~." ~ tn ~ c~ m > ~ ;-. y '~,.,~ .~ ~ V7 y ~ O .... N
c~ y .b >m ~ ~" N ~ ~" ,~'r y O~ N ~ ~ A,
~ y b :~ b b ~ ~ v> >, ~ ~ > ~ U ~ ~ °' rr b
'~"., b ~»' T..' N cd .. ,L" ~ ,:' N O U y U x ~ ~ V ~ ~ y' ~' ',,,
° ~d ~p ~ ~ ~ -O U M V7 O U ~ 'O O ~ ,~ ~ N ~ ° ~ %~ M ~ ~ U V
.~ ~ U d O
y U O U ~ ~ ~ ~ N O U C~ ~~ f'U" ty.'1' ~ ~ ~ ~ .,Ur ~ ~ N U y >
f..' . U ~ c~ ~ S'.. y au ~ N >> ~ y N ~ ~"'"GO U
y ~ o c~ .n ~ ~ > ,~ o y o ~ ~ '° o ~ o ~ o o .,
3 0 0 o:bc~~~ ~ >,~ ~ u~a,°~' ~U~ a.~N~ ~ ~d ~ ~Q.o ~,s~
NNUO~'~s...~ .~~~...U.~;~~'~,~+_;.~G~w'CM ~~O~U t=n.yd'~O ,~"
~ N ~ U ~,~, O U ~ tn ~ ~.. ~ U ~ > N 'O O .yC O ~ ~ .~ E-~ ~ N p O _N
S»' '~ L»" ~ .f., ~ b " N ~~" (, ° O ''' ~' ~ ~.' ° ~ -C ~ U ~ ~
U -C d F'.. 4~ bD au N
O ,~
.O ~ C7 y ~ 'G O U ~ >> ~p ~' _>> C.' ~ .> ~ N N N U O x '_' ~ G ~ v~
O o0 U ~ ~ U .O ~ ~ ~ ~ c~ w c~ O ~ ~ p p ~' O w C c~
M y ~~N °U~..~UO .~.", ~'.'W,t~~ O~t.,
~ ~n ~' ~ G 'y ° ~.. ., a; y, °U y; ~ .' .f", >, ° c~ v~
"'b'yn~UCC>p0~~N~~U~~ O~~~C~N~~>> ~_ °N,,'~,''f"'''
.O b y ~ '~ p~ O N 'n O ~ O ~ O '~ ~O '~" C W b ~ ~ N N ~ ~ '~ '~ O '~
0~.~.~~p O~v''.C-G_O.U°~~'a~p'~a~~C~'_a~.~'-'~U~ppj,d
m c~ U O ~ ,Wn v~ 'O cd
~~.s.~~~,.y>',Ov_ml7~,i:yU~d'ON~bC.'UwO~~~O~~QNOb~_N
p c~ ° O ° > N b vj fir? ~ 0 ~ ~ ~ '~ ~ ~ ~ Q ~ ~ ~ ~ p .», N y
~ ~ ~ O
'U-'~'"C~NOy~,~b-0~N ~'O~~u.'Q't~'nN OUC~c~~O~nr~~aJ
c~ O '~-~ O U '.:, >, d' N 3 G >, ,W,..., ~ ~ O y~ . ~ ~ O ~ >, ~ ,~ '*'
° °.» _~ 'b
yc0>~s..~~c~~.r,y"'pyUf..' ~ ~_~N~ ooM'~~ ~N~>,~~'G
c~ ~ Y a' ~ N ~ O U U c~ .C W n 'b " ~ ~ ~. c~ Q\ ~' t.. ~ p i N ~ a' ~ O
U .D O ~ ~~ c~ U s.. G G m G ,~ d' N ~ C
C. ~ r~ c~ cd ~ ,.'~ G. y N ~ a) c~ y 3 ~s d ~ ~ ~ U ~ ~ .. N ..c a. ~ t~ d ~
~ W
O ~.» .~ O O N~ ~w" O
c o .Y (~ ~ v E~ o
du >, a. ° ~y a~ ~ a, ° '.~
V'O'~~y ~V~OC1~ ~.~ ~VCOA.
.~..
d W U ~ 0.~ d ~ '~ ~ a~ . ~ ~ U d ~ '~ ~ a~
a\ a' a\
M M M
-r
A
W ~ W
U U U
M M M
196
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
.c Yo . °~' a? .
U 'O cd U ~' M ,~ ~ ,~ N U ~ >>
da»~~~ ~d,p~~p~G~N vov~. ~~p>,.~ 'n '~ .~v
00 v~ U p 'b ~ ,O ~ C ~ .-~ ~ c~ N ~ O ~ ~ ~ ~ w .~, ~ 'C ~ ~ c~ cd
~ ~~ ~ .a
YO~~ ~~iG~,y.'~.~ M~.~'~C~".N~ ~~".,~~OQ'L.O~,t'-.~
OC/~~y~~p'' ~~W~b~O~U~~~~~~G~OpwO~~~00~i.U.iU
.-d~~-d~,~ '~~~0~.~00 3~sUO >,. ~'~.o~.o'~~°zPA~.~~
'-' V .~ ~ ~ c~ 3 ~ a) ~ .b .-. ° w a) V _ ~ ~ ~ O C N ~ ~ .J
vp ~ N p '~ y ..>, O .O E., .~ cd Ov V7 '~ ,~ N .d i.N. ~ ,D > '~ ~ ~ ~
° ~ 00 c~ ~
p G C ~~',~~ ~~ ~~ N yv p ~ U~~'Ooo
C ~ ~ O M O N
"Z'~°' c~ U °. 3.~~p~O QO'~~,'+. oo~~ E-~'~~ ~~~ ~ ca0oo,~ ~;
oU~ ~E-~ ~ ~.N ,..,p , b : o ~~~b~b ~w ~ >,~ i i~c%i
.-~ i.-~ ~ ~ ~ Ci i..~ iU.~ .ri vW..~ a.~ '~ U CC ,,, 'Cy >' .S"" a.U.W/7
° '~ f~ ° it 00 ~ ~ '~' 'b O
c~A"'~ .C~~' c~"NO~~Q'.r~O~~c~cn,,N,~~"~~N .~'.rN,L,ON
~OG.n~ ,_,~.~V~N_>afw .~,'~,y~U°~_
i.. c~ ~ 00 ~~ ~ N ~ iG ~ b~ U ~ at ~ U c~ a V O ~ ~ ~ > N ."
o°~.o~~'oo °~ 'b ~ °~ °' ~ C ~z ~ ° '~'~wdb
a°D.~~~~~ ~~~w~o'D'fi
p.,a~~,~°wp:j~d~°~.~x°~~°p
H p p., a .. ° _. .W n ..., p O ~ ~ y~ y y O~ _~
'b N ~ N p ~ ~ p., O ~ .~ ~ p ~ ~ ~ ~ ~ ~ ~ ~ p p ~ ~ ~ " s~ ~ ~ ~~ N
can x ~p ~~ ,."T.', W Wn G.n ~ .° ~ ~ ~ ~ ccS ~ V w ~ ~'~" . ~ 'O ~ ~ ~
O
o _. _ M o .~ ~; w ~ ,,r ~ o~,o a~ ~ .,- ~ ~ o ~ °' '~ i ~ '~' :v oo ~
W ° °
V N ~ ~ >, (~ ~"~" 00 ~ N ~ N N ~" M O '_' ~ 'v~ ,~ . '~~y' °b1~ N
° ~ j, M ~ a3 x.~ ~ U w
~ 3 U ~ ~ ,~ °' :b ~ ~ ,~ ~ '~ ~ z ,~ ~ o E-~ °p. ~ i° pa
~ °' ~
cd 00 N ~ N N O N ,~~ N M ~ p A,, ~ N O c~ ~ ~ O~ ,~
N N ..~ N r., Q~, w U ~O ~ c~
W~~,~ ~v~ > p 'n UN~M~ iG.~''~bip~'Q ~~ ~ UN Uw_Ov,~~ O
~ M U ~ .p ~ U O N ~~ ~. b b O_Wn ~ ~ W U O ~ ~_ G1..~ .> v ~ ~ Ov ~ N
U v0 O '.'' i: ° _ c~'C .C s., O. ~ .~ ~ p ~ ,~ ~ X ~ G ~'~, ~ ~ ;'
U Q~ N
~ ~ CA ~ ~ ~ ~ ~ ° w N ~ ~ ~ ~ U .~ U 3 ~ '~ ~ ~ ~ ~ v ~ 'c~ v ono ~
aocn °b°~>'~M~o~~'°'° ~,~o°~wwo~~
... ~ .N c. a~ ~ pa
~ b ~ ~ ~ 0 0 .~ 0
-d ~ ~ ° G ~ ,'y~' c~ .° o a~ w .'~ ° y~ '~ ~ ~ " 00 0_ ~
~~ .~ a~
_~ oo ~. a~ U ~~ ._
Os'r~r~0,-~'~ ~p~~Y ''~~'~US'U'' N~p~N~~ i"~,~~" Ov,~
Ui~M~C.~"~~~ ~~~OUU .~'" ~~'~~~~O.~H"'F.'~b4~~MUtU,bp~
°° Ov ~ ~ > s~ C ~:~ ~ ~ W ~ ~ ~ aJ y > G ~ d ~ ~ ~ o w ~ v
~ 00 0~ ~ ~ o . ~ _°' ~ ~ ~1 'b ' -d . ,~ a~ ~ .~ .b o 0
bD ~ ~ ~' ~-U. ~ v~ U .b ~ V N ,~ '~ U b ~ U .~ U ,~ ,~ .~ ~, ~ ~ M ~ (~ t-r
cWr~NNUN ~N fnN~'~.s~~y~~Ucd~wp,~~~ ~O~
a~ ~ b ~ ~ w o ~ ~ o ,~ ~ c~ 3 ° W ~ a~ o ~ N a~
M ~.~. >, y W.. Or ~ N U O > t.. -d f..' 7, a.~ v~ ~ M ar a U
0~~~ ~bDNO~~~~~ O~~Nw_~'~'y~_c~'C~~U~D~,"
00 U ~ ;~ yn c~ b N ;" ~ ;~ ~ ' ~' ~ cn C ~ LL U p°p i~ 00 V
NM'~,~~s~~ ~~~~,Npp~~~.,~.~.~y~~OCL~~~..'af~ 0
WD v~~w~"UD CCw C ,~~N~~ O~ Cry--~.,~.~c>a.~
~U~ca o.~ ~ Ud ~ ~ ~U ~~..N~ ~.~a ~ ~.~w ~ ~~.
_°~
U H o '~ ~ ° .~ U E'~ ..°. ar ° '~ ~ E""
G ~ _ a3 U b(1 G ~ ~ ~ _ cd V b-0 C y
p U ~ ~~ ~ O G. ~ ~ U ,~ ~: .S". O O. ~ p V
cd cd
.~ ~ U ~ ~ ~ tUr N .~ a U Q~ ~ ~ N N .~ ~ U
M M
D\
A
W
U U
M M
197
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ ~ -o ~o ~ °~'
U ~'-'.., N N >> c~ O O ~ N ~U
~" N ~ m . ~-~ ~ ~p N ,~ c~ b-0 'O ~ ~ V ~ C. b4 p
3 N -T'~. w ~ M m U ~ U . 'O
p,,O.CUvON U,~'.~ ~ U ~~.j ~~~ ~ ~.~, ~ p ~w
s~.,~~ .f",~~~_ .f.dp~ ~._~tv'.b0~'OO '~ a ~~",'~'~~O
w N 'a-' Y '''x 4~" ~ Ov a t~ .~ ~ p V O ~ ~ O y ~p ~, ~ V ~ O '_' ~ ~ '~ p p
~ p z
°~~W:b;b~VjoUw~~ ,~.~w~~»~_3~G~~~~~~b°'o
00.""i' .~".,~p~~0>'bi0~ '~N~~~'"vWcCV-.~~~ ~ ~v' UFP.
',:,>'~~~~~'O~~'~_Ny U~y'~'~Uw'bV~~~~.b~w~~.,CNN
U N .r ~ .Y b0 ~p cd _- s.., ~ c~ -~ U U ~' O O ,~ y~ '..' 'C O ~ ~ O ~ c~ O
s..
a.t'"'~,~'~;.dNa~~O.~'b ~'w~t..'OY~Ga'~"~~v~~~'y~~~y'N
"d O t. ~ ~ O ~ _ p., ~ '~ O ~ O y,~,~ c~ O.,m U ~ O ~ O N ._.>, ~ '~ .~ y ~p
O
~O p ~ ,U ~ ~n ~ pU ~ ~ ~ ..~ ~~ ~.~. O
;b ~'~'., O ~ ~ .F, O~ U b ~,~ a 'b GO ~ ~., ~ N
O~~c~p~~.GU.j, ~O.~mx~~~.t",Oc~~O.,t,._,~ .S",~N-~'~r~
O U O G ~ O ''' ~-' ~ c~ tn N >> ~ ~ 0 U ~', T! t~ ~b at > ~. ,~
p ~ ~° ... -d ~ ~ c~ ~ ~ Wn O 'b M ~ ~b ~ ~ .~. O ~ ~ ~ O
,' p N
~ N ~ ~ ~ N iUr w pip ~ ~' ~ ~ ~ ~ O .~ a ~ ~ ~ wn ~ ~ ~ v
y x ~ U ~ ~+w. ~ .~ v~ ~ ~ O w ~ ~..0 ~ ~_ M ~ N N w ~ ~ ~ N ~ ~ b o0
i~ ..N.r~_~~OOVU>,OvixLOQ'..Ob4~~~~UOU~~Uø''O.>,M
h~p'b O s"r y w .b x." ~ ..~ ~ U ~' _ p N ~ U VW . ~ F-~ N ~ O C~ GO ~ ,'~, ~
N
i o ~ o ~ o ~ :b ~, a~ ~ o W o ~ o ~ ~ ~ ~ ~ ~ o ~ ~ E-~ °a, ~ ~
y cd ~ x ~ vl i-.W.. N 'i~ O~ C~ t'. a
b V p~ O_v ~ y O U .r ,~ G vW' O\ ~ ~ .~ ~ U .~ ~d ~' O O ~C ~
O N ~ "C N N c~ U w ~p ~ 7 ~ ~, ~C v ~ pMp ~ ~ O ~ ~ ~b y ~ ,~,.,~', V N
O b cn ~ ~ 00 U O '~ ~ D ~ N U O p V ~~''v~ O O t. U '>
'~ ~ cd ~ tn ~ O bQ ~ O O ran N ~ ~ ~ ~ ~ M_ U =~ ~ O .~ .O GL ,,,. r ~
.~~GU'C~O~~~-'~ ~mCv~v' ccf~"'..~ ''' .r'.'~~G~ .~.~,U >,.S"~N.s"'..~
O O '~ N 4~ U U ~ N ~ N "d U d. O ~ O ~ ~O by ~ a N 7, iUG ~ p ~ ~ _~ p ~ .p w
..~ W .. ~ .~ M I~ ~ O ~ i . "G C ~ G
.~ O O s~ ~ 'G i ~ N .r. U ~ y ~ ~ ~. ~ ~ c~ N W c~ ~'-' 'b O ~_,
O U M t j O O ~ ~O ~ ~ ~ O b ~ U ~r p ~~' ~ .'~ ~ c~ ~ b ~. '~ b
U U N w ~ ~ N '~ ~ U b U U ~ s-r ~ U ,~ U U O N
~'3> d~-_~~_~o.~_a~~~~p°oo~.~ °o~°'U
~~N~ ~~yN~~:~~N~'~p,w~E"'''~~N'-'~.apwN
a, ~ y '~ ~ p ~ ~., ~ ~ ~ ~ ~.. .. w a 3 ,..~ ,Y C cW..~ O~ O
~ '~ O b O ~ .~ a w U c~ O N . G w ~ v~ ~ v~
y:, .~ G p ~, p s-~ >, 'y t-~ 'O ' ~ N O ~ ',.., t-~ ~
pOcUn,~C~~~,~~N~c~UO~'~0...~~bD~'c~dU"~~ ~~N~~H
O ~"., N ~", Gp U ~"» N (.~ "~ a _O "~S' y w > i-a N ~ C"..y, _ O > U a~ G".
.~ > ~ ~ ,~ o ov w U > ~ w
~ y0 ~ N y .f"., Y c~ ~ ~ _c~ ~ '~; O O~ . ~ ~ , ~ G1 N
O A. a ~ v' w v' U ~_' Q.' cd b c~ 'n ~ w 'b ~ .~.r ~ ~ ~ w LL cd ~
S".. ~'' ~ ~ ~O O O O ~ .4: M U U ~~ .~ ~ G' ~ ~ ~ O ~ '..'~ ~ bD ~ .C 3 O ~U
c~~C ''.'' ~ ._~
~ O ~ G. G~. ~ ~ O M x ~n ~ p c~ x N y~ .~ 'd 4j ~-~ p ~ v~ .r
~ yo °o°~ ~ U ~ a-~ ~ ~ >'b ~ ~ ~~'° ~ ° o p ~ ~ ~
.n~ b .~ ~
~a ~,~a~ ooo...~~~N ~.~~,;;~"Np~~~~°,,'a~b~a,
ooF,~~o,o~'~H~~~~o~o~~n~>~ ~??o xo
o a ~ o ~ '~ '~ o a
o
.f.' .~ C U N ~ .~ ~ U E'r C .~ ,~, ~ U
.~ v''~ou '° ~ ~ ~ ' ~ ' ~o~o ~ ~ ~ ~ . ~ ' 'ion ~ ~ ~ ~ ~s
~~ G' O a O. ~ U ._~ 'y ,y~., O O.y ~ .~ ~~ L: O a. ~
a,
N U ~ N ~ N fn
a .,.~3 ~ C/~ ~.U., U . ~ ~ U a ~ ~ ~ ~ N . ~ U a ~ c~
.r ,r t, N . ~ t"..
Q\
M M M
O~ O~ O\
A A A
U U U
M M M
198
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
U M
a ~. -d M _~ ~ ... ~ .,
~° G", ~ ~ '.' .3 ~ bD ~ ° c~ N V~ ~ ._~ U ~ O W ~ '~ W ~ ~ ~ ~
M
~n " U ~ O
,.' c~ O. N ~ O ~ 'b G~". N C." Wit' O c~ N ~' ~' .b ~ >, w U ~ G1 i-s O ~ ~
v'
,_~ ' W ° O O ~ .~ ~ ,~4 '~ -~ p fn >, v~ ~ M ~ U U
s.. v b O ai ~ ~ D '_, ,~ U ~O
~ 5,~,~ ~ ~"" ~ U ~ N V _ w Q~ ° ccf y ~~' (~ d' [w ,
c~ L~'. 3 S: O b ~ ~ ._ ,~" ' ~ ~ 1-
~ b , U v ~' 3 b Cad ~ Cd/~ Vi ~ a' ,Ø, U ,'T C." ~ N ~d ~ ~ N
U c~ s.. N ~ U U ~ c~ ~ ~ c~ i~. > ~ N '~ ',~' ~, ~ .v~
~~,, w ° ~ N ~ ~ N ~ iUG ~ ~ O ~ U '~ .C ~ W ~ ~ M .W,
W ~ .r U U ~ y.., U U U" N W ~ O ~ ~ ~ U N U ~ ~ ~ pp N
w p ~ 'n '~ ~ b tUn O c~ ~''' ~~ V ~ U U .~ c~ t~ ~ ~", i O >, tn ~ p U M U
w ~ ~~ > ~U ~ ° on,o ~ ~ °'v~,~~a~..fl,~ ox
" .° ~' ~ '~° ~
p~p ~ ~ U ~ ~ N A. ~ '~ ~ V ~ Q X' N .C 3 W ~ U W Qi .S", ~ ..C O ~.U..~ ~ ~ ~
O
cd a~ U v~ c~.., O U ~ .f-'. U ~~ it ~ ~ ~ U >
,~ ~ ~b ~ ~, ~ O ~' ,~ _.. ~ ,~ U ~ O c~ 'b W O_ O ~ ~ '
~ y1". 'n rn ,~ ~Q" .,..~', ~ ~ ~ G N ," ~ ~.U.~ O C w ~" .O ~ N ° ~~,,
~ ~ ~ O ° °
p ~ ,'~. U ,~ ._° G4 ,i, .° ~. i~ 'b ,~ ,~ ,~-, c0 '~ ,C G ..~ ,
a.. t3~ ~ C3 ~
'-~~U.OU ~'~~i.U,~pbON~~ ..~ ~cpC~~O.~~~, y.~.,yU,~GO
,~ ~n~z c~ U ~~ C y~ O~O~ ~~~..i c~ Ub c~!~' cd~~U ~ c~ O Ub
C ~ 'n ~ ~ O ~ . ~ ~ ° ~ p ,~ U .Y o ~ ~ .~ .d ~ ~ v c~ c~
a,w~~~~ ..,~03 A.o~~!l~U'c~N ',~O"~>,~~x~:~G.1~~
Xc~M .~O ~ mO~~m ~00~ ,_~C ~~ M~.~~Uv,
W ~ p~ V ~ ~ p~~p ,,,0 ~ b-0 ~ .b v_~ ~ M ~ c~ '~ W ° .°
° C O O~ O ,~ y ~ O
_ ~ Os-, ~~T..' r..' ~ aubO~~'y.~b f..
G4 ~4:r b°Q. ~ ~ N'-i00 N..U..~ ~~ > N O~~~"~ ~ pp>,~~C
a.~ ~ ~ ~ V cd ~ ~" CL c~ 00 M .~ 'p U . ~ ~ ~ ~' ~, c~ U N ~ .C
°'~N>,s°e;~ oo~>~>'~'°~a>~.~~ r~3'°ooano~t~~b
y W .~' ~, c~ O m O C~ r; v c~ ø' ~ ~;r ~. N .~ ~' .s"'~' ~ M '~ s.. ~ U 'b
~. v0 r., ~ 3 p, w. > >, O. U N M N~, >> ... c~ ., t1. 'G :b fW0 _ 3 O cd
N ~ ~F' ~ N i. '~' ° G can U b ~ ~ U cC tin U y ~ ~ ~ ~ ,~ ~ ~ Vii'
4-, U y
Noo~~,-~ c~~~~ O'~'~~3N~~~~~b~'.a~U~~U~Ubcd
N ~ ' N ~ p O pUp c~ >, ~ N ~ p v~ N O vi ': .~ ~ >, G". N p ~ N
is .~; N ~.~"» U U ~-'O i.~"'.i c~ 4. Q, ..~'., G O ~, ~ y O ''~' .S-'" ~ ~ O
~.", r..y. ~+.n N " i.. .,-~,
~NU~~ ~O'G°~'~'~~r-~UtUnO7,~y~~y,~ ~O~UO~Vp''
V ~"'., f".. ,~ ~ ° ~ ~ O iC ~ y N ~ N ~ OU .~ cd ~-' O O ~ ~ ~ ~ ~ ~
cd C11 ~ O
~ M U U O ~ :3 G~ ~Vi W ~ W w O O ~ C".' vU7 'd Aa ~ " ~ ~ ~ C~ _N
\D p 4-~ O '> U ~ cd .~, a~ "Cy ~ a! i.~ 4-i O ~ ~ U 'b ~ z Tr' ~ cd
~OCLNV1N.~~~~0.~ ~OO~.y,~cUn~~'~~~
f-' au c~ y W am~~,' U '~ Cr' ~ O~ .~ ~ O ~' O '~,' O
N Ncd~U~~w~Opb~~ ,~,.= Q.~O~~.c~C,~,~OCt.U.,O
~N~~~"~ ,~'~'~~~OO~.~UO~b~' ~y'cO~~NNb~.~',~YN~
0~0 N ~', O ~ ~ ~, ~' "d ,~ ~,, N Op ,~ ,~ 'b N . U O ~' .y f3. c~ '~.,' Qv
.'~, G
>, ~ ~ oo t~ ~ ~ v~ ~ ,~ a~ ~ W a,p ,_~ U p. c~ °
O.r N °U c~ ~ ~ ~ N U O ~ O ~ c0 O~ O~ ~ cd U .S"~' ~ ~ j x ~ U ._~ ~ p
t3. ~ ..'n. N
~>wU ~ G .~,~U G Nm ~p ~O~bx''-'N
. ~ Cd C~ C~ ~ W / . ~ CW / w/ .~ ~ ~.~ ~ U CC ..~-v W GL a~..~ U U ~ C~ W
O ~ ~ ~' O
O ~ O cN/~ . '~'~' U O ~ OD
'~.:.' c~
> ~ ~ O U ~ ,~ ~ ~ > ° c~ 3
U ~ ~ ~ tU. N . ~ C U Q~ ~ W C/~ CL
Q\
M M
q U
M
199
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~.
°' -c ~ ~~ i o-oM " o
w a ~ ~ ~ ~ "d ;.d Y ~ ~ ~ ~ ''' O w :-~ ~ ~ y >,
O c~~.>' ~v'C~Oy ~' Ny~~>,.~~00 ~O~w
y N ~ ~ m ~ ~ ~ ~ cWn O ._-., M ~ y .~ ~ U O U w ~. O
0,~ ~O ~Otn~~O~U,x'N~c~'~O ~c~~U ~.~"~yl"'"
~ ,~ i~ .~, .~ ~ ~C ~ O ~ V ~ .~" ~ > m ~ c~ m p .b H .O
O~ ~..U~'..'r,.~,O '''~ ~c~by.'cC>,.~ ~'nOG.~ V
U o ~o o ~.~ ~-d.~b.b i ~ ~~drs. ~ °~,,,>,~ ~ N ~d ~ n.~ ~
t~, ~ ~ ~ ~ ~ O .
.~» ~ .., ,~
can '~ Cr yU. by ~ O .~ O ~ N ,~ ~ ,~ ~ ~ ~ N ~ ~ '~ '~" U O d ,,~', ~ 'O
~~'c~:.ON.t~.O ~,N~~='wiGN~~~, ~N.~NbA ~ t3. .-.OO
:b ~ .C ~ j ,O W ~~ ~ y :~ ~ ~ ~ ~ C O y ~ ~ ~ ~ ~ N
'~ b ., ~ ~ ~, ~ ~ " z ,~ o .b o
~ a, ° ~ ~ o : ~ ;~
~t ~ ~ o ~ o ~ ~ ~ ~ ~ ~ 3 ,~ .ty .~' w 3 ,~ H ~ ~ . ~ w
ooy~. O ~ f~..~~~,~.. pvW~, ~'!~.~w'''ay~ ~~-O~' ~c?O
> ~ O p _O ~ ~ ~ "O ~ ca a~
;~w °'~ p.,O;~ .~ ~Nb~b~.p ~ ~~U v ~'°a~ ~~v ap'~
U ~ E..., a> ~ 00 a~ ° ~ ~ ..o 'C .~
.b ~ a C7 0 ~ ~ ~ o > o o ~ ;~ U o d
C..'' ~ O C: ,~ U O M '~' ~.Ur O ~ N ~ w .C-w~' ,'~-' O (3.~ ~u ~ ~ N ~ ~~ ~ 0
0 ~ .f.' ~m s.U.n O
~ N ~ ~" O O ~ M t~ c~ ~. .O cue, ~b G ~ ~', ~ U ~"'., U t~ O N E-'
~ ~°~'° ~ d ;~ d 'a-' ~ a~ : o ~ ~ ~ ~ °' 'b '~ .r U ~' o
° ~ °° ~ d w
0 3 ~ ~ ': a ~ ~ ~ ~ ~ ~ ~ ~ °~ ° N O, an ~ ~ ~ ~ ~ ~ fi ~
O . _ 'C~ U
~ O ~ O ~ .a U' ~" O ~, _~ '~ Ov y N ~ U s""' ~ 'x .r ~"O O O >
C'' ~ 0 y O ~ ~ ~ c~ ,~ c~ ~ ' d7 N b ~ ~,' N y ~ ~ ~ ~ '.~ N ~ ~ ~ y
G~.v',~ w,~"'poov;~>''J>' ~ ~~w~v~'~~m~~ccf
a~ o o ~ .~ .~ . w ~ oo v~ :-; ~ ~ ~ .~ o
.~'~'~3'~~0'~~'" ~a ~~~~°°o.~c-~°n~~~~~a~'~ ~.oz.boona.o~
w ~' .~ U O ~ j ~ A" w ~ N c~ ~ ~ ~ ~' ~ U ~~ ~ .~ ~ ~ 7C
p~,~~'CUO~ ~~ ~.~Ot.U.O'C~OW rpn~c~b~,~~'O'OU
'~ .~ ~ ~ p ~ ~ .~ ~ ~ ~ U C3. M ~ ~ M CO ~ Ov ~ .~ cd ~~ ,~ ~bQ U ~ ~' O N
bU;-,>wn~~ U~OD,~..,~d~>~~~~~~U~.~c~ UNp~
cd N O '~ ~ ~..:~ w ' E-i '.=~ . N M ' ~ ~ U O >, y~ O , G.
O ~d f3~ cd ~n ' ~1, '~ O ~' U ,~ ..., O'' i \O ~ m ,_, c~ 'C
UO V~'bO~N~' Nr;~~'t~,cn~'U,,~,~O.~~N~~,~U ~'c~d ~'00~'v~
a"~-due. '~ ~ ~ ~ ~ a~ ~. ~ o,~~ a~.~x ~ a-d:~ ~
o ~ ~ ~ ~ o ~, ~o ~ ~ ~ o .~ an ~ ~ ~ N o M ~ ~ ,~ ~ ~ ~ o o ~ .b ~ ~.
~~r~.,-,~~_oo. a~Q,~~o~~.~a~~U~.~Yw~,~ °~Wc,'~
~ U ~~.~w ~~~~~~'o a~ ~E-,'~, '~~' on~~od
.~~.u y;, cdwOU~,~"~'ANN.'~~'~O~r-.i'~U3U>,dVUJN'~~"OVJ
~s ~ _~ ~ o c ~ ~ ~ o ~ x ~ a~ N o ~ U ai ~ ~ ~ ~ _~ ~
>, U ~ ~ O ~ O ~~ .O O w~~, '~ O w ~ ~ O ~
'b ~.",, ~ .S"~. t3. s., ',=, c~ O v~ O .S", ~" O ~"~, > '1"" '-' N O w '
N 'r ...'~'. U c~ U a3 > t..' ~ O in v~ y, ~ ~ ~ ~ U ,-, .YC O .t". ~ O O
am' C ,S"," ~'.r > 'y Lw f~' . yU,~ a, N 3"'., N ~'r ~', 3 y
cd ~ ~ O .f.' ~.' y N O '~; U O ~ ~~S", .O ''' i ...~'. G~ . N ..r U O p .~.'
O>,'~~U~~ OO~.C~~dUO~~'~Ud0~0~O ONE T..' ~~c'~d OU
~"' '~ a b0 > 'n ~ CC N U it ~ 'd !3r ~c".' ~ ~ C~ 01 w. w O U ~~ 'i' ..~ y >
C N
p .~ ~ ~ '~~ ~~..w ~ ,~ ~ Hd ~ 3.~ yw ~
ctt d w f3, .~ w ~ ~ c~ H ;~ W ~ cad N .u O '-~ N cd U
O ~ N n.a O .t"' c~ O ~~"~~ ~' ~'
O '-' O
p U a~.r O ~ ~ 'a., . 'rte' U ~ ~ 'ate ~'~' U
~ cd p O ~ .c~C .U bQ d ~ N O ~ ~ .~ ,Pr GU ~ .N O
~1C~ ~>fnD(-r0 .~ >
O O N U ~.~. ,~ d N ~ ~ ~ U tc~. U
~ .C N U d a, ~ ~ s., U . wr U d ~ ~ s., N . ~ U
00 00 ~O
D\ D\
M M M
U U U
U U U
200
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
w ° -~ ~. b
N y
o " y a; ~ ~, y ,,~ ~ y
. V _~-~ O .~ c~ d' ~ b U c'~n O ~_ ' ~ c~ ~ c~ p ~
c~ oMO °'~ ~ ~ ~ ~ ',~ a~ ~ o .~ o~ ~ °' w ~ ~ ~ ~ ~ .a
O 'b N M 'b ~ s.U, ~ w c~C ~ ~ p O ~ .., n M ~ ,~ ~ G ~ ~,
... ~O .f"~, V t-~ 'a-' p v~ p ~ ~ O .b ~. 'p O~ V'» p N ~ ~ O O y
~i ~ V ~ pU b cad G» ~ "., ~ it ~' G> O y O ~ l~ p' 1..i 'C1 y f..' ~ a., U vi
v0 ~ ~ M ~ j, ~ ~ C1 .yn O ~y w p ~" N U ~_ ~ ~ O cat ~ ~' b s.. y .~~,
V z OW O N ~ 'O .., ~ ~ N ~ '~ c~ ~ ,~ p ~~ ~ O ~ ~O rx ~V '~ p ~ O ~ ~ V y
p0_~~c~~N~w ~'.~',NN~aJ~ .~.,'b09~~_p~'~ N .~"'~. E'.'~UN
C7 P-y.'~ I~ V ~ N V O .~ O ~ ~~ O ,~ ,.C T ~(7 U pp N N ~ '~ ~ ~ ~b b >, ~~ ~
N
N .D U ..~ ~ p,, U ~ .' ~ ~ ~ M ~ ~ N ~ ~ ~ ~ ~ ~~ ~ U
c~i~NO~"~>,C~n V Nay .fJj,b'.rc~O~~~;~.~0~~ ~vW"y
N p p0 ~ N U ~ ~ b ° j ~ ~ %b ~ N OO U y '" ,G N ~ b0 Q'. O ~C .~
N ~ .~ G cd V ~ ~ O O ~ ~ ~ ~ a.. O pa .~ ~ ~ ... ~d V ~ >, ~ 'C N .~
~ O ~ ~y ~ :d .L~' ~ ~ ~ ø, .~." ...err ~ ~,' a O ~ ''y ca' N ' ~~~', vW"~. ~
.~~.. .p ~' w :'~., b
L~ ~ p U w ~ ,~-, ~' V V ~ N b0 ~ (3y cad ~ ~ c~ U O N U a' ~ U vi ~ ~
U N 7, V cC p _cct b0 ~. ~ ~ p4 a.. ' ~ bU C~ ~ '"'O ~"" ~ ~ P.. '-'
~~c~dcpd N~a~~ NV N~V~"'" .t""LU.
Nr'~~~~~~ ~'~O~~~jN~b~_c~0 ~wV~~w '~c~~a~.~.,
>, G D ~ p 'n V ~ O V ~ c~ ,~ Op e.. ° ~ '.' v~ O N V N ~ c~ ,~,
V ° N ~,' N ~ ~ b O ~ ~ ~ V ~ .!". s'.J' pa, ~' ~ >, ~ 'V-' ~ ''' v O
~ '~ DC
Q cC 1..~ .. '~ O .b . v~ y . ~" ~ V c~ ~ '~ .D . v~ U .C O .S"'~. (1,i w
~ '~° U ~j ~ ~ a ~ ~ ? ~ ~ o ~
'~ M U n ~ ~ "d V ~ V ~ 'b >> cn y' a.' '~ O i.~r y Q" ..w 'b ~ ~ ~ N
N '~" o0 ~ p V ~' ~ ~ O V c~ ~ ~ V ~ 0 0 _c~ ~ ~G O O y
N p~ cct . c~ ~ N 'b ,~~ ~ ~ v~ V vy.~., N O 7, V ~ > m ~ ~ c~
~ M V .b O~ ~ ,~ p, v~ V c~'C ~ ~ c~ .r"~, ~ Q'' by ~ O ,O
~-i O, ~ C". ~ .'", F". ~ C". p,, O
U ~ h O M U ~ ,~ x ~ ~ .T', 'b U ~ ~ C% ~' ~ ~ ~ ~ ~ ~ V N ~'' ~ ~ YC
w V; ,~ W U p CL ~ c~ O C .b w ~ ~, ~ 00 . cct ~p N . ~, O ~. ~ N
p ~ c~ v~ C~.
v,N~U 3.~ o.o ~~ ~ aro ~ N.~~'-~r.'.~ ~ ~.~ o~;oU ~.o v
O W ' .r V y V V c~ N V y~ ',=, 'b c~ p., ~ N V ,>, ~' [-r v~ ~ ' ~ ~ N
p00~SU~~ ~Wy~UO~.b~~~~~~~~Aa~~U(3~~~
Nd~ ~ '~ ~:b ~ y 0 ~°aM,...,s"r ~ °~1 >~ >,
~~ ~ o ~ '~ ° a~ ~ ~ :~ ~~ ,~ ~ ~ ~ '~ b = ~ M ".~ a~ ~ U '~ 0 0 0~~o V
b
3 ,~ .~ 0 0
w i V ~ ~~ ~ ~ ~ .3 ~ .~ ~ V ~ ~ ,_-, 0 .~ i M O p V ~ v, N O O V O
O~~NW ~ OU.r 0.... O_~ V v~ N ~~,b~~~ ~' UC~ s.V. V y 0,.~.,.V c7
y ~Nh' ~ N ...nVV'~p~'~V~O~~~V~~UU~'~' p .~"
'~~~.~r~~nco~ °~ o~~°''~~o-d';r~ ~ °;?~ri
y~~0~ ~w'°'.Nw >,~~ V ,S"'"~ ~. ~.. >,~~1: Q~.i"~, y V xU y..~~,'~
.i"~.~,
o ~ ~~ ~ ~ .° ~° o ~~ o .° ~ Gq U ~ .b ~ $ ~
o~'°,~~~~~o ~~NO~~~~=~wa°', 'o>,no~
Oc~y~,~~~, .~0~ ~ ,~ O ~~>,.~NVw~G~ ~O~
O . ~ ~n O N ~ L~. O c~ O ~y O ~ N ~ ~ ~ c~ ~'.' ~ >, 4=.. p O. O N
apo~-~o°°~~n ~'~,~ o.~~~.N~o~o~;~ "~~~ o
b~~~~0~~~~",~~y~~~~~y~~~~~~~OV~ ~O~ V V
G ,~ ~ .-.-i ~ ~ ~ N N O V O O O G .r r-a ,~ N C ,~
cd ~ W --m ...» GL ~ G. U ~ N U C1. ... GL .... N . c~ ~ O G7 wr ~ ~ E'~ ~ Q ~
cd a.. .~ f~-.
O O
C p >
O . O ~ .i~ U cad
.U ~U
.L"" wr
au
o U
0.~ d p; ~ ~ v .~
a\ o\
M M
U U
U U
201
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
a> >, ~..~ °' v ~ .r ~ ~ .r c~ ~ o
~>U~ b~~0~~~'~ TJ U ~~~.YC~O_~ .t~. ~~-f,E-~~
N.~ ~'~°mp>> C O ~c~~>,'_+'
~' y i0.. C",~, 7, b-0 'd ~.,' ~ ~ ~ U .'p' SU~. ' ~ ~ ~ ~"i ~ OD t~/J O
~° .C.~ .O 'L»'
~., c~ N O . ~ -. U ~ 'n cF", 'O .,r ~ 'i' ~., .~.~ ~ c~ >, U
V Q' ° ° .y c~ U ~ y U f..' ~ O ~ J~.a..~. cci ~ C: ~ °
~ ~ .~ N ° O O Ty 7,
3 ~ a. o ~ o ~ ~ ° :.c ~'o. ~ ~ ~ ~ ~ .° ~ " ~ .~ .~ '~ ono
° o ~ ~ ~ u. ~
o ~ ~ Q .° w .~ ~ ~ ~ '~-~' ~ v a~ .~ '~ ~ ~ W .b 'n '-a ~ 'b
'-iCCGdt/~ ~~ ~~~~V_~~~ ~V7~0'OU °~ ~~ ~ ~~UW
~..' (n >o cC pn ai."~n ~ S".' p >o ° U C~ U ~ can ~ ~ N '~'
T ~ .~ ~' t+r ° ~ a > ~ ~ ~ ~ ~ .-I ,~_r ~ ~ .~3 r1 ~ ~ V ~ b f~'
UNi.~.np" b '~.~O.,pa~-~~cdO~~G'r~U -S~'.~ 4r~.~ '"a ~~ ~~"'N
~p 'b O cd V O p .f.' O ~ ~ ~ ~ t"" O ",~ ~ ~, ~ Q .~ ~O ~' U a~ 1..
° ~ a~ ~ ~ ~? v ~~ ~ a~ ~ ~ ~ ~ ~ .o ~ ~ v U
~° '~ t-Q. ~ c~ O ~. U tn ~ W a ,~ c~ O ~ .~ V ~ y ~, . N ~ ,Y GAD m
.L~ O ~.~,'
° ° _o ~ on w o ~ U " w. :c 'b -d ~ >, ~ o ~ o _~ .~ .'~ ~
°' ~ ~ oo .~ o W ~ o ° ° '~ ~ ~ ~ b ~°' o ~ U N
°' .° ~ ~~ ~ ~aS ~
a~ 'b . N ~ ~~ O. ,~ . ~ ~n a~ ~ a~
U I~ ~ ~ ~ ~ ~ ° a~ ~s ~ o v a~ ~ ~ :. ~ ~ o
U acv-.' ~ °~~~ ~>dU~~~4~.~~dp~'~~,~~~~.~e
cd G' O''~~~On...~''.~p~7 ~U~."~O~°G0~~0' ~,ONtl.
V) ~ ° e~ 'a, ~ au ~ ~ ~, .~ ~.-n ,.'~"~~ +~r a C~ U ~ ~ ~ ~ .~.n 3 ~
° .r _Cd
~' 'J U :3 yy '~, O ~ W ~ U ~ U O y ~ bald ~' ~O ,., ~.. O ~.
W '~ ~ ~ ~" ~,N,1, Vi b a~ .~ ~ ~ _° c~ 'b N U N ~~ ~ ~ d ~ ~ i.U.~
N > w W
o~a~ ~.~~,~ar~_o °~a~~~~~ ~,~ ~~,on~, a~o.~
c~~~°U ~'~'~O~~~U~cYdU~.:13~.D>U ~~N ~~~~~'~V V~4~
.~ f3~ 4~ 'b o0 O ~ O b4 U w ~ ~ ~ y ~ c~ p .~ .~ w ~ .~ N p O ~ +. y
p ?~ 7-.~ ° ~ p, N F".~, . ~ ~ U '~'~ c~ ° a~ ~ c~ p ~ ' V~ (~ O
'~ ~ C~rr . .y-'~' 'O ,_,
,b a~ a~ _O c,.., y c"' W ~~ ~ ~ ~ .b ~ ~n ~~ .b s"~ c_~ >~ ° ~'"r
° >, '" ~ 'b °
O O ~.d ~ ~ C ~ a~ ~ c~ ~ Q' ~O cd .-".' .' O_ ,~
E'' ~~. ~ O O. ~ '.' ~ O N ° ° Q ..~, ~ ~ ~ ~ ~ i h
° y~ vi
00 ~~o.'°'~ob°~~~~~ U~~d~+;y.,s+:o~ ~~.~a~~,b!~
w ° ;n ': o o a~ ~ ~ . .b . ~ :b av ~ U o ~ v
b ~ t3r c~ ~ N ~~ ~ 'y '~ V ~ V ~ ~ ~ O ~ O ~ d ~~ ~ A'' ~ .b p. O
cdOQUO~.Lw_c~~',~Nc~pp'y 3,~N O>>~>>~~p0>,. .fl0.
N j~ N 0.0 O ~ ~ N > b ~ ~' ~ a4 ~ ~ ~ ~ ~ ~ ~ N ~ ~ ~ ~ ~ N ~ ~ N
UNOOO~c~n~..~~ ~~.~~.:~O~~O~°'oN -CO.~CU.~~p.,0
b ~ D ,~., 'n ~ '~ ~ O .T'. > ~ ° ~ '~ C~. ,~ V~' ~ b O 'b ° ~
4.. N N > ~ ~ ~b
!+~ a~ '~ . ..~ p op a~ v~ O ~~ a>
~,~O~~v~~ b-0~'b c~~0',=~."p~s.Q,~NCW n~~~c~~.~ ;"Nv~
V~C.~~'n~~°~~° CNOO~G~U~GNGN'.~.~~~'n°.~.~>,N
,~ ~ o.... s~ W ~ W e, ... c~ . p c~ ~ d C7 a~ d .r .~ ~
c
_ o ~ o ~ .~ _ ° o
~ ~ ~.~'r U c~ c~ ° c~ U > ' c~ U ~ ~" 4r "'
W V ?~.~ ~ ~ .,~ ,~ .v .'~~' .~ ~ C ~V ~ ~~ C ~O N N
o ~ ~d~ o~ ~~-d,b~ b~ o~ ~~ o,~ ~~~ ? v
N U~ pr~ N Ut'~~UWU Q,i.U-.ii N U.~ ~ N U~ VI.W n p.,~
00 OO °~
M M M
a
U U
202
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
y ~ ~ >, ~ M a_Ur
y _'~ U .~ ~ ,~ 'T3 cn U C/~ ~ w ~ ~ ' H
~b by UNNQ y H~G;>''C~ ~ ~,0~..'~"',~M
~ G c~ , y., bD cc ~ c~f ~ c~ ~ ~ w bD O w O
s.~ >, U -~ N i.Ur ~ b t".~,~ ~t"" 0 ~ c~ ~ O O O~ ''' w~ .S", ,~ O U .f.', U
,.~., b O j,
C N c~ s.. 'O y U 'r.:' ~ ' ~ U '~" N ~ ~ ~ N ~ .r i.r ~ "~~. ~ U ~ a!
~C~n~G'~~x.,~ ~~UG~V+~r~~>s..'n.i-s'-'c"CUG_N~a...i"~~~i
~O w ~ ,~ U ~ .~ O ~ ~ 'b ~ N G~ O O Cv N ~ ~1 ~ >, >> [-~ ~ ~' G"" O b-0
jN~i,~~~c~~~ _,ONp,O~~?UGc~d~~~~~~p,
~ a~ W ., ~ ~ Q al G1.
.~ ~ ~ c3 0 Q' ~ ~ N N ~ ._ ~ .~ W ~ y. ~ N ~ ~ N ~ 0 ~0 0 0 b C
N !-. 'r O OD ~ ~ ~ 3 > O ~ ~ ~ N v O ~ ~ '-' ~D Q\ ~ ~ y ~ ..~ O U
a p~ ~ ~ iG U N ~ p",~ y~~" ,O N ~ ~ o0 ~ ~ N ~ ~ ~ U .~ ~ b O n W
w b W U ' ~ c~ ~ v~ ~' ' cn N ~ U '-' .-. ~ C >' ~, .
N~ ~~~ ~~~~N~'.u.y'~~~0.-WOO~U'_'~p ~s..pC
t"n~nOU~~~y U~(Sa~~A~''U~bOmN~~M~~~~A.' '~',~~~O
a ~..,
~T.~.'~~~~~~y~" f.'s ~m ~ Q~G~~ ~~NydVUc~C ~~~b~cC
N ~ U ~ N ~ w O ~~ ~ U ~ M ~ ~ N v0 >, U ~ ~ N
~~°'~~°~,~~cn ~~~lo~_~.b~~NU~~~~~~~.~u~ W~ i i
~ a, ~ o a~ ~ a~ -o ~ C7 ~ a~ ~ ~ ,~ .~ ~ ~ ~e >, ~ w
ca ~ ~ ~ ~ >' v ~ b4 o p, ~ G w ~ N b ~ O ~ N .~ bA v, U O
'_' ~ i~. _>, _U c~ ~ p cWn O U d d _. d D cn ~.. ~ w O 'C
O ~ V~ " ~ ~ ~ ~ U O Cd ~ b ~ w ~ ~ U ~ z O O O U "'~ N >, b ~ b
~ i-s _~ ~C Vj ,.,.. ~ O, > N ~-' O ~ O '~ _ ~ ~ O ~,' >, pn M 'b ~ c~ ~, .i".
'~"'
Y W p~ '.' O ~ ~ w .... O t.. " ~ ~ ~ O ' N ~ N ~ ~ .~ M ~ p ~ ~ ~ cC
a\ ~ s.. Y U . W O ~ ~ y ~ ~ c~ 7 _ bD ...' . cG d-0 ~
bipd. ~~'r~ ~b~~-~ ~ O O O ~O~ ~~ j ~ ~W.~~~ ~~:b
CW r ~i ~ ~ ~ N ~ ~~ _ a, N G~ L~ ~b ~ N N ~ N ~ U b GC
I~ ~ ~ V c~ 'b ~ U ~ ~ ~ G", ~' ~ "f,~ ~ ~ ~ cd a C U ~~ ,.'"', ~ ~ O U V !~
NUNU~U~~'O.CN'~ Q''~y~, ~''' .~ 'bG,~'G~v~ ,~,C
O ~ M ~y' ~"' ~ ~ .D M " .~ Q ~ ~ " A ~ N ~ ~, ~ O .U . ~"O ,~ i.U, ..-~ ~~, "
c~
;.d~~x~ ~~~~1~ ~~ ~~ ~~~.G~''. rUn ~ .S-'.,~ ~~3 O~ ~ U ~ U,'r~'H y','~-, 3 O
O
~U~~~~~~pN.'~.i'yr~~..'OUa.~'~ aU~~~,N>,~~ .!-'.UW O~'.'~y
pp cad ,~ ~ ,~~ s.U, O~ ~ ~ N ,Y ~ w ,~ ~ ~ iv N ~ ~ ~ ~ ~ y O ~ ~ ~ y 1.~"
~ r~r ~~ ~ U ~ ~ ~ ~ O ~ ~ ~ ~ N O > ~c'~ O ~'~ ~ ~ ~ ~ N ~ ~~ .4» N ~". .w~~,
pp ~» _. 'C." U N w cC ~ au ~ .C au ~ ~ a, ~v~» L' ON O ~ ~ ~ N ~ ~ ,~ f~ ,3
.S~'~, d l~ y a, ~ N 'b ~' O au b VJ . 'r" . .f"~' ~ ~ .b U E"~ ~..i .c~ . ~ ~
~ ~ ~ U ...~.~ " N ,s: 1.w
b .~ O~ ~ ~ ~' '~ ~ U tY U ~ c~ ,", ~ G U ,'~,, . 'r~' 00 ~ C: U .>, O ~ c~ .'
G.
U . > O . 4,, ~ cn ,..I O 4:, ~ L~ 'b c~ Q. id s.. ?~ ~ w
U~, ~~~~~O~c~n:. ~ppO~.~~~O~N~GU~4~~~~'bpc~U,
N ~d bD .... ~ U pp U U ,,.,, pn O M .c» s".' >' '.' c~ ,~ O '
~ ;b ,~ 0 'b ~ >Wr' ~.' ~ y . 'r.:' >, .b ~ ~ ~L ~ ~ ~ C.~ .~ y ~ .0
~o~Mao-~ooa~~Ww~~~,.~~,~~a.~o~a~~Vo~s~a~°~°~>,~a,;~
~ N ~ O N ,~ U U ~ ~ 0 ~ ~. ~ " ~p ~n G N ~ N ~ ~ b C ~ N ~ O i"
Q M~U ~~ O. ~'a~0 yU,~~'"_'G.~>>~~~~' NUOsy~" v~N>,L.~
> ,~.. ~ p F.' O >, ~ .~ ~ ~ S'" cC ~ '~' cd ~ W' ~ .T~.' .f~ .~.," a..~ O cC
''~,
WD b ,~ .r .~ .~ O ~ U '~~, '+~ ~, O ~ tn I~ p O . ~ ,.~ ~, s~ U O U
~ N v~ N ~ s.. . ~ ~ N cn N M ~ N .r 'b ~ b GL ,~
00 ~ c~ ~ ~ 'b U ~ i..n G ~ ~ '~ w ø' ~ ~" ~ s"' ~ . ~ -t"', U ccf i.r w
~r -o o .
:: d a~ ~ -d ~ o N ~ ~ ~ U U ~ o .c '° ~ -d ~ ~ '~, r-
o .b y ~ U .~ ~, ,~ ., ~ _ o ~ ,.-~ ~ o W ~s .b ~ a ~ ~ o
N ~ O ~ U ~ cct ~ Q T.J v~ a~ Q >, ~., '.~.~ ~ U c~ s..
.d U O ., > ~ m :., N O N ~ ~ .D U ~ ~ c~ ,~ ,~ .~ U ~ v~ C w N
c~ ." U ,~ V +O~ ~D ~ U ~.~ ~ ~ >, O ~ ~ U ~ 3 c~ ~ ..~. ~ .O
Uymcdb~f3r~~~~'~~"~.,4,.~',p~Ow'C~.~~N~~~',O
0 ~ ~ .~ 'i~ ~ 'b ~ ,~ p a ~ N > ~ b y U ~ ~U '.L~~ p r.>.' '~~" ~. N N
O m ~ p ~ N N Q .~. .f., y .S~'. ,y-.~ ,~»~ m--i ~ c~ N N ,~ O N
C. cC W C/) . p., U U s~ C1~ d cC c~ s., A cct CJ ~ O.~ . N -_ ~"'.. ~U N ~ Gp
3 ~+. U x U cd . ~
w
O O ,~ ~ >, O
O ~~= ~ ~ N p p ~ b-0
.t.'~~.
U ~ N b ~ x c~
~ V ~d ~"~ ~_
> i? a~ ~ o. d d W rr~
O
O O
d'
N
M
C/~ r-~
203
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
y ~: >,
°' a ' U '~' ~ .~ ,", °' ~ ' U M
W ~ °~' ~ E- c~'n ~ o o vo ~ W ~ ~ ~ E-, cE"'n
~ ~ a\ d _ai
a M ~ y V U 'b ~ ~ p ~ ~ G ~ ~.i M ~ ~ V V ~~ ~ U rUn ~ ~ a' O
00 ~--i .r,. .~,. U y
'> ,y W ~ ~ T ~ a ~ ~ o o ~ '~ :~ .~ ~ oo ~ ~ ~ a ~ ~ ~3 " ~ ~ a~io
°c%yo ~~~,~~~~-d~oa~°M~o °opqo'~a Wc~;
d' CA C '~ M .n ~ b ~ ~ ~ ~ .~ ~ '~? L~ C ,'~., M ~ w ~:
N N O N ~ U bQ > U N . O .
,b ~"u c~ C~' ° ~ ~ b M .>f"., ~ ~:~ '~'' (~ ,b ~y~'' ~ Pr °
.yes. G~ b M Ci '3 . '~"'..' N ~'p v' f3~ ~ .~".
C.' w ~,' a ~ E."'i O b ~ .~ F', w ~." ~ ~ ~ .~ E..i O U y ~y ~ ~ ~O
~ ~ O ~ >, w ~ _U U M U ~ y~ ~ ~ ~ p ~ yn ~ _U U M U t~ ~ ~ U ~ a N
tUn ~ ~ .C U ~~ ~ ~ O .~Ud ° bD , O tUn ~ U ~ .L'~ U ~ ' O .~ y w pip ~
O b-0 ~a,
ce v1 U (~., U ~ v~ , TJ ce y ~ v1 a U ~ U ~ rn p y U .~ ~,~r' '~
..r . ~ O G i . >, .t". ~; v~ N c~ ~ ~ O .t". . >, .S", ' ~' N ° s..
..~ ;.d O
N>~'~'n~~'~' x~~~~~"~p°pOv~CA~>~~~~ ~.y~V
,'Y~, Y ~ ~ pp ~ c~ v~ ~ ~ U tn ~-U. x ce. O_~ ~ pp ~ c~ m ~ ~ ~ w Y ~ ~ O
O
W ~ ~ W W ~ O
y f"i .-1 ° ~ .Ly Vl 4O ° b y U'q .-1 ~ ~ ,S~r VJ '~" ~' ~ N_ V
i~.n
v~ O ,~ ~ x ~b ~ y ~ ~ ~ ~ ,~ m O r, ~ x ~b ,~.~, y p ~ O v~ ~ ~ 4N ~ N
w/1 ~ O' O ~ aU.~ c~ ~ G~. ~ y ~ _ ~ ~ ~ .~~ ~ ~ ~ ~ ~ au 4~
O ~~ O h ~ i' w GO C ~ ~ ce ce O ~~ O_ ~--~ .D s"~ i.~-~ WD ~ V ~. w U ~
'n0 .~,''wb~Gr N~~°~b°p,~'n0 ,~',~'mb~G. ~>,~'~~,'~
U s, ~ v~ y ~b 'y ~, ctf ,~ U U ~ s"' ~ ~-, ..y~ ° 3 y0 U °
'.'
.b ~b Q\ '~ b s'.~. N ~ c~ cC ~ .f", x v ,> b ~ O; '~', 'C ~ ~ ~ ~ ~ ~ ~ ~ ~
'~ ~ > V y
O~ovo>,~'pc~cd.~y,U,c~.~~~ V°cd~>'~p~c~..'~,~.U.,c~iN~O,~w~w
W n O~ '~ ~ .U ~ ~d ~ ~, N ~~ '~ ~ c~ ~ (n Q~ '~ ~ ~~ ~ .b ~ G, N y ~ ~ ~b w>'
~~
N 'L7 M 0\ U N 'n y ~ .' ~ 3 p0 ~ N 'C M ~ ,~ N N ~ ~ ~ ~~.r ~C '"" > .~
C O ~ ~ p ~ ~ ~ N b°-0~~ W ° ': '° ~ O ~ ~ OO '~ .~ ~ U
b°-0.~ ~ y .~ O U .~ P. N
'~ ~ U ~ N N O C E~ ~ C c~ .r ~ N ~ N N O ~ ~. O v> > 'G '.C~
o~~,~~o ~ ao~>,~-d 3 '~~ ~,i o~~.c~o ~ on~'~b 3.~
~.~U_N~,..c~~ ~o~,,,~'a~~ ~~~UN~.~~~'-'~° ow i-d.~~o
~I~Ub '~'U~~ p'''3~UOp~O,M-,~~U~'b .~.U~~p.'O~.Nmyn
-o:bf.~.~'.''3$~°3~~ ~~~c~b:b~l~'.''3o~°y'~~'~~~~oa~
U ~ N ~-~ U ,~ >, c~ C ~ 'c~ w ,~ a) ~ N ,-. U .~ >, c~ ~ . L:, .~ w U U
w U y U ~', .O N O y ~ r-~. ~ ,~ ~ w U au U r4' .O y:, ~ O ~ ply y A-I
OU~..NO~~O°~, ~~ V~~J~..NO~~°O~,Ub Oy..,
~"'., ~C C1 ~y, ;~ O . ~ N y N ~ y ~ j ~ ~"'.. 'C ~ G. .~, ;b ~ °
p°q '~' >> C~. ~O
.fl v N " ~ U ~ V ;.d _~ C w ~ ~b ~ ..O ~ U ~ ~ V ~ U 'd ~ ~ cd ~ _~ -O ce ;b
>' G N O ~ N ~ U ~ O ° vi '~ ~ >> ~ i.. I~ O N ~ c~ O ° '~'-' >,
O ~ ~ ce V U
w a~ ~ ~. ._~
N y,U,~ O ~ N cC O v~ N _p>," 7., y ~ w _N ~ ~ ~ U N c~ O ~ ~y ° ~ ~
.a: O _C
~ cd t~ ~ p0 ~ ~ ~ O ° ,~ > G U E ~ ~ O, '~ p ~ O D ~~, N ~ O N
~ O ~ ~y ° ~ ~.., f.. tn ~~
,~ ~ o o ° ~ ~°' ~ ~ z o ~ ~ ~ .c .~ ~y o ~o
.f.' U y ~ ~ ~ N G ~ O .~ ~ p ~ U ~ ~ G' ~ W ce b ce 'd Q' 'b
w0 G ~a:. N ,~ ° s.N. O '''.'' x -~ :-. O. ~ O N ~ .~ ,~ ,~ O s.~,
° '~-' y ~ b ° ~ ~ ~ ~O
a~a bW~~a~~°',s_'~'b ~~~oc~ iTS'~~:Ja~~".~'b.~~a~
ova ~'~.'~'b~ ~~~~ i:°~o~ov~ .~~.'~'b~o~ i~~U:~
aj >,'d p~ .~ ~ U . ~ ~ ,~ ~ >,'b ov y U . w ~ W a
n: o °' ~~ ,~ o :b ~ ~, ~ ~ ~ ~ > rx o ~ '~ .~ °o b ~ ~~ ~ ~ ~ ~
~ ~ H ~ o 0
W tz.~UU~ ~ W W~v ~ ~4 U ~.~ W p.,~UU~n c~W ~.lb red ~ ~wMU vw
C.
0 0 0 ~ °'
O " pp O '''' V G
3 .> o .~ 3 .> .ay.~ou c ~ ;-, v
. i b p(, ~ ~ .U ~ ° ~ ~ 'C
w d d W rr~ p. d b ~ °~ a~ V
N N
O O
~O
GA ~G
00 00
204
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~p M N U ~ .r . " >, v ,,U"" O
N w ~ 'O O v~ .. ~ ,1 ccf ~ N ~
u.~T7M~ ~ .~M~in "C ~ ~ p~p ~~ .1~,
~ .USr.. ~ ~ ~ >' ~~' " p0 ~_ 01 '.' Q ~ ~ N
.:~ ~MM a~~~O O N O c~'.u ° °~ C."O v~"~E"'~ ~ cC A"C/~
N _p0 vy O n ~ ~ ~ s.0, O O y ~ m -C! O O
~ U 00 ~» ~ c~C eti t~ x cC N 'd cef y, ~ ~ ~ r' ~ ~ N ~ U H N ~ V ~ U
.U .fl~v'G°dp.~c~pp ~Ocy0v0NI~.CGL>, U~UU
c~ a°~. ,,v~~ U >, U .~ ~ o o ~ ~ w ~ .b ~~ _~~'' ~ ~ ~ a ~' o'~o v ~ o
~ ~ ~ ~ .o
pNE-'~~~" ~bOp°O~~G1,~Y~4:M.U~'~"p'~~ p,,~O~c~
O C%] ~s'~~. ~ .r O ~ ~ p".~ y N ~ ~ ~ c~ ° ~ O ~
N bD ~ ° y ~ N ~ ~ y ~ ~ .b ,b U ~ y v~ ~ c~
_ y..i
b0 \p ~ ...~ p ~ OU OU c~ OV 'y ~ '~ ~C7 ~ y c~ b W .~'
~C ~ z ~ ~U .~ ~ ~ f-1. .~ ~ U ~ ~ ~ C~ ~ U ~" ~ c~ U ~ >'~ N O ~ N
b4 O _ b4 '-'
.S"', ~' N ~ ~ s'"., N ~ ~tj v~ i.0, O b :~ . ~ G :b ,c~ ~ Q O ..S"~, 'b ~ y ~
~ ~ ~n
'''''' 'G~'-U~~U~ NN~~~U~~~~'~~Oc~~NN~4,U~c~
'~ N ~ ~ ~ .a cd ~~ O >, H V ~n ~~ " ~ ~ .r0 ~ ~ ~''a~ ~ U N
bDN~" ~ ~ °'~ ~ 'b>, ~.C~G ~, pU
.~. -c ~ ~ ~. ~ .~ .c ~ 3 o a~ U o ~ ~ ~ C~ w ~ ~' 0 0 0 ~ N ~
O'-'~c~~Ub ~.~~GU°'F,,O~'~''OO.~U.., NU.~_~~~bOO
.~~.ONOO~~j,p~"'.. ~~~"~~N.~,~ .t".~.C.~'V.~-~~>,~fn~O~N~N
N . ~ ~ >> ~ ~ "~ > ~ O N ~ c~ ~ cd by S'~.
.~ C ~' U "C ~ ~ ~ U . U > ° s-' ~ - ,1 ~ C y N O p ~~ .v~ .~
'..~~N~O...U"N°~.~~.:'. 'C~'b 'Gt..V..O,~ a'~l~'bm>'~~~U~c~
OU~UC.~c~~U~.Y~3.N00~>wUn~O~Ov~~O O U
O ~, ~ O ~ ''' .--r > '~ c~ ~ O ~ O ~ y ~O 'n ~ ~ s"' ~ ,~ N C O
~° G'
'O ~ O ~.U..W~' ° A'' N H c~ U ~ vy,' U c~ c~ U M O~ O O ,
~~nO~N~,,ON~~~~~~°NI~~.,.N.~N' ~c~
~MO~~~~'~pb~00~.~p''~b~mU~'>'is~jyyy>,~N~.O~
W ~O ~NOCU~pNi.,i~U~_>'~[fNcd'~~.~!~~.~N ~'~~p, ~c~
U m N U ~1. U ~ O N > .C 'r ~~ ~ ~' ~ N ~, U c~ ,~
° ~ M ° '~ U ~ ~ .~ U C~ b-0 ~ b U O.y' ~ G7 U O ~ r"; ~ O U ~'
c~ > ° V7 1..~ .
U~_~_3,~ ~~G z~o~~," ~-~rnOQ.UC~ ~~c~~°°''i'~,.~.,w3
N O O ,--~ c~
.~'~N_ ,., ~°~_cd~V~~yO~N~O,.~.~U~~.S~'~~~~0
'~ ~ .c ~ o ~ .c ~ '~ ~ .~ ° v ~U ~ ~ U
> ~. ~ ~ ~' ... U .c
N N .~ j ~ '° °~ ~, N e~ ~ U ~N O ~ N c~ ~ ~ o N ~~ ,.., ~
cUd ~ E-, c~i ~
N ~ m ~ b c~ M b ~ d ~,' ~ ~ N .~ ~ ~d O ~ ,~ ~ N ~ ~ ~ N
a- IN it U v7 ~ a, VJ
G. y ~ ~ U ~ ~ ~ U ~ cd W ° ~ ~ ,.~, N C V ° ~ ~ U .~ ~ O ~
~ ~ ~ O O
U ..'i'r ''~'i G~i y >, U ~ ~ ~ m .b ~..v', ~ O c~ ~ 'n n] cd ~ c~ 0 y C~" ~
~ c~ ~ ,~'-, t.,~ ' U .S", U U ~., 4: ~ ,~ p ~d O .'~_ 4.w Cp O v~
~~o ~ o~"~ ~zy ~ ~'~ o ~~y ~ ~ ~°~ o o~ ~~ ~ ~ ~w_~
U c~ W r ~ a, it M ~+r '~ ~ p..., . c~ ~ cd H W c~ . c~ ~ ~ L~ ar ~ ~ it ~ O
Gl, 4r
W ~
O
~ U ° O .~
. o ~r E-~ . ~ N
N C
O ;~ . C'~'' O N ~-O. t~:,
U Glyr
N . M
D\
Pa G,
U
00 a\
205
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
w .C N
c .= ~ ~ a~ o " o >,
W n ~ ~ v ~a ~ ° >' > ~ w ~ ~ V ~ >, s~ ~ ~ O ~ U
C ~ ~ O ~ d ~ ~ N s., '-' ~ ° b c~ y; '~ N j ~ ° Q\ y b0 A.
'i'
~~ra~~+~ar~u.~~:~,.~ ~UOOnW.d~~°~a~~~3~.b°,o~a~M.~~Wv~
~ 'b o O ° ~ _O G .'~-~'' b ~ 'd c~ ~' ~ cd ~ ~ U C. ~' O ~d ~ ~ 00 O
'C ~
y~° Yr~~C~.~~ C~~f~..>-n~Or'~,r"a~V~J~.r VJ C~~NM~~1"i._~
oo.~a~~va~ b~~ ~~~°~b°~oa~~,~~~'!v~a~
~ O O ° O 3 ~ ~y ~ ~ G ~ 'b w p ~ ~ '~" N ~ ~ ~b ~ c~ ~ _~ ~'
cet~~..'v Ncd~~'~V c~~GO~"~z~ ~'d~°~b0~'O°~
C 'L'' ~ N V ~"' p ,i: '~"' .S"~, ~O Y p~p ~ V ~ ~ 'ice.. ~ ,~ V '~-~' ~
o '° ,~ " a, 0 3 ' -~ :.° ~ ~ ov .n a~ a. ~ ° ';r ~ TS C.
. ~ ~ ~ a~ o
3 ~~ vow o~'° v ~~N~ ~.~ v ~'°r-~~U>,~
V
~ 3 ° o°~,o:b ~ ~ ~ o' "Y o ~ ~_ N ~''W a ~~ .~ ~W
va,°°~'wa >,o'~~~,~o~~~~jEM-i>~3~od~~°N.~°~o
a..~~~~~~VN~VN~~>U'~.br'00°~._-.v~"_-.~,~._.~.>t-V~U~,~~~'C
G".'.' ran" V ~''p ~. b U M N~G O ~ ~~~.~d ° .~ Gln~~O.,' U"
c~C ~ w G1. ~ ~ ~ N b0 ° ~ v~ N V U ~" N
>, ~ 3 s~ ~ . ~ .~ ° ° 3 ,~ a> C o ' U
i~U.y~~Vuc~~U'~y'~y~"Na~.~.'~,HV~~,.,~,'..'.~~~ au~0'C'., NH.
G. ~ ~ '.r '~ ,> > ~n ~ C/7 '~ ''-' ~ ° ~d o~ p ~ '~ ~~ c~ °) w
~ ~w a~ ~ V d w
a~ o ' ~ ~ c ~ ~ ~ N :_° M ~ o
~ ,O U~, U ~ + V c~ y ~ ~ .; ~O t., ~ C. '~", ~ V ,~ M ~ ~~..t- ~ b V iOG~'
.~Q U ~ ,~ cd
~o ~ " 3 ~ can ~ °' '~ ° a. ~ ø. ~ ~ own ,~ ~ ~ -d ~" ~ a. ~
°~' Q'' ~ ~ ~ '~'
n~o
v oQ ~ c:~ i~ oo'~ ~ ~° ~ o g~:~ ~.~4a ,~ ~~~ °.° o g
~o..c ° ao
'_' w b .~y .b ° c~ ~ O > '~ s. 'G >, c~ N ~ ' t-. ;~ O ~ 01 V ~p c,
o ~ w o ~ ~ ~c ~ ~ ~ ~ a ~ ~ o . a. o. ~
.!7 m .O ''_' ~U N U .D >' N vl V it ~ a.~ N ..r U
N~~N~~,F'~' ~,..~~ U N,.~.,~>N.'~~,'wO,..U.~ OO b0~.>O" NON
N U ~ s5 ~.' ~..' U 1-i c~ N ...W-~J Vi O c~ ~ ,., O .t'. ~ ~ .TJ au O~ ~ i.r
N i.~. ~ ~ ~ ~ ~N ~ ~ -~ O O ~ Gp ~y ~ ~~ tin U
V ~O C V iG ~ '~' ~ ~ '~ .~ w 'b ~ ~" N G ~ p ~ ~ y t,_, ~ '.~ .fl
N ~'., ~ ~; ON ~ V ~ .~.I N c~ O ~ w M O m ~ ~ b ~ U N ~ w -pn .~ -O >>
~.. E-i ,.., ~.. .r >, U O i--mn O ~ O ~' O O O ~ U ~ c~
N O O ~ ~ ~ > :~ ~ ~ c~ ~ O m ~ N ~ N .~ 'n V c~ ~ O w
.S." ~ 'aWL Y V V .~.' ~ a~ N ~ ~ a~ ~ ~,. 'C tVn M G~", c~ V .'~. U p
3c~0°~'~~3° .S".~ ~~~~''~''C'''dNs,O",~'~CJc~O~n~~N ~:;w~~,.Od
'~'b0'',~~"~°~~.~ c~'-
'~"'bD''~,V''~,~~JNv'~'bc~~bD~~'~'NCJ°>'~.C'"
~ O :... ~ .b U ~ ~ > G ~ 0 ~ ~ ran '-' N N ~ V N ~ O '~' ~ '~ sØ V ~ >
d C7 a~ ~ U ~
M
O p., °
'C O ~'' ~ 0
U G c~ ~a.r
U .~ O
..>. C_.~ at ~ ~ ~d
° .b ' cn ~ o U
dd~~na. a.~~-.
M M
O O
~r
U U
a\ o,
206
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
a~
.U ~~ O U ~ .~ U cn "~~ .~ s~~ ~ U
N N a> ~ . y c~ .~ ~., U U >, ~
~ oo ~ ~ ~ ~0 0 4, ~° ~ ~ a, a~ -d >, ~ 0 4.
V vy' v~ vi '.~ ~ ~ d ~ ,~ 'N c~ O 'C ~ ~ [+" ~ ~ ° n .~ ~ ~' ~ .~
U , r
c~ .4; b O O ~' ~' d M ~ tn U N .r ;,d C ~ a.~W.r' U ~ w v ~ ccf a' :~ p
ccf ~ Q ~ E"~ .~ ~. ~ ~ ~ n M ~ ~ ~ ~ .f", O ~ j .O O ~ ~ U >, V ~ O bD
.Ut",O~N~01~_D~~~p~ '~~~~~V GW >'c~dNyC y
.~,OO.~zN~~~C7~~I"~~NN~ 'dU~.-~~'~~~~~~>ND 'bNy.'
O L1 ~ ~,' p U .. .. ~O V V N p ~ .Y ~ .y O N V y cn
w ~ ~ O ~ i~ cd N ° ~ ~ >> G v~ c~ ~ y ~ ~ ,r' ' ~,.~, ~ s~" ~ ,~_ cd
~~ .b ~ p GO:~ .a .~ ~ ~ ~ 3 O ce3 ~-= ~~, fJ". ~p .~ w ~ w .'~ °
° ~ ° q ~ O ~v~
~ >, ~ Q7 G~ ~ NC ~ .' ~, ~ ~ ~ ~.., . ° y.,r U ~" ~ a, of ~ ~", .~.'
~_00~~.~,'N~N~,~~_~v~ °G°~0~~~~~bO~~~ ~ObD
cdCO~>U~_L;..U~y., '~~ in~.b.~G ~~""~ y'b m
m N O C". ~
~'Ut~nN 'C'".tU.'..~..x~O~~w~~ W~UUx~~OU>>~U W
b.0 ~ ~ ~ ~ ~ ~ b ~ ~ W ~ O ~ ~ w 'fl
C N . ~-' > p '~ b 00 O ~ ,.0, -p v~ c~ y ~ .~ ,~ .L~ m
0 0 ~ ~ ~ ~ j ~ ~ ~ ~ ~ ~ °~ G .v o ° ~ 3 " >' 3 ~ ~ on
~~pd ~ v ~ ~Q.'~r; U.-: '~".~ 'C rUn ~:j'O4-U~. c~i~1'pNp"-' O -'n~, ii ~'C
.r 4., :b ~ yV" >' m N N ~, 00 .... O cC U p ~ O~ ~O ° b-0 ~
y >, O p ~ ~m O WO 01 cd ~.. c~ ~ ~ ~ b T3 ~
E., o o ~ a°A ~ E-' ,Q. y'MO c~ ~ _'~ p. ~ ~ ;~ ~ ~ -~ ° ~
o~o o ~
o ° ; ~~ o ~ ° ~ ~ w ~ ~ w ~ ~° ~° a o ~ ~
° ~ ~ ~ W
U G ~ O ~".. ,,~~,, .: ~ ~ ~ ~ ~ . .i» .S".' ~ 'i' ~ U c~ C 'b Cr'
° .n z ° o °~' o ~ c w :j ~ ° ~, H .~ ~ ø' 3 ~~ o
o an o y ° ~ ~ ~ °''
ces ,y'-' ~ -d a~ .~ .~ v~ a~ O p '''y'.~' a~ a~ ~ ~ '~' v-' ."" ~ ,~ °
~ ~ ~ a~ ~ '~ 4,
'.~ ~ bD °~ cpC '-' p U N O Ga O ~ Q '.' U -_G ~. Q ~ U ~ U id ~ :-: ~
~ 0 ~ O O
~ ~-~.~,ow ayM ~ ~ o~oU 3 ~..~b~ >,~ ~.
O ~ '~ ~b ~ ~,Q' "~ ~ 00 ~ ~" ~V ~ ~ '~ ~ N ~ s.. ~ ~~ (~ U O U ~ ...~ ~ ~ 0.
N G ~: cd G ~ ~ ~ ~ ~ ~_ c~ p ,~ A. ~ ~ ~ ° ,~ > ~ ~ ~ s.~ W N ~ w
~ O d ~ ~ " N ~ ~'' ~ ''' c~ ~ 'd G. .~ '-' ~ . ~ ~ ~ . can T3 ~~
~~", '+" ~ .b ~O l~ ~, w ~ .b 4.~ c~ w, 4-.~ O ~ ~O ~ ~ ~ ~~ ~ ~ c~ ~.. w
~d ~ a~ o ~~ a ~:-;a~ °~, ° o ~ o o ~. .~ ~,~_ U °_ 0 0
~ a-a L~ v-, ~ ~ N ~ ~ ~ ,~ ~ ° '.N P~' CUd ° N ~ a ~ d c~C U
NO~~p~~~°~ ~~p 'G~c~v~p ~s.~.,~~NNbOv,.-~c~~~''~.,~
O O .t"" 3 C ~O ~ y ~ U ~ ~ ~ cd f0 c~ ~ ~ ~ N ~~,r C~ .~ ~ N ~ Z' y cYC '~,
t~/~ ~ N
O ° ~L ~ b .~'.n ° it ~ it C~ .t.n' ~, '~ ~ ~ Cry ~ ' ~r
>CC pN ~~OO~'~~1 ~~NCr_VJ CCS~~~~'~UC~~~i-O~rpCC~C~L~VJ
H d cd 3 . .r w ~ c~ ~ ~ r-mr ... O. .~ t1. U x U c~ . w f3, ,..~ C/~ N a.~ ~
~r U cd
~..
O ~ Q ~ '" O .~ O
cd
U . U
~~ ~ ~ ~ U tn ~~ ~ ~ -~ ~ ~~ V
> rU/W O U ~ U ~~ Y W Ci .L" '"
~~ .s~. O G. ~ ~ O
~zU~a. Qdw
M M
O
207
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
a, ~ j ~ ~ ...
.,
w° ~ W ..~ H M ~n ..
>, ~ y an on
c~ O. NOVA 0,.~,~' ~, N O '~'~ O O c'~n'i p~NON'~~' H cd
y V N C7~ ~ ~ ~' >,~ ~ NOM~~,~ c~
.f, ~ '-' ~ ~,, U ~ 'C d0 N ~, O w ~ a.W.r O ~ i U N 'C Q
~,,> .~ ~ ~ ~ ~, oan a ~ ~ ~ ~ ~ ~a ~ '~ ~ ~ .~ vW N ~ " ~ i
.~ ,,, E-, u. ~" O ~ w ~ ~ G ..~ c~ ~ ~ op cn c~ O c~ . '~" a~
Pad ,.M~tr '~O~°QC~U ~N'b~~' 0~0~"'~-"O~ ~~
,U~ N U ~ O m ~ U ~ > ~ p" .~ a.'~', N ~ ~ ~, U ° ~ O ~ ~ M ~ C ~ 4._'
W ~ w ~ ~ ~ ~ °"i a EM-~ o ,~ ~ N .~ '° ~ ° ~ ~ ~ ~
.D ~ b x ~~ ~ _~ ~ o
i ~ .~ ,_, ~ M U ~ , U b ~ W N ~ s.. U O >, N 'b y b
O ~ O ~ ~ ~'", N .fl ' O ,~ '~" ~ k'' ~ '~~ ~ ~ 4'.' O ~ ~,, ~' YC N .C >>
a.U.. f..' .~.~
~ m . ~ p P.i ~ ~ ~, '1...' ' O .~ U 'b ~,'~, ~ a1 'd ~ ~"' cd ''., ~ ..~'a 'b
,s..' c~ N
~W ~O o >'~ N ~ ~ ~-v a y,~'~ ~.., ~ .r.'.b.~ ~~' o,r.~'.'n ~ ~ ° c o
'bNNp.--r '~~,~v~0 ~(~]v~,~~-'V,-,~t~~"'~~pp~ ~yN_~~..U°_
~ E-~ ~ N ., f, . ~ N N N ~ .w
O . ~ ~~ i.~r y,U, b-0 'L >> tn v~ ,Us," ,..--,_, ~ C t, .b >, p v ,~, p .~
'O O ~ v~ 0 cd ~ ~ ° N '" . v O .~ ~ U 4-. 'b ° ~ U ~ b s~ N ~
U bD tn 'b p. ~ ~ 'd
>bbQ\.~b~~Uc~c~ ~ 'Z,~'> N°~N~~W c~~tny~.b~v~
~y~~00>,~~~~.~~ ...n~.°~3~UOOUU~'~~~~lt~b~>'c~°
c~ m Ov r~ Q ~b ~ GL N U cd : C~ ~ ~ >, ~ cUn ~ 01 O~ ..U.~ ~ O O y ~'
O N b M ~ ~O N ~_"',U" ,°~..5. ~ O .f~.' ~,.,~, .~ .>.. .~ ~ r+Y,
° t~-i y,~0 ~,'' .~.r 'b N ~_ ~ p ~ Q. N ~ bD O
'ice ~ y O_1 ~_ N _O U .t". ~'Q ~Q ~ ~~ U ~ ~ ~ ~.' ø' ~ O ~ U M V7
~y.~. b0>,~'b3°'~NH'~b ,~~yU~,~N~0U0~' N. 4
.4"'.. ~..' c~ U N ~ .s' G~", cd -~"" O s"' y ~ >> U ~a:~ .... ~ b c~ ry ~ ~ G
U ~ U _O
'b b~Q.~Gw~~~~~~~~,N~.~~~N~.~O
U Q U ~ ~ N O cUd ~ 0 .f. .~ U t1. ~ ~ V ~ ~ .U~..! ~ U ~ ~ - . ~ ~ ,~ ~ ~ ~ ~
V N
U N G ,., ~ ~ .C ~b ,-~y O. O c~ GO ~ O y~ ~ ~ y~ ~ p C. U cd ~ ~ >, ~
.D ''~, U ~ ~ U N N ~ b W Z., t, N ° ° O C» V~ ~+, .f, ,.,
s-.I~ON~Uc~OOc~~U~~>,~~U °~U~ ,W n~~'~O~O
~ O ~ ~ ~ '+. U :j s.U. .,.'n, U G4 ~ ~ ~ :~ ~ ~ O ,~ ~ C 'b ~ U c~ G. ~ ~
,+., s...
O~Ut~. ~~N~b'Nly ,O ~~.>.°~~~""~~E.U.OU °a..
~~ > ~ ~ ~ ~ ~ °o.~W°Z:~~~ ox ~ ~_o ~,Uy ~ 3''~ aW.c~~ a o-d
.~~E-Hv'°~~~.~~~°~'yc~U~
O.UOU°.~U,~O~O~ OUr.». O,r.~'-'~,_,d+.~b~ O
_o '~ ~ ~y~~_a~ ~,~,~_'vw ~ ~.bb ~ o ~ ~ >-o o~_~ '_o o ~bb~ ~
cd .b ~ o b Ov U ~ ~ b ~ by ° ~ ~ ~ U ~'' U ° t~~'n ~ U aW' U ~
~ ~ ~ 'G
cd '~ ~ ~ a.~ c~ N .~ y--y0 y b ~ ~G1'' ~ c~ p . O ~ N ~.U, ~ x s.. ~ 4'.'
'~ .~ N N W pp ~ U f~. ~ p cC G~-, ~ ~ '~ 4=,, ° ~ ~ Q O ~' c~ 0 ~ O
~~, >,
N~r~~C~ 0.~...~,N~G4~~Q'>bc~N' '~Oc~C~.Nt".,
~ .~ ,~ °o ~ ~ ~ ~ z y ~ ~ y o ~ x ~. ~ ~ ~ ~ o 0
~ W a. ~ U U ~n ~ W ~...yo ~ ~ c. .~ . ~ ~ ~ E-~ w° ~ ... ~ ~ C7 ~G ~ ~
~
° O
O
_~c~ .Uc~
Q b-0 b4
O -~-~ ~ ~
'v~ a: a~ E~ ~ d b
0 0
00 00
0 0
208
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
00
N >, O ~ ~O "~ ~ y N ~ ~ a ~ '~ O ~ ,~ ~ ~' U ~ ~a U~ ~U ~ N ~ ~
o°°a~Y"ic~v~~a~~ ~~.,~~o~~~~ '~~U.3.~~'n ~o~xa
U ~ ~~ ~.~. ~ M ~ ~ U _4: ~ N U ~ ~ C.' ~ i; ,tU,' ,SV." ~ Y ~ ~b ,.p, ~' 'b ~
.O U U
w ~ a O a '° ~ ,~ H ..~ O 'a O ~ '~ ~a ~ ° o y ~ p ~, ~ U ~ c ~
W '~
~.V, ~ ~ (~ pV'7p '~ N ~, ~' ~"" O ~ y ~. O c~ ~ . ~ ~ ~ ~ b ~ y ~ p Ar
r.~'~ p'bi-v ~ U.~ ~, ,~~ ~ N.a ~.r CM~0~1~~ ~ O ~ ~ '~~' OU.~."' N
'~oio ~ b ~
UOw~O~~ .!'.,gyp .!'". ~~,~..,p'~..~~UN~~~.,~~ .~,J~f...l" UU ~pV~'..Gpv
~.~oa~...~°'.~,~a ao~. w~'vo°'~w~.U,~~oo 3aoa
oovy.YW~ °~~~~~~°~~M~~'~~E''°_p-' ov~o>
~'ic~Ud~~V~"'.. ,.00~~'~c~~~UQ~~~~U~~~ ~'a:~~Q~U
d ~ ~ H ~ ~ ~ ~ ~ .~ ~ ~ v° .b o ~ U ~ .~ ° ~ ~ 3 ~ ~~ ~G,, i
a~o~o~."~aQ. a.b-d~U~ a~~~>,Va~~~'..~a~ ~>~.~.,
.~ a ,~ c a ~ ~e ~.. ,~ ~ a a~ ~ b W ~ ~ .r ~ ~ ~ O ~ O
d4p~bU'~''NU~~ ~~~p,,~~--ate UNiV.d~~,y,V~O~ ~~V
t-V.~y~W7U~pV~~3 ~~V~p~>>~Y~~~~N"ctt.'Cc~CC~G ~'~~c~0
O~C/~~ ' ~~.pp ~:b~O~~~N'">Ny~~ ~ OwO.b
a-'yaa~ °C~I~O~ ~~~ ~~cov~ovz~an~.~'p~.~ O~UoU
~ an i ~ ~ ~ ~ ~ ~ >,'~ _~ a ~ ~ oo '~ o '~ >' U p ~' ~'"'~ W ': W
N G. ~ N ~ ~ ~O blD U bU ~ c~ ~ f3, ~ ~ ~ ~ U '~ ~ ~ OU ~ <Y U ~' ~ ~ ar
> a > ~ d. .°3 ai H ~ ~ ~ " . ~ . rn O a ~ _a ~ ,~ p. a
fsr o ~.~., W w .b ;-; ,~ ~ ~ ~ ~ ~ C~.~ N N ~ ~ p :~
'*' " p~ ~ ~ x M O ~ ~" : i ~' O N O ~ ~ U >, ~ N ~ ~ ~ '~ O '~ ~ O
a., U p U N M ' ~ aJ O ~ w ~y '~ U M 'Zy ~.~ ,~ ~ ~' G ~', b0 ;= cd
b ~~N.~ N ~y O ~ U'-' ~'~'(, ~' c~:~ ~ c~ U a O U
,.ri ~ Cd ~ '~ ~ ~p U b ~ ~ V7 ~ ~r ~ T, ~ ~ ~ ~ ~ p G .~ p ~ ~ C~
c~C ~ ~ GLc~00M.~~p U 3,~ ,~,.~ ~,~_~~ ~ ~ O U~ ~ ~ cC ~'.O.O
p,~4~>~~M~Ny.,.,a~.~~NU~cct~V O~~NO::~~'QU~ O~~p.
O cn O cC i ~ cC cn ~ > ~ ~"'., V .~ O ~ c~ U ~ ,~'_, p ,-ar ~; 'a:yn N
~.»,o.~NM a~>,..» .-,~a~a>,~'~W.~a~a~ anw a.a~>
V 'd ~ r~.r U c~ ~ U ~ ~ O U U ~~ ~ "C O ~' ~ A" U U G ,d O~ 4. ~ .C ~ .C
.~ ~ ~ ~-, U ~ O '~ >> '~ ,~ ~ a~ w p U O a U a ~ ~°~' ~ '~ :.: ~ ~ ~ ~
O .~ W O
.t".~ ~~~' O .T'~"~'~''3N~iG ~~'d U~': +rn',t~"~W UN~c~NUN a,''.'
c~wp,..'''~~0~~~~0,~~~U~~~~~i~ .~~~p"~U~r;O4=a~~b
.b0 .~~O~ U~O~ c~S~~ ~c~~U.O'~'Ly,~ai~N~ac~00 "'v_~O~N
.S~.NU~N~N~~UU_~,U~w'C3c~0 V ~UNG~.~,.,tN-~bU'dQ1,00~~~O
cd O iG cd N ~ . w .~ ~ ~d ~ O N > c~ ~ U ~ x ~ ,~ m p G, >> O ~ ~ O V
'btV-.vi ~..r~ppt-'U~O~>~ 7,a ~~~O ~''~,~Nvi~'bON~U
OGLU~~'NN~~~';;c~>,O,~V~~,~dU~.~~~~ ~yM~,~c~a
°' y, ~ '~, o 0 0 -d ~ o ~ ~ ~ >, y ~ ~ ~, o ,~ ~ ~ ~ ~ v a rx ~ a~ ~ o
''' p ~," ~n V O .b ~' ~ ~ O ~ rG ~ O ~ ~n N ;b W ~ ~ .~ M '~
pp'~VO~NV~U~Uc~V~ WQ''~~V'11~00b~.~~l~~~~.,~_~.r
W au ~ a "~ ~ ~ ~ N ~ ~ ~ y U ~ ~ H ..~, l~ 00 w O ~ N
'b '~ ~ t+ O ~ ~ ~ p cpn .:, ~ ~ . ~, O .~ ~ ~", ~ c~ ,~ ,~ ~ ~ ~ b0 _c~'C O
,~ a ~ on ~ oO t~ ~ 3 ~, ~ a ~ . ~ ~s on ~~ M a~ ~ ~, o ,~ . >, ~, ~s
~ b ~ b ~ ~ ~ a >, ~ ~ a~ a~ U a 'b ~ r, ,.., ~' 'b ~~, ~ " ~ d ~ a a
c~OvQ\U ~d~>Ucd.~O~O~O~N~~.~ C~v~ V~b-0O
;J ~ .~ ~ ~ ~ ..... ~ ~ ;~ ~ .~ U U ~ ~ ~ ~D ... U a on x v~ 3 U ~ ~ ~ ~s
V .y ~ _m O O ,a~..m..n
'~oiD G a a '~ ~ ~ ~ ~ ~'~ 'a ~''~''' o
N a ~ a . ~ U U
O GL '~" U y ._~ . U GL ~ bD ~ O Gr
c~ N t' ~ ~ V V ~ ~ W L
a.n it N . a L: U ~ U . .~ ~ y au
M O1
z
~x
N
209
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o .d
~' N ~ ~ ~ ° w ~ ~ ° ~ ~>, o ~ on
~?c~~?w..-d ~.~ .~Uc~.c ~o>,~~~OU~~~ ~c~
'~ > ~b O ~ G.p O O O ~y O .'~~" N _N 00 O .O ~'~ '~ ~ 's',.;' ~ '~ O ~ ~' c~
GN~N~~C3.N ~p"~.GOr., nN'-'~'OO~~O.U~N ~~U~~Uwc~
O ~ ~ ~ ~ .=. ~ ~ ~' O b ~O b 'd O '~ ~ ~ '~ ~ O ~ ~ O ~ _N O ~O
~j~~~N~~~ Uf3.0'~0~~~~'C1~~G~.N>'O_O~ '~~O''~'~X
~W V'~~ V Uc~O'~i.U, y'~cCQN~ ~x"~v>>s.V. N~~.~U~W
~V~~ ~bD~ . ~U ~~~~~C~", ~~ cn~UO 3~C~~ .r.,U
4-~ 'O O .1-J 'b ~ " ~ d 'b 4..~ c~ 4: O C~ ~ ~ ~ U '~ 'n "O ~ c~
O O U ~ ~ ',=, ~ ' 'O a~ ~ ~n ~ b bU ~ >, ~a! V U ~ ~ .~ ~C ,r ,~ ~ N N y 'y
S~' O wr .s~" ~ U ~ y". N N >> -d O ~ cC ~ c~ -~ amn a~ .S". . .~",'~ '-' .--~
~ w
i a o ~' o ~ ~' ~ ~ °'° N ~ ~ ~ a~ > ~ an o 3 Q o ~s ~a ~ a~ w w
a, ~
-C~., '~ ;-~ N .~ ~ '~ ~~ vi U .C ~ ~ ~ p 'y U ., p ~ O,'~' ' N '.~~, ,~ 'iC
'~'~ O ((11~~ pulp N 'n
~U~c~b~~OUd~OD~~~~~ ~~'-'~b~UpNb~i..~O
;~ ~ ~ ~ ,"V., ~ tin O ~ '~" U .0i-'., V U G ~ ,.V, ~ > .~ cd ~ b ~ V s.. '"'
~ ~' A 0 ~ _~ .b
-:". ~ '~ ,~_, >, cd U Cl. y", c~ O G ~~ b 'O O~ ~ .~ ,b U N O ~ 0 0 U ~ ~ ,~
~C ~.f.,
OOU~".,V~.~''"~bD~~~.f.~.'.~OCL~ N~U~U~'t,'~'GOG~" .S-'. 4r~,
"' .b ~ l~ ~ p ~ O U 4..' .b ,b ~,O ' U ~ ~ U ~ c~f O c~ O'' ..~.~ N Q. >, Q
c~ ~ O c~
Y'cti ~~N~ U~~ c0U3vr~~U4-.U ~QU~O:b~f3r>N~O.G
'n ~ N N x c~ ~p ~ .O~ vyn >, O ~ c~ c~ ~ O w c~ N w ~ b0 N ~ ~+. '~ ~ a5 ~y
~.
'~ _a~ ~ " ~ ~ .~ a; ~ ~ ~.r~. .Q v~ ~ 'b w ~ ~ w o U ~ ~ _~ a~
° ~ ~~_ y
bD ~ ~ l~ _>, U .~~' y; ~ N V U ~ ._~ p O 'b ;-d T ~? ~ ~ . 'rte' ~ y O O O
.QUp~pN N~'d'~ E".i,~ L'n'~ V >~,~ .~."~ Orc~n U V >>,~3 c~d~'~' V ~~'~ ø,~
do3,~o0.~ 3~ao~~~~~'~b~o~o ~~~~,~°
v~ ~ ~ ~ a~ o ~ E-~ ,~ ~''~ ~ ~ on 'b
;b~~U~~~~.~~~ ,b.o~,~o~o°~~,N,~o~~;~~~>Ca7~.c
O ~ U O ~ bD m .b U .~ 4-a s., C/~ O O . ~ ~-' 'C ~ ~ m ~ y N c~ ~ N ~ t-r
~,~~W' ~ ~ ° ~ o 0 0 ~U ~, a ~, o off- N.~ ~ -d a~ o °~~ ~a o
_i .b N O Q ~ >, . s., ~ ~ N O '~ >, U : N y~ ~ c~ ~ ~-~ ~ ~ N ~ C~ 'r-~ . ~
~., b ~ i~ ~ U v~ ~ i vi .., c~ ~ -G
~" 'yes" ~ '~ ~" ~ ,~ ~ '~ ~ (, a:u .~ ~ .> > ~~ ar v it >' ~~'-, >> ~~~~ Q y
~ ~.V.' N
Gp ~O ~ cC i.V, ' cd ~ ~ G' .r.' ~ O 4-W' N y V a' ~ N 00 U N '~ ~ ~ a' ~ .
.>r
"C O ~ U N N ~ ~ ~ w ~ C ,yd O G~.i ~ ~ ~ ~ O ~ V '~,~ t, ~ .~ V ~ ~ ~ ~~ ~
.f~' a, cn
~ cn N N ~ _> 'C ~U 4.øw'' ~' >, b _~ > O ~ ..~.. U ~.. ~ U ~ O b°~ O V
v~~'b°~~n'~~~~~O~E-'N°w~..'~:~~G1.~~
~ N ~ '-" O .5~, U ~ ° .N w y ~ ..t"" ,~ U .T0.1 ° ~ ~.~i ,s"' ~
~ > .° '~ ~ .s_i ~ ~ ..~~.
wV~r~ ~~p. ~N~ ~~pp~ O~,m
° ° oo.~ ~ ~ ~~~~~ ~U o ~.~ ~~ ~'~o ~ ~ oZZ ~ ~ o o~a~ o
.c . .~,c o ~ ~,, .c a~ U .~, ~ ~ ~ a~ ~ ~ , o c~ y y ~ ~ b-0 ~ ,~ ~ ~,o,
C7 o Q. N 4.. U ay .~ ~.., . ~ a~ a~ ~~ 'o o U °
0 o.c~;~~. c o. ~r~o~~~'~s ° a~.~o ~~°~o.~~_
-p U ~ ~ ~ >, >, .~ cn '~ O ~ ~ ..~..~ j, ~ ~.. ~ 'C U ~ ~ ~ y.., ~ ~ O V c~
w N ~p ' c~ w, ~ .S-', . .~ ~, ~ U vi O bD .t'.~ U ~.. 7..
o Wo ov w ~ ~ o ~ ~ :~ ~ ° ° ° ~+. >, ° on U
° >, > o o ~ ~ a
o. ~ r~ ~ o .., W U C7 4.., ~ a, a. a. ~ ~s o U ~ ~ rr~ ... ~ ~s ~''~' -d ~ d
~ ~ ~. ~1 ~ C7
0 0 ~
C ~ .~ w ~ ~ U
~o w .o ~ ~ ~ .~ ~ o
O U C~ ~ a:. C .S-'. U
.r "~~' U ~ ~ A O V
G. O
.~ 0.. C7 fx L" ~ > ,.a~. a~
O O
a\
N M
210
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
'b'~ c~:-: ~ O '~",.~,~~M., ~~,.?,~'~' °~~i ~ >'N ~ ~E~ v bppOw
O ~ O U ~ O >' N ~ ~ c~ O U .3 .~ ~ ~ ~ " O
>,..N.i~VC~NON.Da~J~' O~~O~w,~bp~O~.~~E-'i .~."t-a~bU .~.~C
O O ~ N ~ G~ ~ >, >, [-[-M-ii p ~ ~ ~ X N ~ O ~ ~ ... ~ .' ~ O ~ ~~ ~ ~ .O
b0.0
CL by O~ ~ by N U ~C M ~ O ~ c~ O ~' ~ y", ~ M W ~ .~ .O w '~ U ~ O C~ c~
~ tU-n ~ ~ C, ~ ~ ~ :b N ~ ~ ~ ~ O c~ '~ ~ ~ U cC
N.~~N~0000 ~"O~'~w GDy~~~.~~~s,J" U~z 'b
,., Cv '~ p ~. a ~ b O ~ ~ t-~ U v~ U O
NOV p.~ U.Y :: O n ~ ~ G~~_ ~~M s.U,T~.v~ UH ~CL'
y '~ ~ o~ o ,~ ~ b U ~ ~ o ° o ~ ~ '~ >, ~ ~~ ~
~°o~c~°~~a.~c,~°n~U"b~G,, ~°°o°>~o~u-
d~°~°p;U~~oo~ ~n-d~
pp~n ~ ~E''~Ob ~~.'.~y:.,~~~'d0 U~~~,ci.vN 'N
O l~ N ,., ~ U a3 'd ~C y U ~ cd ~~ >, N y yn 'G
~~.~'b~M Ux.~ ~ °s~' ~ '~ ~ ca.~~ ~
U N ,C~. O am p, pn ~n U ~ ~ 'y a.u ,,, f..'
°~d .~ ~ ~.~ d°,p o >,U:b ~ c ~ o ~~ onG ° o ."
~~~c~Zo o ° ~~ ~~ 'bP ~ ~ ~ Ovioy. c,~~ ~. ~,-,
>,'U _~ ~ ,~ ~ o°~o v o
N ~ ~ ~ ~ N N u. ~ ~ M ~ .O c~ CO N ed ~ L1. > ~ ~ ~ U ~ ~ O b ~ ~ b-0
,~~~~~~W~~N~~ ,.d,~bc~~V~~yO~rN "at0,~'~~ N
c~a~U~v'.'"p~'~~~~~a''~4.Ww~O~ ~U~N~p~,N
o . '~"~' '~ ~ ,~ °' 3 yr ~ ~ O ~ ° ~ ~ () >, ,~ U ~ ~ tOn ~ r;
~O :..
_ ~; >, ,.a --. ~ U .~ ° _ai ~ .~ a a. b U ~ > ~ ~ .~ a
., ~.~o o ~ ~ ~ ° ~ o ~ °. ~ ~ a~ ~ o ~ o ~ o.~,~.,~ ~ X0.1 a.3.
a'~U.~~~.~~G~U~~'~, ~~ O'-'yes
a,..,b~~~U~~c~~t3.~~iGw~V U'~~~CO~~~O.'UUp-d~ ~~O
pO~Ny"~~~'n~'bOWG"~.-~~L~~~~iC,~'b~'~UUc~bp~U O
w M ~ O ,_~ ~' >' .' c~ ,~ U O U O O U ~ ~ s~ c~ ':~ ' ~ ~ ~ O ~O N
N ~ ~p ~~ ~ O ~ ~ i.U.n U b ~ 'b U ~ 'a; +~r C W U N ~ ftt N U N w
~N~N~y~byn~~O~c~LI~~~~'U'~NC"~~~U'n '~00 ~N
G7 U O ,y~, U ~ U y, w ,~'"~ c~ U C~. ~ N by .b O~ w
0 0 ~ ~ o o '~ ~ .~ ~ ~ ~r ° o~u o ° > ~ ~ v ~ x ~ -~ ~ ~ ~ a.
>, o r, ~ w o
f~. ~ N M ~ p~p .~ O _cd ~ ~ .~ wp".~ U ~ ~ ~ ,~ ~~ N 3 ,~ ~ N ~ .a a M ~ b 0.
O >, U ~ ~ ~ ~ .~ Gp øC' s.N. O ~.. ~ O ~ ~ y >' ~~" N c~ ~ O O ~.' b ,~ ~ 'v~
M .~,~. O O
~O~'dNp~',~~~GU Ucd>,O.~U~c~.CbO'~,~~'~c~ ~4"''
~,~-o~~.... :br~eb>'~~ ~>,,_~,3a~wo~UO~o~~v~~Y~..,a\x
OWE-d~~~O~~~OO ~w;~W ~~,~ M c~
U ~ . c~ ,~ .--i ~ U ~ ~ ~ y~ U ~ .~'., W GL .r ~ ~ l~ O w0 'G ~ ,~ ~ I~ ~ ~ U
Q'.~ W~'''~~wb ~.~ as ~ 'n ~ O O ~ ~ Ga\~ ~ V y~_E".~t~
~.~~', O~NO~~U_O>~tnG."~~~c~L"iGOvMyc~~~OU i~~ ~f3~
~ N ~ N ~ .t'. x ~ y.., vl U N U O b ~ ~ ...~ C: N ~i ~ '" ~ ~ G '-' rUn
,~~ .~~.,.~bDU~NN'~'~0~~ .~~.,Uc~.~O~O~OtnN~~'~ ~ Nm
o. ... a~ . .~ C7 a~ ~ an 3 c~. U ~ . U U ~ ~ wo ~. U ~ wo x v~ 3 U ~ ~4 v ~
w
O ~G ~ w
O
_O LL ~ ~ p
~au
~ U j
.~.~ U
y
O U b ~.,
v~U.~.a d~W
o\
O O
M
N
O
W
211
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
w
U c.~ ~ ,~ ~, a~ c~.~ . U M ~ m ,~
p b W ov EU", M ayo o w ° "b W ~ ov U E-
w ~ ~ t~ ~ ~ y. O N ~ ~ ~ ~ ~' M ~ ay ~ ~ U
~ ~ M ~ ~ V .b y :~ O ~ ~ G N ~ ~ ~ ~. U y 'b
> .~ 1.. 00 .~ pp .~ vWr" O O O > ~~ ~ 00 .~ dp ~ v~ 'r" ~ ø, c~C
'ice ~ ~ ...~~ a ~ ~ _~ ~~ ~ ''' f~ ~ ~ _>~ a _cti O N ~ c~
~ N 'p ~ p w O M ~ O ~U >> ~ ~ N ~d Ov O N O M ~ O '~'3' b V ~> cd ~ O
G~. > q N .~"y~ ~ ~ . ~ O ~ c~ C3. » N . ~ ,~ ~ O . ~ ~ ~ ~ w . ~ c~ v~
N ~ ~N U ~ ~ N n N 4-'~ U C, 'y O U ~ ~N U ~D Pa U dD U ~ N ..S-'~ _~ w G) ~D
~~_.~ .f'.
W ~~ ~ ~~ ~_a~i ~E,M", o b o ~W-o'y ~ ~~ ~_~ ~~, o ° ° ~
~n ,~ _U U M U ~ ~ O ~ .~ p ~ >, ~.~ N ~ ~ ~ ,~ .O D
O ~ y U ~ ~ N ~ v wO .k ~ O b0,0 ~ ~ U ~ .~ U ~ ' 0 ..~ ~ cd ~ O ~ c~
'y~maUQ,U~tn .~bcda:~~v~aUO,U~v~ NN~..~C7
a~ ~ ~ ~ w c~ ~' b 0 ~ y ~ a~ by ~ ~ w ~ ~ N p
w ~, y.~". ~ .~ O sr ~ ~ ~ :~ W ~ U w ~, ~ ~ .~ O ~"' >' ~ ~ ;.~ O y G.' ~ ~
.D
w W cat O U ~ >, ~ yn ~ ~' ~ ;.d w W cd O U ~", '' U U w ceS w b c~ ø,
b ~ O ,_~.., O .b ~ ,~., ~ ~O '~..' ~ b v O ~ ~ .b ~ y ~ ~,O > ~ c~ ~ s.. cd
x y C. O ~ y ~ b ~ ~ ~ ~ ~; ~ '~ ~ Cn ~ ~ y ~ b .~' >, ~
c~ O -'i'. "~ ~ ~ t~-~ N b-0 .l-'. >, ~n ~ c~ ~ _O . 'n "'' ~., sue. U b0
.~~~~, >, ~ ~ ~ ~ N -~~.
r.",~' y Up ~ ~ by L: .b ~ ~ ~'' ~ O c~ f,~~" a' UO N N ~ '~ ~ O O
ONpp~'n0 ~n'COOt~. Nc~~_OUpp,~'n0 v~'C~O,P, Up.,.'~c~GO.r
'~w~,_,'~Uo~oUb ~a~b~o:.~s~~Uo>,~~ w>,>~W~oG
O~.~TlG~U."~V~~, t.S .S'.',..,r' V~>'d~0~.~'O~N~c~~~' ~»f~.~ V4_ru
.,O~o~~o>,~~~c~c~.~'~c~,~.~~U°c~~>'~~c~c~.~wc~.Ow ~;~'b
~ ~" ~n O~ ~ ...w p .b a~ f3n N ~"-~ L ~ ~ v~ ~ ~ N b au G~ N ~ O pOp'' 3 O ~N
N ~ NO N O U ~ ~ ~ C', ~ cd ~ ~ U ~ ON N O U O ~ O
O ~a;, W r ~ ~ .~ y~ O N i., a '~ ~yr a.. ~ ... U C O ~ ~ ~ N
O ~ W. c~ ~ ~ ~ ~b 3 ~ .~ > U O ~ 'W . c~~' bD >, ~ ~~ 3 ~, ~ G r.. ~.~ N
~ O ,~ N ,~ ~ ~ ~ U ~N ~ ~ .~.~. ~ N ~ O "C7 ",.~, '~ cUn ~
O ~ ~ ,~ I~ ~' b ~ U ,b ~ ~ 3 ~ O~ O ~ O ,~ t~ b ~ U ,.S"y ~ ~ ~ N ~, ~ ',-~
G.'G:dW OM30~~~v~~U~,~A.'b;b(~~M30c~~0~~ ~N>
.~ a) .. N ~~ w v ~ ~ c~ C"» ~ cC cf., ~-~ ~ ~ ~ N ~ U ,~ >, ~ C ,~ v~ ~ N
U O U c~ ~N O cd ~ Up ~ ~~ ~ ~ O V O v ~ ~N O
V.b ~ ~'+-' ~b~~~ N~~ ~ ~ V:b~ ~.~ ~~ O p
s"..c~~NO~N~~~O~ ~'~~.Cc~pNO~N~~~O~~~O~t".
Ny~.~Ua.0~0'~~''~~~~~,ww..~o~~~~N~~c~p.,~
.~ a~ ~ o o a~ ~ .~ a~ U
O ._~ ~ p ~_ .S-'. °U '~ m ~ b4 N G' ~ O .~ ~ Q _~ G' ~ ,~,, ~ ~ ~ ~N ~
~ .~~~', ~ N ~ >> U
f~. U O U ° .~ ~ ,~ O ~ O w '~ O . p, U O U O '~ ~ ~ O ~ O .'~~'' N ~ O
''' O '~ y
b~Ubi-vU ~~~ ~ ~ ~ ~ ~ ~,~b Vin U ~b~ ~ yY,w O ~
0 p G1~ c~ b ~ ~ ~ c~ ~ ~ .~ ~ ~w~' ~ G ~ : >, -d ~ O~ ~ cd ~ ~ .~ c~ O ~ c~
~' ~.Ur
... .S-', ~ O~ >, .~,. C1, ~=. p a.. O ø, c~ ,r, ~ p~ >> C" C~. ~ O
Q. N W ~ ~ O ~~' ~ ~ O fn G. ~ ~~.t~. ~ A. N W ~ ~ O ~' ~ O O >' ~ c~ ~ a.. ø"
y,U.,
Nr~>,~~ctiO,O.N' j~~.~~>x~Nv~O'~U.~> c'~n0'C~. N
~W c.~UU° ~W~-d ~~ v ~.~W °c.~UU° ~WWb ~~~ ~W° vW
a
o ~ 'b a ..U,
.'
d0 >, O ~, tD >, O cd .y.U.
;~ ~ ~ U ~ ~ ~ ~' N U U
C%» ~~Wv~Qr ~1i~> ~p..0~
O
212
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~N ~C ~.~ ~ ° ~ ~~'G~~ ~a '-' O ~w a~ p
'-'pN_O'~,''~ c"C~~_c~0~~_~~~0~~_~~'u.~ U~~O .l".,~p
U U v~ N x ~ ~ v~ ~ ~ cn v M ~ y U U U '-' >> N N ~
C U ~ ~ c~ ~ -d O O
t~ 00 V ~ 'O ~O ' '~ _00 .°~.', ~ ~'.> .~ ~ ~ ~ j~ a ~ ~ ~ '~' a N Q,a
.V ~ ~ c~
~!~Gy~w.~.,~ "~' ~.~'ceJUO ~ j0 ip~ Q ~~~~O~~z
"p ~ 'b ~ Q ~ ,~ ~ f~. '~ > p N ~ .~ ,~ ~ O .~ ~ ~ O ~ ,~, w ~ ~ N O
,~-~N~.U..~~~"W.cti.vi ~y°UU~NV~~~ ..MAN ~ON°~~~~U
.C ~ ~. cc3 N ccf Q ..N,., ~ ~ ~.' ø, ° ~ ~ b M > '~ ~ ~" w ~ ~
o,~W ~,~~ ~~y °~',~E-~ o ~ off °~~ ~ >,~ ~ i
U ~, ~ ~. .b ~ o
y ° ~ ~ y i -~ i c o a~ ° a~ r~ >, . °' ~ w a~ o. ~ ~
',., '"
N~~ ~-CcW°~~aUp.,U~'~°:x U~,~DO~.~~bUUo
w_ Y o a~ °~' a~ a~ o ~ ~ ~ ~ x ~ ~ ~ oo c ~ ~ ~ °o. ~
U U .,~ w ~ U O ~. N
~ N U +°, ~ ° ~d y ~"' ""i ° ~ ._~ (n y U b
C~ i.U.~~UU~~ .~,'.d~byO.~~xN~00U GZ.L:~U-'~,~~bUN~O~
a~~~C~c~'b~_~ v'cacd'~O ~" ~~aD~>> ~a~~~~w> b
~ .~~',~~ c~~b0.f".~.dO~N~O~~~Up ~UN~00~~~0
"G ~,' ~~ '~ N cC ~ ~ U nn ~ o .~.' v~ 'C a. ~~ :"~ d' ~,~, y > '~~ ~, M
W ~ V '-' c~ ~ ~ ,G ~ ~ ;.d '~ t+; c~ iy ' ~ U O ~ a-'° ° ~O ~p
° w :~ .~ .~ y ~ N
Q., N ' ~ ~ ~ .~ > ~d 'b av . ~ ~~y C v~ U c~ cat . v, ~, O O ~ N ~. ~ v~ ~D
wGN~~~ ,s~~G~U~~~>'~~~~.~~~[~Op~teO~E-'O~~M
,~»' ~'' ,--i ~ " cW n O~ ~' . U .b ~. f3. N Q', '-' V >-, ~ N a O .y0
O~ ~ b W ~ y b x ~ ~ ~ >, ~ M ~ r, s.' ayi ,~ cd '~ ~G c~ y ~ ~ ~'~-' >, ,~ N
o Wo o, ~ y ° w ~ ~ U
W ° -.~ ' ° ~ o ~ cv °o ~ '~ ~ a~ ti°,~ , ~
.x ,~ .y ~. o
,~Ur' °'
c~ ~ _cd O > N O .T', ~ bQ ~, ~ b 3 ~ U s"' m ~ c~ ~ N
N a~ ~ ~. U .~ a~ ~ .w.. ~" c~ U N ~ s~r .t"~r C~ ~ ~ ° o ~ ~~ Y., ' v7
~ y .° .s"r
-o~~~~ ~~oao °'3~a~°o°~~'°o~~~b~~-d~'~'
~~z.°o°~'o~~w
Na>'n ~~a~i~'_~ ~o ~~a;~~~,yv'~p.~°~o'~,~°"p~cy_°~
b ~ .C ~ ~.' ,~ -d ~ l~ w ~ ..d ~ 'fl '-' a~ ~ ~ U ~ ~ 'b ~ ~ ~ ~ O ~ ~ ~ C~ ~
~' °L', '.' c~ O ~ U .~..'' ~ vi : ~, ~ ~~ G ~ ~ O ~ ~ U ~ O O m y ~ c~
;,O ~d 't=W° w0 N
~~ ~.CitC~~ '~ >,.S-'.~G~.L'CC~° ~ wNy.'i-~.~ULUrNa..~~°O~~_v~
~0~,~~ ~NOM~Np~.,''s.~~UwU~~~~UcdO~ O~~,bcd:..
~ O~ ~ ~ ~ ~ V .~ c~ '~, ~ ° ~ > ~ ~ ~ ~ c~ A~ ~ ~O cyC N G : c~i ~ ~ y
E-~
'" ;~N ~b u.°~,'.' ~. ~ ~ a~ ~:o ° w ~. a. ~ od and
~ W oy ~ ~ aW; a~ a\ cd ~ w O ~ ' ~ -v '~ Z ~ ~, ~ ~ ~ E.., -'" ~ on ~ '~..,
i.U.~ O U r'" '~, x O ,y.~. O '~' w ~ O 'i. N ~ N ~ 4~ ~ ~ ~ ~ ~ cd ~ y,~~ c~
-.ay~U~~'~~ ,~GZ.UO~ c~.~.~0~,°t~..,~~ .~~w
_ .S'. . ~, ° " ~ O tC ~ ' .C'. r~r '~ N ~"' ~ ~ p~ 0 ~ "
>> O U ~ N ~ ~ rUn ~b b U .O ~ U ~b ~ ~.. O O
>, U ~ ~d a..~ '~ o ~ o ° ar ~ ~ ~ ~ a ~ ~ o. ~. r3. y ,° O o
~o~ ,~ ~ ~o U
> '~ M a.~ E'i c~ _G7 U U N i..i ~ '~ '~ U ~ W pp ..-~ U C~ C~ p y,U~ c~ ~
.,:r V ~ t~, pp
'~ O N .~ ~ cUn '~ > -d ~ ~ N N ~'~, _~ ~ ~ ~ O ~ ~ .~ N W n .~ > ~_' N C. N
'b O~
~ O C .~ ,~ ~ ~ ~ N ~ ~ ~ O ~ ' ~ p '~ ~G "'' N -C v U ~ G w ~ ° ~ Ov
y ~ ~ N y y . ~"r W ~ U C~ . W Ar y U U ~ ~ w a -o ~ H a ~ 3 ... y w ~
y
O O ~ a ~_' 'i'
U
Q ~ bQ p
~ ~b-0 ~ ~ G
> O. ~c~ 3 ,~ N a O ~
.a:, ~r ~ a~.~ y
U b ~" ~ U ~ ~ ~ N
aaw~a. a ~ ~, ~ ~.
N N
D\ a\
00 00
U U
00 00
213
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
a~ .~ c~ a,
,. . ~ ~ ~ ~ o ,b uj ~ a; U ~ ~c --
.~ M ,Or O N ~ O O w V ,7"~ Ov '~' ~ vp ~ ~ y" ~ U ~ b0
°.: o .c ~ o ~ ~ Y ~ ~ ~ o .~ ~ o ~ ~
M ~~ >' ~ ~ .~ O O ~ > .O ~ o0 ,--v.~ ,WO ~ ~ ~ ~ b '~' ~ N _c~ ~ ~ ,b s~
OvMU~'b~..~ p .~._c~~''.~'..'fy~~l~~~,-.~N wn~:bONUN~~NOo
~ c~ ~ cn c~C 4"' ~' >> ~ ~' ~ ~ ~b ~ O U O N ~ ..U.~ t'r y~ ~ ~ .D ~O p ~
4~..
Mu.C.C~O'-' ~~OOU,NU~.rN ~UC~ ~U Ø~~~.i~'.,~,~~~'f~."~3'
,N-, ~ 3 Y cC '~ 'i:. ~ O v W b ~ c~i Q~ ~ W O '~ ~ ~ ~b ~ c~ L N c~
i N W ~ N y sr ~'" ~,~, '~'-' ''~'~, ~' .t~ '-U' a N C. ~ ~ 't, i yU~, '~c~' q
~"" O U . ~O
.-r O ~ ~ ~ V ~ w' p .s". ~ ~ O N C~ >> ~ U b U ~ ~ O O O G~ '" ~~ ~ E'~ ~ c~C
N ~' .C ~ ccf U ~ ~ O ~ O ~ ~ .~ U p ~ ~ ~ ~ U c~ ~+. ~ ~ ~ w ar v~
,OOUV~ .t". R;~v~s.U,r~~~NaON~>,~'~ U'y~"Q,'~.0,~~~U~~N
MCA~.b~~~ G,T~~~~~~~VO~>'~~.~ Up~,~ ,~~~~~OO~G
O ~b W t-~ ~ ~ .a ~~ ~ ~ N ~ ~ ~ N 3 O y 'G p ~ p by
U p vi 'b ~ G ~ O ~; ~ '~' ~ py N O w ~ >, ~ y ~ G ~ ~ ~ >, ~d
_ ~ .D c~ ~, ~ ~ ~ ~ O ~m ,-, cct ,~ ~ 4, ~ c~V ~n vo U ~ O .b
U ~ .~.r cC ~ ~N ~ 'n t" by 'S-»" ~d 00 ~ ~' ~ O ~ O ~.U, ~ caU.., ~.' ,~ 'b
~+.
C~ . ftS ~ y ~ ~ 'b b ~ ~ "b ~ V~7 ~ V ~i ~~ ~ ~ O o y .~
V 'b ~ y C", ~ U ~ O ~ 0o ~ v~ 'd ~ O G w ~ ~ U U
'~ ~~v~ '~"fnOVr~r~~'b0~~ N.OOw>~bp:~~
(~ ~ I~ y U .'" ~~ ~ ~~ ~ p .~ ~ .M ~ ~ ~~ v~ U ~ y~ ~ U p O U
~ O~ UW V,x ,~ O.p ~ ~ ~~O"~S~' ~~Ci ~ c~ ~. ~p.~, bD
~ i ~ ~ ~'.r.~ ~O .~'b0.4."~~~~'~p>, ~NNU
'SU~~U3,~ ae~_~>~ioaU~o~~ao~ ~ø.'a.~T-d~.~~"
id ~ 00 U N V ~' U v ~, ~, ~ M ~ U ~.~.' U '~"r ~ ,~ ~ O ~ 'fl ~ O
~ 3 ~ o 0 00 0 ,~ ~ ~ ~ ~° ~ -o
~ " '~ o, -d :b t~ vo 'r' 3 0 ~ °~' 'b ' ~ °.3 ~o ~ o ~ ~ yo ~ -
d
~ o
M ~ ' .'~ U 3 vi 'a, ,., ~ >, ~' ~ l~ O W n V1 "C N ~ U C~ Vi a~ .S"'., Vi
~N~~~ y C~ N N ~"'~ .~.~~~t 0 U U~"".'-, Ob~',~ ~n'Cj y,O~ '~'~C W ~
Nb~ A,:~~'~~~~~N~~'''~ ~oV~A~
~OI~U4~~U4r ~t..4-1O~~ 'b~'Z,C~~~O~~N'.U >>0~~,~~,pin.~
~N~N~O x_".00~'..>~~~ O.Yd>>.O ~O.~U~UD~a..W O
M ' "N ~" .b T..' >, O . p 'S~' U y O yp, ' ~.. " CC w ~' c~
.~r i.r iu W ~
" '~ ''~ >
N ~'fl~~~~ x~O.:t~.~0~_~~~~~~~~~G.y'~ ~~ w~ O
r..' U ~d m ~ U y
M~b~»,'O c~~'c~_~~N~C~U"'!~'a~U~'c~~HW~O~~~~. O~O_~cd
yp,~~c'"'CCC~cWn.+~..U~cC.b>,~b~~~ '~~'. u. Q''~U>,'~'b O~~.O~.C
a.n U au ,'>> ~' ~, a.n
O ~ ~ ~ N ~O ~ .~ ~ ~ ~ G ~ Ov c~ 'y ~ ~ ~ N ~ N ~ N c~ N V O w
~ a ~~ a~ a~ a~ ~ ~ o ~~ o w ~ a a~ o
o. .~ a, U ~ U ~ . W o. ~ U U ~n ~ W ~ ~ I~ . . Q., ~o ~, ~. o a. a. w w
_ o
0
°' an 0
o U
a~ '~
> a~ ~ x ~ ~
~n
Q ~ ~ w v~ a, p, I~
N M
U rx
H
0o Ov
214
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
°' " ~ _c _° .b ~c .~ Y ~ ~ 'd ° ;-. ~ ~? b ° .~,
~ .r
cdN ~~ ~~~p~~~UU~~,y-U.U OcYnO~~.~,C V pp~y
v''_'U ~p ~~NU N..~,N..-~OON~O ~'~E'~c~N
N O pp U by N b b-0 y.., ~ ~ N U ~ p~ u" ~ cC 7, O d N .D O U
O~y,U,.~p,~,N, ~~O,,N,-U~'_"''~~~'_"~,r~A.'' ~d0 ~cdn~~~~N
p C. ~ ~' y ~ O N a"~.,. p '~ ~ O O_ ..~. ~ ,~ .~ ~ OU tin ,.-~~ .O
b 'b~~~p~,A.~c~~.~U~_~~Os..~~ VN..~O_~U
irN .", ~ ~"' ~~."ri.~..OyiCU~ .~.~a.NUay. U
~~ ~ O ~ ~ 'G N ~ U N '+-~ ~ ~ U ,~ bD W cd ~ ~ N .~ iG .S"' 4., ~ <h ~ .f".
_N
o0 0 '° ~ ~ ~ ~ x ~ Pte... ~ N ~ ~ ~ ~ ~ b ~ ~ ~ ~ ~ ~ W ~ o ~ oo W~.,
O ~ ~ U ~ v c~ ~ ~ ~ ~ ' ~ ~ _~ 4-' O ..~ c~ ~, p ~ ~ Y Q . c~
c~ O ~.' .~.," c~ U b-0 Q\ a,.~ c~ .r' ~ 7
.~'''"WW O~ ~OU~~~G~.:.~~~~'-'dDC~(/~'3~C~
U ~ N ~ N U ~ O N ~ CR ~ ~ ~ l~ '~ by Y N by ~ .S-', Q U ,~ b O ~ ~ c'~d ~"~
r~ ~ ~ o ~ ~ ~; .~ ~ ~~ ,~ .~ .~ ~ ~ ~ ~ ~ ~ .o ~ ,~ non ~ ~ o a ~ ~ Z c; o ~:
ø'3Gx~ 04. ~~C~bO ~~O~y'Nx~~O~_N~ fnbD~00
Q U O p ~ ~ N ~ O r~'n 'b C G b ~ ~ "'.' a ~' ~ ~ 0 ~ ~ V ~ w ~b
c~ _ .~ C, Q . c~ c~ p ~~. " .--~ (n .~C ~,,,, ~ ~ ~ Q O ~ v N c~
c~~0~~'b WC.~~~~p,~b~OMUO.b~_ON~'c~tOy~
p,v~Qp'.~.~~'bG~°ON~~,~ O.~O
~ 3 ~ ~ >, ~ ~ ~ o o ~° ~ o ~° a. ~ ~ ~ > f~' w ~ ~ ~° ~
x ~ ~ o
~ .~ o ~ ~ ~ °_' o O .'~ ~ ~ r~ ~ on,~ ~ M N U ~ ~ y ~~ a~ ~ ~. an W
~a. ~. ° b
~ ~.r .~ ~ ~fwn ~ Clr t. G~." c~ ~ N ~ ~ H N N W U U ~ O ~ ." ._: N .f..' O
N ~ O t~ ~ ~ ~N W
U c~ c~ O ~ p. ~ 'b O v ~ ~ y ~ (n ~'r ~'"~" p '~ ~ ~ ~ ~ ~ p~ v7 O N
_~ N
U y v ~ W ~
N O '~ O y '.' O "'" N O O .f'"., M '~ ~ ~ .O U ~ ,~ c~ .b ~ '_~ _ ,t~" O
~ U ~ U ~~ Qj ~O O ~ '~ '~~' ~ ~ ~ .~ Gr iv U wn ~~ ~ O ~ ~ .U N '+;, y . t~ ~
~.. N t-n 'b '~ U O N " vi ~ N
y.. ~ G ~ ~ ~ N ~ u~ ~ N N ~ ~ ~ ~ '.:C ~ A.,~ ~ '~ p ~ ~ ~ 0 7,
U ccS
o'~ o~ ~ o.av °~ ~ ~; goo
U~i U~U~, ~N7~cd U ~~V '!-.'~.y
o
~ ~ Ov ~ ~ ~ ~ ~ ~ 4-. N .r c~ ~,'~ G ;~ " w .~ ~b ~~ :-~ _O ~ v ~ ~ ~ N O~1
.O 0N0~ .~~.''Ui'pyU;.d y~~~ .U'..O~UO ~~c~d~~~~~p~~O~,M-,V
pbp.,y,'~.~~0~~"~,.~,''-'y~0'bd~'b~~p~'p0~p.,~N~O .. uU
N p "'~ x pn U t-~ ~ .f~., ~' ,., O ~ b U ~ ' ~; 7 U tr ~ . m U O
'b ~ ~ tin ~ w 7, ~ .NT'., ~ ~' ~ 'au .~.~ W ~9 (~ ~ ~ ~ +Q. fn C: . .S"~.' G
O b N G (~ D 'i~
. ~ .Cy,a'~COmN~Q~~~~~ON~."Op~,r.~'.c~m~>~.~.',~~~Vi"-,
N ~N~ ~,~~'Ubl3r O.>, ~G~~".~~ ~'N~~~Nv~G.>,O :Ms.,
c~ O .~~~~~pOs.~.~~3 ~p~~~~~~~ ~~~~>,UO~~i..
O Qi ~ N .~ U U d ~. O ~ ~ ~ ~ C~. c~ ~C i--i U . O. ..~ d ., .~ c~ .O .D G.
c~ W N ~ fir
W
O
O
O .~ .~ N
.p~
_ O
U . c~
by0 C ~ N ~ .~ U
~, ~ O W ~ r'~~' C!~
M ~h
M
~O O_O
d
O~ O
.~ N
215
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
on _o '~ ° ~ ~ .r ,~ >, ~ .~ ~ ~ o ~ .o
o ., _
y,'~, .~ U %d ~ '~ ~ ~ b ~ ,~ ~ U t-U. U ~p ~, ~ U ~~ N _
cd. Oc~'O~r 0~~~'O U LU.i ~UNN 'bOa~"~U~~~D O~L7
~ N C.m' p ~ ~ [-~ ~ ~' C U ?' U .~ ~ s.. G ~ N j ~ ~ ~ ~ .'~L s..
Wn >, .., ~ s.. 'G y U ~ a~ , O
W n U O p ~ O Q N ~ ~ ~ ~ can U c,~ S',., N ~' ~ U .~. 4..i b.p o0 ., U
y'~O~c~ UbA ~c~~~ b~c~3~ H~ ~cd~U_NcUdO~~
Oc~i".'~,~/] ~~ ~~._~,~~~,~~ø" ~ UCDc~C~~O.n~M~U~"Cf
~ -C ,b p . . ~ ~ c~ >, .~ c~ N .S"', . J ;1 . U U ~ ~ cc~ ~ ~ y.U. ~ ~ s. ~-~
~ C N
.t"~, ~ ~ ~ V~ p t-r .D b4 U N N ~ .~ y ~ c~
"'O >' O ~b I~ O ..N.~ U ~ A. c~ ' ._~ '~-' ~ U p U C1. y,r O ~ ~vW _n N . .a
~ G.' ~ ~ N U ,,,~,, ~ Ov .C f.~.' iG ~ ~ ~ O a O ~ ~ ~~~~~ 0 ,-i ,tU". ~,
.~ o _~ ~ ~ ~ o°n '~ ~ G j ~ o a M ~ 'v W v '~ -~ ,~'r' ~~ o ~ ~ ~~ '~
~ o b
'n b ~ p, N ~ b ~ ~ vi ~ ~ ~ N w ~ Tj ;i ,~ ~'~~' ~ ~~...' ~ '~" ~+'p +. ~ U
~ C ~ ~-~ >, ~ >-' ~ ~ ~ p~ ~ ° ~ °, C/~ ;~ N a~ a~ y .C y
° c~ O ~ ~ ,o 'y
,'~,p~.~"~yU d;a'~c~ b-0~OI~..U,m!-." .G.I_'~ N°UU~y'CW_~ONU
~OU~bO_~~~;OU~'-'~~ O~G'~y.U,
m O O ~ .~ U ~ ~ .~-"' a~ cd ,n ~ U ~ _,'~, U s,~, b-0 ~+, 'p c~ t3, ap .,
,~U~~~ ~'c~'~~~U'-'U~pOVa~~N..-"..,~ >~c~ U~.U,~ ."~~/]'c~N
,~ ccf ~ I cC b
O~~G ,-~r,,~, ~~0~ ~~~ ~f~.~~~~bUx~~CL
U t".~~,~ ~aj~ c~np0~ ..~yN~~~ V~.c~~pp'''~',
O w ~ U O ~ ~ ~ ~ yn ~ s., b y., >, 7 y '~ 'G U pa ~ V y cd
4r~ ~ Ob Owr ~ ~O ~l~ ~'O V cd ~~~U~ ~ P.~~~ U4" V N01 3 dD
Ux,~U~ c~~U ~NNN .~. ~~0.~~~~~.~~.O.~~c~,
~~~.on,~~ ~~o~~'"~o~o My>~~''~M~ on>3 ~Ua,o
~ .f", ~ ~O
i~ ~ ~ ~ C w. v ~ ~r '~ c,..,
~ b ~ ~ ~ ~ G ~a~ o .° ~ ~~ ~ ~ ~ .~ 0.. U ~ ~ ~ ~ ,b y ~° N 0..
o ~ ~
~ f~; M ;~ ~ ~y
~, ~ ~ 4-' U U N 4"' ~ ~ l~ N N ~ .L", ~ N O ~ ~ U .S~'.' ~ a~, O U M U ~ tU~
W ~ ~ '~ M ~~ ~ cdn~ 'Ui' ~_ ~ ~ ~ ~ ~ .~ U ~ _~ ~ ~ ~ ~ ~C N b U _O ~ ~ ~ >,
b cC3 N W [~ M 4--~ U .T,"'. .~~.' "p ~U,, U ~, a I.., '~" 'S~~' ''' O c~ '
.1~, ~ N .~ 'ate.. ~ '~ U pip ~ ~ N
~ ~ .b ~~ ~ ~ p ~ U p ~ ~ b-0 ~ ~~n 4-, O ~ O ,~ p ~ ~ ~ b ° ~ ~ C
c~U., ~ ~ .~ ~ ~ ~ C...p, ~ ~; U p ~ '~ N ~~ O ~ G7 ° ~ w ~ °
~UC~/7V >, b~~CN~~'U~OUCVW OL~~Y'~cdO~U~~N
N O ~ G~ b M U U ~ ~ ø~ ~ 'C ~ ,,~, G. fn O
vi~.~U~ vyp"~b ~.° 7~~ O ~ ~~ O Y ~,O O O(~.~ ~' ~,cd ~~ ~ ~,
~' by O ~ O N ~ .~ ~ ~ N. ~ 4-a N U ~ ~ by ~ ~ ,~ ~ b W ~
~L ~ m U ~ .~~"'. ~ A. .~, 00 ~ c~; ~ ~ "O U ~ ~ cd U ....
"3~~'V] ~yyN N~ W ~ ~U~ ~ ~ I.
.'"~, '~ N ~'.. ~ M O U U ~ N ',~ ~ b-0 N C 6' cn ~ U
.,.., v~ ~ ~ ~ O ~ ' O .y c,.~., b c~ ~' ~O ~, ~ ~ ~ ~ ~ ~~ s.. ~~~ '~" '~ U v
.-' Iy.Ur O
~,N" .b U N ~ ~ f~~" '_' ~ O p ~ .O ,_, ~' ~, Q~, N ~~ O O
U ~O ~ ~ N ~ u. O rn O ° ' ~b ~~ c0 c~ U ~ W n ~ b c~ U G Q," ,~ ~
c~
7, w U U . "~ O ~ Ll' s., U V p U ~ ~ cd ~ >~. N
oz ~ ~ > ,~ wv ~'b.C _ o,~,~ c v ~ ~-d o ~ ~ u.~ >.~ n yU
O b " U O >' vW.~.' I-~~ N ~ C1~ ,'~, Up ~ ~ ..U, ~' ~.. ,t~" t-I A N c~ U w~
t..' Cue' :~ I~
U U U ~ ~ ~ ~:w U ~ ~ c~ b a.i O ~ ~ ,-~~- ~ 4~ ~ '~ .b I", ~ ~ ~ ' O N
,~ _~ ~ cn O ~ ~ >, N O ~ G U ~ ~ N N j U 'n N ~ O ~ ~ c~ ~
cd . U H b-0 P~W a, ~, cd ~ ~ GL c~ W V7 . CL U U t-W.i d .~ c~ (1~ U W f3,
~., ,~I U ,~
O c1..,
O O ~ ,Or . U
w
° .,.U, ,~ p c~ ..~ LU..~ -'~~
N _~~~UN
~ N s., U p ,~ W
v .TU.' ~ ~ ~ .p Q'' :d
y~ c~ U >.. W N
C/~ ~.. v~ f3. ~ ~-I ~~ f3. O ~
N
N N
216
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ ° ~ x U ~ ~. ~s
o .~ ~ ,~ a~ U >, c aio r+: o ~ ~~ ~ " ,~ ~ U
o '° ~ v°~ a. ~a~ °'. o
~' ø, ~-i y 'd y >> W ~ ,~"' O ~S"r ~ >W' '~ E-1 ~ ~ .S", _t°/1 U O Vi
N pr i'' N
>>c~ ~U~c~O~ N~C>~af~j ~" fn>>...~ Vj~yN~'U~
U a.r ..C~' ~>,~~f.'GUN~~~N>,OQ~N>,~~~ ~~~ ~ yy'
U ~':d~~~ .t,.U04~. ~> N~ Ot~n~GrG. .s..-1.'~b-0Oc~
O O pp j .O O ~.., ~,U" c~ p ',;, ~ ...~ U v~ ~_.. .O .. ~ °'~' ~.
~ .C b
au
w.~ci.~., ~~~,.~,~~V ~~~>,~y>.~cOQ>,~ UGc~Q\~NOb~D00~.--i
vl U ~ G~" ~ N x ~ ~ ~~ 'y;, O s., ~ ti4 U N .r O~ U ~ ~ .f"~, cC U ~ V~
_~ ~ ~ y~ ° ~ ~ ~a~ N .o ~ ~ ~ ate, ° ~ '~ ~ ø' ~ '~ ~ °
~~ aio Wi ° -W
.C U ~ ~ ~ W b ~~ ~~ '~ O O O ~ U O N ~ U U y ~ O N ~ U ~, °U N v1
'ENO' ~'+.~O GL.,.., v'ON.~YG ~ U c~
~~o~w O~~,Uo°~~°U ~~~~W~o~~Pa~~~~ os
pulp ° ~ O ~ y 'r~r C U ~ ~ ~"' ~ 'b ~ ~ ~ Y :~ ~D ° U ~c~" '~
.b b CL N
~, y~ N . ~ ~ ~ c~ ~ . .. c~ . '~.;' T U O ~ L..' ' ~".' y O ~'~ ~ 00 c~ LU,
cad N ~'.
~'' ~ ~ b ~~ ~ ~p 0~O i-: G ~ b yo O ~ U w O .~ ~U ~, ~ > ~ ..'~. 'b
ct3 ~ x tU ~ '~ U ~n O ~ U '~ ~ ~ ~ bD ~ '.~C ~--, .d T c~ O .C
UU.~ W~~~ "'~ONU~ .fv".,~'Cs.,N-d~O~~ ° "->'r~~'~~U
~, p ~ ~ ~ ~ ~ ~ ~ ~ v ~ ~ U ...~ c~ ~ N N . .~"' ~ cd U .... .., ~ U m O O
WOO~c~'~~b_~C.~~U~UOQd~;O~.~C~
E-~ 'n ,~ .b ''' ~ ~ ~ '_'~ i ~"''..' O ~ O N ~ ~ U ~ y N ~"~ O ~',' O'' ~--
y., ~ y
o .~ ,~ M ~ ~ ~ .~ ~ ~ ~ ~ o ~ .~ ~ Z v~ O °' = ~ o on o
N ~ .° U b°0 O N +3-~ b '~-' U ~~ ~ ~~ ~' ~ ~ ° ~ ~
~ j, U U
-: oo ° ° = 0 3 ~ ~ ~ o 'c :~ N ~ ~ .~ ~ y .~ an ~
C'~~V.~O~~OOOUUU~ °~~C".~0~''~ ~c~lUr..fU,UOb
U m ~ ~ ~ G U W r ~ cCf a3 U c~ ~ ~ c~ ~ ~ ~ O U ~ ~ U
c~~~ O ~'~~_>,N~~y.U, ~ ~' y0~'.~ U ~cd O ~~ ~~b..'n.. ~ ~ ~ ~dD'b .
W ° ~° ° O 0 M ~ O ~ ~ ~ 3 N ° O ~~ ~'~ O ~..
x '~ U y ~ ~ y >' O o0
V ~ N ,~~ ~.5~', ~ ~~ ~O N ~ ~ ~ G. ° N > ~ '~ ~° ~ ~ 0 i-: ~
_O N f"i ~ a Ov
G' ~ ,~ ~ N s.~ '.~ a, ~, "~ _Gj N ~f"'~ T.r' ~ ,"' .b O O~ '3 ~ ~ U ~ _N
C/~ O. O U N .~ .~' ° ~ U C ~ y~ ~ ~ U O .~ ~~ n ~ O ~ ~ W ~ ~ 'G
w cps N
a. 3 0 ~ an o .~ ~ ~ ~ ° . ,y y a~ ~ ,~ on W c~. ~ ° 'b °
~ '-' ~ R; r,
U .~ p., ~b :b ~ ~ N ~ ~~ ~ ~ WO V N ~ 4~ ~ c~ ~" N U pU W ~ V _~
NON ~~" b a'~3~~N N~N~"~tUcCS Uv~ (~M
U w. ~ ~ .y ~ ,.., p C ., cti Q1 .~ O ; d ~~ ~ .t7 O . ~ ~ ~ ~ ° ~ ~ ~
,~ . ~.'~.
~d V ~ W ~ ~O ~ ~ N ~ O~ N ~ C~, N ~ ~' '~ xi 01 ~O ~ cn '~ ,-~
V7 ~ ~ ~ >, O Q..~ c~ p U c~C ~ '~ ~ ~'~' ~~~-' C..~ ~ ~ ~ p ~ ~ ~ N
~ >, U ~ cd '~,' ~ O ~ ~ ~"~ V~ ~ W ,t' cn ~' ~ b A, ° > ,i", ~ ~-~ U
cd >> ~ .~"~,
N rUn'C CLY'_' ~' ~~ U 3 ~ O ~~O p,~~~Crl~MN.C ~~C~
U i N ~ c~ t-i W O y ~ U 'L1 ~ ~, ~"'.. ~ ~ >, ~~, .., ,_, N ~ ~ ~ ~ .
C/~
'~ ~ O\ G O O '? ~ ~ ~ ~ ~ U ~ ~~ ~ vy" ~ p y '~ ~ ~ y O U ~ ~
'~ 00 .'"'.T. O~V4"' ~00~, _.>,~ V c~C;~ O c~'U.~c~-, ~~.~Ov~~ ~v'7 N ~
'~ ~ O~ ~ O N ~ ~ '.' Q' ~~ U c~ ~ ~ ~ ~ ° m ~ (~ 01 N '~ ~. tUr 'd U
m ~ O ~ c~ '~" N G t-. Oyn O ~ V ~ ~ O O ~'
~~bA.',~~,~p'~O~~cd~~j,.~p~~~~. cd~dp,b..O~.,Pa~
a~~Ua,~,s..~,>r;~ay ~~on.b>,ii>~~aW~U ~ ~~...b~a~Uz
~ c~ ~ ~ N ~ tx O ~ >, G ,y ~ O ,~ ~ >, N O fn ~ .~ cct ~ O y ..C ~.,
~, . ~ W ~ U ~ . W c. .~ v~ a~ ..~ .., Q ..~ ~ cc .~ ~ o. c~ W a~ ~ P.~ ~ . U
E-~ an 0..
O U
U ~ ~.~. ~ O
O
wr
f3y x cad ~'.~ .~ .N
a ~ U
xi W v) P~-i r~'a v~
~D
N
M
N N
217
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
_° " ..
a~ G ~, >, ~ ~ a~ ~ °~' ~, on ° ~ ° x do
'-' O ~ > ,.U., R" C~ y.~, ~ cd "C1 44: . 'r~' tU/J ~ ~,~'' ' ~", E",i C~ N ~
, ~ ~ tU.~ ,S; ~
~o~~~?~~~ >'°~d~~~~~~v~
~ ~ ~ z .o 'b a' c. ~ ~ ~ ° ~ ~ o _ ,=; ~ .~ on o ~s '" ~ rn
c~ ~ ~' O '~ .~ ~ ~~ ~' U ~ ~ c~ ~ ,..~ ~ ~ O '~ bD .U > U OyN ~ C '~ ., >> ~
.~ c~ O U x ~ ~v ~. ~ O p ~ ~ O ~ ~ ~ P.. ~ '~ O .p ° p .>,.O
py,~ ~ .~, ~ ~ U C/~ y., 'n i.. ~ O~ .O yU .~ "C ...~'" ~ b ~ ~ U ~ ~ ~ ~.r by
U C~ U
O "C t?. ,_, ~ O >, c~ ~ N ~ ~ :~ N c~ '~
_c~ p" ~ N wn c~ .-~ '~ ~ ..~~ . '~.:' D b°p N cd iG ~ c,.., ~ ~ ~ _U O
~ yU~ Q_~
O G ~b c~ 'vi O N '~ ~ N ~ N ~ ~ b~U W t1 ~ N ~ O ~' ~ ~ '*'' ~ per, N
b", ~ .1C", 0~ ,,, tin y Q\ N '~ ,7., ~ ~ ~ .,.~.n y,U ~ ~, ~ ~ O~O ~ ~ ~~ ~ ~
bf.'
~ W ~ ~ ~ ~ O M G~ ~ ~ ~ ~ ~ ~ p ~~ w O ~ 'v F
''~-' ...~~ O .'n ~ ~ U >' D '.C ~ O~ N ctt 'C 0 'O a" ~ "_' ~ ~ c~ C% ~ O ~
>, cC
>. ~ ~, oro ~ ~ y w . >, ~ ~ ~n .~ ~ ~" a~ ... '-'~ o ~ ~~ ° o an
~ > p ~d O 'n O O ~ _,~ ~ .~ U ~' G O $'.~. 'a, U ~, ~.., ~ O ~ ~ s.. ~ c~ U
a, c~ (~
~~N'b~OU>, Op .,~ps".'~~.~ Nc~~'~-'~N~~r'~'i~~,ø,~.~~",~J
~~ ~ N_ ~ w ~ ~ ~ ~ ~ ~ '° ~ .~ ~ ~ z v~ o ° ~ ,~ o ao
O cC ~ ~, ~ ~ > U O ~» ~d pp ~_ "~ y ~ O ~ '~ ~ ~ U U f.J O ~..
O.. ~ -d O ~ U O ~,~~ ~ ~ ~ ~ ~ ~~ .3 U f~ ~.U, OU .~ cdN ~ ~ .'~,~' ~ '~ .~ b-
0
~ cc3 O ~ ~ ~ N ~ U c~ O ~ ~ 4-~ ~ w ~ ~ ~ ~ N N ~
'4j ~, C ~ ~i ~ ,,~F,'~' 3 ~ ~p .O ,~., ~ cC a3 N O ~ ''i c~ .~ ~ U y ~ O Gi
O~I c~~Ocdp00~-....~a'~.~~,'~~"O ~'.~ ~''~. ~~N~.,.~'r~~~bD~c~
O'' ~ i' -d ~ ~ O 'i' ~~ ~ ,~ ~ N c~ '3 N O O .-. O ~..i r~ ~ U ~ >, C". N >'
O
+r"'.0 O, p~W~O~O.> >w'~'Op~~~ ~~O~..N~-~~,~
3 N N y .r .~, N .~.~ U J~ G ~ .~ .~ m ~ v, ~' v-~ ., ,~", -d ~ ,cd N
D N O ~ "_~ O ~ ~ N y ~~,~, ,,, ~n ~ U ' ,.., y~ U p y., b0 W Q. ~ O 'Cf U
0~.,,~O~NO' ~..,0~~~,~. ~O'jwOU~~v'.'~~ NUOUW
U~..-~'C~~~~OM~'"~~~3~y.~vycnvy~~,~~ctlU
%
4~ cUn V O .b ~ .~ ~ ~ ~ O M N G .y ~ ~ N G.n ~ U '~ p .U .~ ~ ,-v,
O ''' O ~ 00 N ,~~ ,~ ~+., ti.., 3 'b Gl. > ,.L~,
~ o.b ~ ø~~ ~ ~vWo~o~';'b ~.n ano ~ o a~ ~.~v~°N~ ~ ~,~ y
o ~ o ,o ~ ~ ~ o ~ ~~ ~ ~' .~ op ~ av ~ o
O i. ø, ~ .LU". 'f, ~ V i v ~ U ~ O c~ p ~' L '.:, '~-' U M S." O\ ,~ it ~ N ~
vi
>> ~ ,,., ~ au ~ 00 ~ x N ~ ~~, N c~ ~ '~-~~" O . ;~ O ~ () G~ N a.. 'O
Hv>> ~-d O~ M_OU :b ccf ~U~' r..OmO'~ ,_~N~E'~~U'O
r~ 0 4..~ ~ ~ O G"., O ~ N ~ 'n ~ W n f'-' ~ O ~ G' ~ O '.:~ ~ Tr'
c~ ~ a.~~ >W .i~~ ~ ~ 'C ~ ~U.. -f' ~ 'y . ~ ~ ~ ~, cdn~ 7 c~C ~~,' ~ N ~
U..'''.U~ ~'.~~.,C.~,_,O~N atw.~ i"Nv~l3.>,O :MUO~~UO
O U cd " N 3'",r ~ .~.w v~ ~ W, U ~ >~ ~ b ~ ~ ~ U U
.a c'~', ~ O ~ f-~ U ~ ~ ,.O ~ N N N N O ,~ ~ >, 4> O v~ ~ ,., ~ cc3 p
h ~+r N c~ a., . wr ~ ~ c~ U r-~ c~ . a~ U U ~ a~ ~ cd ~1 ~ f3, c~ W N ~ p..i
cd . U
O ~
O ,~ V O
~1 : _p. ... O
Cd
"~' ' .~,
'C 'd .
G. E~ b
a\ a\
00 00
~Wn
m v~
N N
218
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
U ' -d ~ -d
7G M
"y° o -o W , ov U E-
Ov ~ ~ ~ M ~O ~,' S~-' y, b0 U N ~ ~.' bD ~_ c~ N p
f~ W n ~ O ~ N ~ ~ O ~ Ir ~ ~ O O 'b ~ y' ~i ~ ~' ~ N ~'r GO N bD
y. t+, . tn ,-~ au ._~ au ~ U G~ V ..d U O c~ C.' y U .t", s.r U
'"p .~,00.~ ~p,p,~~~ .O,~~b""~~.~'St~.bs..ONW~~~C..
p ~ ~, .~ '.:. ~ I~ ~ ~ c~ W n .~ O ~ N a O ~~~' O O M w U
~~U~.b~ a~o'~~~ ~?'o~~>~:bo~~~~a'~'"'bon-d
y..~ y ~ ..C >~ N .
'c~Ar~> .i".,N~~~~''~~.L~~,MO.~ ~DC".,Or.U. O y~p.~ ~..'.fl~"
'b~s~~~'~.~~~WC''"M.~_s~.. p' ~~Cc~~,:'fl~vy~~~.f»~~'.bp
f.."a,OUUNU~ UapN~l..'j ~U~ ~~GI,~,~".G..",~pb-0.t"."da.U.~..~r
_i.~w O '~' ~ ~ ~ ~ A'' ,y-N, _dj b M Cue" ~~' ~ ~ ~ ~O ~ ~ y N c~ ~" ~ U ~'~'
i,
M O 'D O ~~ '0 0. ~ ~ 0 113. E~ . 'O y~ ~ O ~ ~ G~'
O O O U ~ U ~ ~' N .a y ''..' N i U c~ w iG 'O ~ v' cd U O p cry N ~N
'Oc~'..~'~~~'"~Up,U,~v~O~ ~O~nN ~.~~..'Od'~V~OU~.UU
O ~ ~C ~ ~O ~ ~ ~ Q > '~ ~ ~' b m y .' ~ N _~ ~p ~ 'b ~ O
~, N ~ U ~ ~ w ~ C~ c'~n O N O x ~' U .~ ~ U ~ ~ p ~ V O 'N ~ b ~
W~;~wW ~o gyp; ~~ ~ ~'~ ~ o:~d.~ 3.~b ~ ~b ~ o~.~ ~-d
o~o.,~~,~° ~~~~o ~~~ i3o~'no~?.°on~c~n
G ~ y ~ ~ ~, ~ a; ~ ~ ~ Y ~ ~ N ~ ~ ,~ ~ ~ p >> b ~ ~p
c~ O.OO,~~O~b~.U.yU NO.~'OwUU.~~,~OU~'U
cUn ~'~U~~.~00>,~0~ U~biD~»,N'F-~~s.rG~.~dc~3~
c~ U ~ c~ 4.~'". ~ ~ c~ U U c~ O U 'b 0-0 i--~ ~~ y s~ O O Q O y ,~ +~ b c~ ~
>:b-c .'~-°c~U~~ ~~d~.~'~~o~-Y'"_o~Uoo
O ~ oo >, ~ ' ~ ~ ~ N ~ O G w ~ ~ ~ b ~ _a~ ~ 0 ' ~_c~ _ ~ U .~ >,
~. _ U O ~ .~, y ~ U b~ U
.-, aG p p M ~ ,~ ~' N w .~ ~ .' '~ p O ~ c~ . ~ > ~ c~ .ty
00 pOON'C O~O~"."CD OG.~.~"b~~~.~'~' ø,~'Ytyn~.'~'~ ~pNf..'y
W~~~j'~.s",~~'~."DN010NNOUL:~ O'" ~',~_'>'''~~' mUNN~~~O
N s., 'O .:: "O ~ ~ .... ..O .~ U ~f~~ 1: C~ i.'" C3, c~ O , ~ y ~ ~ .r~.' c~
C." N '-'
> ° o a ~- an >, b 3 ~ A~ >, -d a. >, .
N U . ,~~, ~ i--~ f~ U c.~ ° .S"r ~ ~ N ~ ° VJ Q ~ ~'' ~ ~ ~+-~
°y' rNn ~ ~ o 'b ~ yrl ~, U Ct~
N
M~.a»~0~~~M~~~~N'O N~~~~~~>,"O ~y~~'~Oc~fn
y CL 'b w' ~ O cd y .~~. tn U y U 1r ~ y ~p cd ~b U
°N~wU~U'~QE~v',~'~b~~ t1. ~o.Nf3.~~N
000' >,~~~..U.OwcrtO~~~N-C~
w ~ .b ~ ~ ~ N ~ ~ ~ ~ V :b ~ ~ b ~ ~' G Q' ,,~~, ,~ G ?G ~ ~ >' w Q\ N O
l~vi'y~~ >,p~~Oy~~U~pON~Uc~~3m~~WU~G.~>,~
~t0-~~L~~~OON~O~V~...'n.~~~~~'~O~~~NUr~,ccSU'-',.U,
C~ ~ U ~ y~~ y p U ~ ~ U ~ O O ~ ~ O ~lD v~ N O U O V1 ~y ~,
c~'~,~~O~jw~J~yctip_,mG~.~~..C. 0~~~ ,~~"'~NC~>,'G~~N~'~"
N:ZyQ.ar'''~''~~~~cydN ~O,c~~LOV Q.U ..,U~ ~pO.pv~p
V v~ ~ y ~' b O U ~ ~ ',., N ~, ~ O U C', ~ 7 U ~ N y "d U
GO00'.:~Oa~~ZOc~y~.~~~~~~~..~'bywO.::
> ,~., 'n _ ~ U ~ fn '-' by t-' ~ -d . ~ O N y., '_' ~ c~ ~ _ O O
~0,~UOOO~~U._~O~.U.Ow~~Dlvi't-'~,~0 .~.,U.~Op ."N~,
~~yONN'0~.~'.~r~N'~"~~~ ayp '~".~>>Om~O~O~a~V~O'dN
"w~U" .~ .~S-'., G '~ j, b° ~ ~ ~ ~' ~ ~ ~ ~ Wi,.-~°° ~ j
y>0, '~ b ~, . o y . ~ ~ y > .d
Oy0 GLc~p~p~>, CGLs-. ~CmUpy; bDy.,.~pU.~~O>,
z '~ CL c'~n ~ .fa ~ Cln ~ W ~ ~ O v," ~ O O w U U ~'~"~, ~'U' .~ ~ 'v-' W p
~~ N N ~ ~ ~ ~~ ,G
~ N ~ '~~~ U~~~""O ~iC'~ > ~'bb ~~ blD~O c~~O O .r".c~,~'~ ~ ~...ys"~.
~.~ W °o.yUU° ~W W ~o ~ad.~.~ u.b ~ ° o c.c.w~o orx~~ ~
w
0 0
O U ~ c~ .O
c~ O .c~ 3 p
. 7 O. x ~ ..C O ~O
U b CY, ..,
d d W v~ P.
O O
N N
w
~o
N N
219
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
U
>, U .~ ~ cti ~ O ~ ~ t-. 'b M a; ~ ~ ~ M ' n
..'J, ~ 3 b-0 ,~" V Op ~ ~ Gp O ~ ~ c~ O G ~O [~ >, ~ U E.., ~ b
a..Nir 'yU~O'bc~ty'dN~Cb~~.~3 ~~Nt"r~0~0 '~,M~ pO
O U .~ y ,~ ~. ~~ >, C .~ " ~ '~ i1. ~ ~ Y ~ ~ M M A" ~' j, O ° c~
.D
'Y " ~ Q' ~ ~ N U °U ~ U ~ ''' ~ U N ~ ~ ~ O~ ~ ~O I~ 'b ° c~ ~
U
~ o ~ ~ ~ ~ Q.~o .~ ~ ~~ ~ ~ c.U ~ ° o°n~j ~i N '~ ~ ~ y
°
~W ~ ;~ ° ~ ~~ ~ o °~y~ o:~ LW~ ~~~,~a"U ~ ~ ~ ~:d
o >, ~ ° ~ 3.~U ° ~~ 'bo_v~~q.~d o ~ °:r
G w ~ U 'cc ~ ° '_ .~ ~
c~ ~O .~ M ° . U ~ U ~ ~ .s: ~ G '~ ~ ~ y
m ~~ .~... .wn .'-' O ~C ~ ~ ~ C,' ° U 'O
'in~~VQ'''~,'~°.-:,~OU~O ~°N'~-~U~G~W O~yp~OO
N 'b O v ~ " ~ N U U U vW"~ ... U ~ :b ~ ~ U ~ N ~ O U ~ O
~ Q., V ~ O ~ s-~ :b N U ~ ~ m Q' U
b~ c~ n .--~ N b N ,'' ~ ° Z ~ au 'b ..w ~ N
p,do~';~~~~~o_°~
'Oc~~~,.U,ø'a3 y cnUU>>.~,C.' v~G ~ N~~.ON Uw
;'o~;~~ i °o.o~~~;a°''~~a i
o >, ,~ >, _.
°~~~bW'~o~ ~:wv~yb~>'~~o~Di~b~~-~o°n
3 0 ~ ~ ~ ,-, 'o ~ .: M ~ b
~~ " >' °°'~'-" ~ '~' U can ~ °y' ~ ~o ~3 o b U ~ ~ ~ ~
° ~ > '~ '~ '~ '~ ,-.
_ > OV ~y b r.r 00 ° ~ ~ ,~ ~ U ~ ~ ~ cU~ > O a' N .~ Wr ° >' .-
~~r U O '''
ri UNb~O~a\v~ UUUO.CUW~>,~4"'~4-,~x~~~U~G'~~~,~_O
','O-,~~~~~~~~y.'~~'o~"'OHO~0.'t'~','~.~.aU~~~p"3,S"..
y., ~ ° ~O Ov ~ U '~ ,..~ c~ b0 ~ > ... ~ ~ ~~, a~ ~ U N o0 ~ A'' >, U
~ O bJ~
CJ O ;~ 'O O I~ c~ '~ ~ M ~ N ~ N . ~ ° U P.. ~N 'G '~ a\ p '
pn ~ U ~ M p ~d ° ~ > ~~ ~ ~~ ~ ~ b O~ p ~ s~ O ~ ..-~ O ~
y ~ m ,., ~ ~ ~ ~ H a.. p v~ N G' ~ U vWL ~ ~~ ,_, U of ø, N O w ~ c~
b i..~ '~ '~" M ~ ~ .~ c~ .~C ' ~ vy, U ~ '-' ~ .Wn ;b v~ ~ t'.. a N
_N ~" ~.>, p" ° N N ~ ~ .~ L,"' G ~ ~ 4-. N -C ..~, ~ °~ ~ ~ ~p
~ U c~ ~ O
~ G' U ~' G Oip ~ M O O .O O ~ ~ ~ s~i" w ° ~ M O ~ ~ ~ °
'j~~p>,''~cd:bOU' GjUM~ G.U~~~ Nv..O.UNN.C
': ?GU ~~ ~V~t'.~.'wN~~~..r4-.N~y 4r.~~D~,.U",NO ~S-'~U°~y~,~
~'~i~ w.~'v~c~U_~~~~~~~NU>v_NNO_O~"0
~~>W..' .r"r:~'O~N~i..~>c~~,~W~~~>y.~»' .f.'~~UL:°U.S."p,4A'''~' ~~~~i
V O > ~~ s" 'C >> cct N ~ ,~ O y.., c~ ~ ~ ,.., c~ O ~ O cU~ f~." ~ ~ .b ,C
°
T..' ~ ~ ~ ~ ~ ~ N ~ ~ >> N N y .S-'.' 'a~.~ ° ~ ~ U Or ~t: ''-' a, >,
N ~O k ~..'n, U i.Nr -f» 'b
' "'b~.C~n'n O~~U~Oa)~NUN "-'t"' .-iQ'N° .~,
° >w~~ o~ ~.~W~~°,b , a~;.d >_
cd C ~ ~ N C ~ ~~ ° O ~ by ~y c~C 'y, O O ~ ~ y ~ U U ~f.~»' a..y'. '~
~ M U U
x G7 N y" .~~ ~ 'Ly ~ .~,' N '..' .t".~ O c~ b ~ b ~ ~ ~~', O U ,"O., ,~ U '-'
~ ~~cC,~ M 'd ~ cU~ .~
c~>,~~°~O_O~ynOc~~','~,,~ ~'" vW °°°'i'~~~.~N~~
N ~ ~ ~ ,.~, ~ b U N . >' V m U s.. U N b ~ ~"'.r ~a A'' y ~ N U .~ bD N U ~
i~~~ y.,
N ~ cd t+: O w cn ~ U N .C "C >, O t-~ ,~ (~ ' cd Q. 0 00 0o c ~ :D s., >,
.. ago >, a. >, ° v, .~ ~ , ~ ,~ aio ~
o ~ o °~ ~ ~ c ~ ~ ~ ~ ~ H ~ o 0
cd at f~. c~ ~ ~ a, .fl ;~ d c~ cd W M U U 4. U c~ ~ ~ ~ ,r ~. M ~+. ~
M_ ,
O p.., O ~ ~ yes., O
O p,, ~; O
° >, ~ >, ° .Q. U
,~ .
c~ ~ ~ y., ~b-0 ~ ~ n U ~ s:.
> ° '~ ~ 3 > ~U" D O ~ O >
~U ,.O C b-0 y ~U cd ~ ~ U ~ ~U of
d d ~ v~ o. d ~ .~ °~.' ° U ~ d
N N N
N N N
220
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
b _
b y ~ ~ ~ o
y t..'~O~UN ~~ C'."~ ~ 01 ~ ~y '~O U
~,pp'~N~c~~~y0 ~~ b°pV G",>,OOVc~N C~ .C.i ~cH
_c~ a~ O~ ..~ ~ i O ~ c~ N c~ w.. b0 ,_, U ~..~ ~ ~ O
O.'O~,~MOOUj~.~3 aa~c~CbO'C~~O~~'~N~bUNbO cn O
..'i'- ~~ .t'~bN ccf ~ ~~YN,~~~O~i.U,.'~~'p"YU. cct3U~f1
~ 'b aop U ~ ~ w3, ~ ~ ~~ ~" ~ ' o y ~ ~ ~ ~ ~ 'b ''p ~;~ v ~ ~ ~ ~ H a~ ~ 's~
v; 'GooW .~.~a~.bU c~p~o.~~o ~~p~~ ~~~~~ ~~.rca
~~~N".~~,a~o~~ .~ o~~-d.~o.ooon c;~,~~ o:-.ono
w Y ~ _ . ~n c~ ~ .~ °-0 ~ ~t7 ..,
~'~ ?;ova o o ~a~~ ~' ~ ~b ~ °"' ~ ~s.~ ~ ~ a~ ~ ~ > ~ °'d
~ b TJ v~ ~ 'fl U t~. ~ O ' N b0 r.., O U . "O ~ O ~ v, ~ 'y U .b
w O O ,...a ~ ~ ., , vm...~ t-W~ .S"~. O ~ ~., t"., y . .~ . U ., Y E'"
w. ~ V ~; ~ .b >' ~, ~O O ~ O C~ .~ O. H N c~ s~ ~ ~'' >, ~ v~ C. rn
NO~'''~d~yO~,.~O ~~mN ~c~~,'O'-''~C!)O~~UU d~,f3~N
N it N O U ~ G; O ~ U ~ U ~, ~ C"., ~ :~ ~ ~.~'-n -~ ~ ~i
N tin ~ ~ Z ~ V ~ '~ P.~ .~ Cr' ~ ~ '~-' " ~ ipr ~ .O 'O O '~ ,f"r ~ ~ .i-'.yp
N O a
.Y ~ ~ G N b ~, ~ ' x N G N ~ ~ y ~ ~ O ~ ~, 'b y ~, U O" oD
UO~,~d,~~~O~O~~C.~~N~NU U O'."
'L3 U ~ U ar ~ Ir .~f 'au 'b pp 'C c~ O ~ .~-." p 'b a., ~ ~ y0
~ c~ , .~"~, ,., iv ~ p E..~ ~ O '~ N ~ ~ O ~ ~ O w .0~., b~A O ~ U ~ ~
~° ~ ~ '..~ ~
,~ ~ ~, ~ au Ov a ~ N y ~ _~ ~ U U ..'~"r cd ~,~' ~~ ,'~ b ~G ~ '~-' ~,' C,' ~
~ ~ ~O
p ~ PA .O ~ c~
'~' °' ~ '~ w0 3 ,..~~.~ '° ~ ~ ,~ U ~' ' s ~ rte. ~
cn ~.. ~ ~ ~ oo ~ ~ 'b w d ~ ,~ ' .~ ~ ' a. 3 ~ on ~ a~ " >
~ O .~ i ~ N U d0 ~ > ,,>', tU.~ O O O p p '~ ~C cC w ~ ~"' '~, b~-0 y to ,G
°' ~.~'~°°o°M°_~ ~a ~Vav.?? ~ ~ oy'~'" o ~U
° ~ '~ ~ vy~ ~ a~
b .~ ~ U M N f~ ~ ~ O O W ~ N '~ ~ _~ ~ O ~ v ~ U o ~ ~ .~ c~ ~ w
Oyc~ OxO~U~~ 'nU~OyOGy.~C'-'~~Uc~~p~_~'C '_'~y00
~ O ~ j °~ ~ ~ X .~ ~ ~ .O ~. tv0 ~ ~ ~ '..~ ~ ~ w. O w 'b
_° ~ i :b ~ ~ o ~ W ~ b o ~ ~' ~ ~ ~ ~ ~ ~ ~ a~ ~ ~ ~ ~ 3 >
G ~ '~ ~ ~ ~ .t'.' ,s.~U. ~ ,y ~ Q' p., >~, ~ 'O O.' ~ y .O ,~ .G c~ ~,' N V ~
.~ b O
.o ,~ ~ ~ ~ cc i ~ ~ U 3
d ~ ~ N N r-i ~ d .~ U ~ ~ ~~ ~ ~ y ~ ~ ~p ~ 'C ~ ~~ O ~ ~3 U 'j ~O C ~ s.
,~ ~ o W'MO '~ W v ~ ~ .a ~ ~ ~ ~ '~ '~~° ° ~ a ~, °~' b
aWJ ,-i U U U N 'b a N ~ N C~ ~ A" ~ l~ O '
O ~ ~ ~ .~ O . yp, O ~ U ~~ ~ ~ ~ 3 ~ O W '~ m O '~ N ~ ~ O ~ C. ~ ~ s., O
v~ . U cWn ~ ~ U 3 _ O b0
_~~~V.~~~Uw~ "C~~~~~ON~ynV wc~U ~Ns.U.,UO~bb
N ~ C~ ~ (n N Q O 1/7 'au N N
~' s.~ w, O ~ O ~ > O N ~..~ p ~ G",
p O
N >, bip J"'..~ A. O U O f3~ ~ c~ G '~ N C/7 Y G1. O~ -d .~ '+~ .~ ~ D c~
O ~ ' ~ N y U ~ . ~p ~ U ~ U .~ -d ., w O U U . ,-~ -d v~ C cd U >,
c~ V .~ ,~ ~~ ~ 'b ~ ~ .b .., cti ~ ~ w b j, ~ cd ~ _ 01 .t". ~ -~ ~ U ~ O
v~ N .~ cd ~ s.. -fl U . a O iG v; w >, ~' O ~ U > ~ ~ : N cci U m p
O ~ U w ~ ,~ ~ O ,~ ~ > ~ O c~ ~ U .b r~ cd w '~ O .~ m ~ ~~, U p,
c~.~n.UE"-~W ~~"''~>'O~~''O~~'~~,~~'Cpa~~NG".
'~ ~'O G1..'n ~U R~, ~ ~ ~ ~ V d ~ U >, ~ ~d ~ ~O '~ ,O c~ ~~ > U ~ x U p ~ ~
~
Ow~~~ ,_,. >,~'~ 'Gw~~~;Nc~~'UOp.~~~~a'~0~~ b
by w y.., O ~ ~ U N N N sr ~ .r ~.. H
c~ >> ~ G4 ~ ~ ~ "U-' ~ U U i.r ,~ .S~'. Y' w O 'a:a N U :3 U >>
~OVN~~>,~C~~w~~p,.~"~OO~w_~p
cd cti cW r ~ ,~ C3~ v.~ U a . . C~ 'C t~ ~. O Gn LL w 'b O W -r N a.~ U U d
wr ... wr
w
O O
U E-r o
N p.
b4 ~ ~ ~ ~ U ~'' ' .~ ~O
~ O ~ .~ ~ O
o a.~ ~~ o~ '~ ~ od
~ H
U o. d b y ~n
N N
O O
U U
a a
N N
221
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
wo ~ a ~ ,~_ ~ U ~ ~ -d H °~' ~, on ° '~ ~"~' on
'° y .b ~ o ~ >, ~ c o ,~ ~ ° ~ ~ ~ o :o ° ~ ~ ~ "d a c
M > ~ L 'd ~ ;_, 3 ~ ~ ~ ~ P-~ ~ ;b ~ ~ O ~ "O ~
E..~ O ,Uf"~ ~ U y ~ OU Y ,,~-, O ~ c~., O .O ~D ' N O ~ ~'~' ~~ ~~ E-~ c~C '~
~, .~
~ ~ N ~ U fr ~ ..p' U .~ ~ p U ~ ''' V >> .-'''~ _>> O d N ~ ~ ~ ~O U
~>C~O~,O,b~'~ ~~'''N~N~ccS~ V Uc~ 0~~~~~C/7
auNN~~ac".u~y~..~ ~..~~'y,U,~.Cln~~~~~,~.r'O ~~~~ V>N~N
~', > G" .~,.
fn ~ U ON ~ O '~ ,~ O ~ ~ N b x ~ ~ U ~ N ~ '~
O c,.., 'O cti ~ y ~ U iC V1 ~' '~ b N N O ~" N y, ~ O N ~.~. X C'" w ~'
': ~ O O N 'b M c~ ~.' ~ N .~ b .~ O ~ >, ~ ~~ ~ N O U cd ~.,' ~ W Q. O .y'
~ "', ~ ~ ~ N p., N w ~ ~ ~ N ~ ~C b ~ b ~ ~ vi
GN~~~~N~~.~~ NUp"~~~N~~~~~3" ~~~p~~w~O~_UCti
c~ t-~ ~ OO ~ I~ U ~ m ~ 'b M ~ U >, N ~ 'a0 ~ ~ ~ b0 c~ C/]
.~'J' ~p c~ ~ ~ N O N CL ~ ~~ W O p ~ D ' p s"' ~b .b N ' p c~ C/~ O
w E-~ " ~ ._~ O ~ c~ ~, c~ y N Cr ~' U V N ,~~ E"~ ~ N ~ 'O ~' v' ~d O ~ , 'b
h
w d '~ yD ON N ~ '~ ~ ~ p ~ ~ w ~~ M ~ ~, ~ ~ ~ -D ~ a~ ~~ j ~ O
>, C/~ O b M ~O ~ W V ..U. O. >> Q ~' O ~ pn ~ U G ~ ~ ~ U O p
c~~,~yDNN,.>', .~~ ~~O~y.ON~.~W~ N~~y~ iia.~~~'~N
U 3 v ~' ~ ~G ~ '> ~ o j
,~ -d '~ U ~ oo U ~ d '~ ~ ~ y '~ ~ ~ '~ ~ ;~ ~~ H :~ .3 U a, °~.'
° .a ~ c~ ~ ~
o d ~_ ° ~~ ,~ a~ '~ ~ ~ ~ o ~ ~ W ,x .°~ d
.r N s.. C/~ U c~ _
O~'p~~O~.N.~,-,~3 .~~OWO"O~c~~,~~ ,_~ONp'''~O'i'~N
W .U. ~ r~ C~' U by ~ a~ c~ O ~ tn ,~ U .-' ;-~ c~ O p b
''~"" :yr . ~ ~" p '~ (, .t'. ~ O ~ ' ~ w; b ~' U ~ C O '~~' ..~,
;' ~ ~ .~ ~ '~ o ~ .o > b o i ~ '" o v w a ~ ~~ ~ ~ o ~ o
a~ " a ~~ ~. on a~ do >~ a ~ ' d o ~ . ~ ~ -d o a.
~ ~ an ~ ~ ~ ? ~ ~ ~ 0 0 0 ~ ~ b ~ ~ o°°o ~ ~ H '~ y '~ ~~ ~ o ~
W a.
s. ~ O y x ~~ "O b '~ ,~ ~' 7.~, '~ O i-r ~ ~ ~ ~ U '~' O U N i.~.~ 'i"' ~ N
O_~N~U~~U_'~Oy.a','~,OU~"O ~~'.'u~.U., .'~~' Vi~N~t"n_~.u
b ~ Z' ~ ~d i~..~ c~~C U ~ U U N ~ N ~ vy0 N " 4-~ N S.~'. b U U i~ ~
G O . G ~ ~ ~ ~ ~ a0 '~'" C M ,~ O b ,C .
~p0'-~~~~ ,~,'yn~Ncti~~~G'p.~~.~",c~~p~~Q .S".'fjyQ~G~~r~rp~~0
O ~ ~ " ~ c~ 0 0U ~ c~ N ~ '~ ~ ~°O O ~ bO~D ~ N '~ ~c~ U . '~ ~.~
,~'~' ~
_O ~-~ ~ ~ ~>,O ~ ~ N ~ y,0~ p ~, ~ ~ ~ ~ ._~ ~ ~ ~ .~ ~ yp,~ _>, p N 4=..
',=, N I~ 00
VJ U~ar~~~".,..w~~am~'.~Q ,~',~Vl p .~.,~~i.U.WI~.> U°Cd~~b~ a
~. a~ .. .., a~ a~ ~s O "o a~ U a~ y ~ a, -- o
p., y' ~ N c~ ~ yp, ~ N A'' ''' ~ v~ G. W n iy '~ ..:, ~ ~ b0 p O p ~
~M.~Q''~N >~N?G~d;~ ~~c~V,~~.~~~''>,' ,M-,N
.~ " ~ N N ~ p " 4.. ~U ~ O N p O ~_ ~ ~ ~ ~ iG O ;~ '~' C C ~ ~ ~~ o~o N
D~N~,~ynbO~~U~~'~_"'O~"~U~~ON~O .f".~a-'~~O~M~,'
;; ~ fn O x N M U ~ ~ w .y ~ ~ ~ :~ c~ ~ ~ ~ '~ ~ O "' ~ U O . O O v~ O
~ .b U ~ p~ .~ b 'b .b ~ ,~'" i 3 >, ~' U i.. ~"'.. .O ~ ~ s.. N ~ O
fnN~DN ~ O U~~ O bD~ bA~"O+~ c~ DD.~ O'''"
b~GL'b~~~c,..,UU~~ cd'~~''b~ 'r~'~VO~G.'-'~'N~N~~.,c~.bp.,'b
O p U ,~ ._-r o0 0o O v, ~ . U ~ ~C O y b ~O d V cd b 3 >, ~ > c~ ~ N U fn
~~ooOwnV'~~~yn Ub UGyy~O.~~~'~.~U~~~bcd
O vW0 l~ I~ cC O vmn ~".. N ,~U~, ~~ f..' ~ .~~. N ct! ~, ~ U ~ 'n O ..C ~~'
>, N O ~ ~' a,
cC it f3~ c~ M ~ N U .r ~ N U d ~ ~ c~ V] v ~ z O ~ cC U d a..~ ar c~ ~ ~ ~L
cd [1~ N
c~
~ ~,." 0 .0 N ~ U H
G ~ ~ ~ ~ ~~b0 ~ ~ ~ ~ O .O
O p O ~ ~ > ~ ~ O ~ ~ .C ~ ' N
N ~ N .U ~ ~ N N ~ N ~ U
La N . ~ U d a~3 y s.. N . 'r U C/~
N N
N N
3 3
d d
z z
N N
222
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
i ~ i~ °.b~ ~c a~~ o~'~~' i;~>,V
N 'Cb~x~~MNc~.U.,b ~~.~ ~ GY~C° ONNyH
i o. ~ ~ ~ ~o ~ U ~ c ~ ~ ° ° :~ ~ ~ 'Wo ~: a~ ~_
>' ,~-p., ,~ ~ U ~ ~'. ~ .p ~ W O n N cC ~ ~ 3 '~, ~ V ~ G~. b . ~ N
.~ 'oo,o o ~ ~ ~ ~ ~ ~ o ~ ~ o o A ~ ~ ~ ~ -o ~ ~ ~ o ~, o W ~ ~''
o ~ .~ :b o . ~ y ~ U °' a. ~Y, ~ ~ o ~ ~ a~ P. 3 ~ ~ a. ~ ~t .~ GA -~s
~ o
° C ~ ~ ~ ~ ,c"~. ~p w, ~ .~"'" U N y U .3 ~ U ° O ct~ N O c~
cyn .~ c~ '~ O U
'i"~'bp~C/~OU~~ ~,.5'~'p"pyN.C~~'~~~~x~.r ~~.~~''"~3'Q.iNi~~s.N.bpa
O _~ ~ Ov , C c~ '.' ~ w b ° ~ ~ ~d G N O U C
i.U.,~Nwblll~.'~ ~'~~C',UOOU~~y~' 1.~.~~Vi~..1"y~ ~0 N~.
N c~ ~ ~O ~. N N O ~ . ~ c~ ~ J".~. O 'r ,Y ~ U ~ ~, ~' ,~t"., Y ~ .S". ., wr
~ ~
O~V O °~00~ N~ >,vi ~' ~ a~.~.~~ ~ ~~M~ ~yb
cad ~~~ '~~ ~~,~p~p oo~U c~-d_,a~.b .~a~>
>, c~ ~ ~~ ~ ,~0~, s..i ~ O .f'. ° y ~ O~ , ~ ~ ~ ° U ~' U p
..f"~' ~' c~ N M O
.~"", ~ ~ .!"'. U ~ a, tr ~ it .S_', cC ~, d' ~ c~ ~ U Or v~ ~ 'W r
'_' ;-~ ... ~ ~ O O ° w t3. b O. c~ ~ ~O ~ ~ a~ N ~ ~ ~ ~ ~ ~ M N
O ~ y ~ c~ ~ ~ O O (, ° U O ~ M ,~ c~ ° ~ ° °~
~ ~ ~ ~ w O ~ v~ "C1 ~ ~ v~
i.r U Sir VJ ~O G~ ar Vj O it U O ~ U 00 N ' ~ CC
au C~
,~ O bU ~ ~'~ W -~ W . n ~ N N x ~ O ~ tU.. w~ pip '~ s' ~ %-' i-v d'
OU UUN~~° MN U~ ~_~~~ ~~~~~~N~S'.U,
.~ ~~ ._~ ~ ~' W o ~ ~ Y ~ U ~ N ~ U b ~' x ~ ~ VJ on.. ~ ~U ~ N ~ o
s~v'NNUO~O Q"'p,,~'~.U~"~ ~"~~~,03~~ ,~"~y.-~v~OV7
's'. ~ U ~ ,~ ~ ~ y 0 .'> w " ~ ~ ~ ,r' ~ N U ~ ~.' a~ '~ ..~~ ~ N i~ ~ c~ ,s'
~ f.~',
N ~ ~ ~ b-0 b ~ ,~ 7, U j~ O ~ ~ ~ V ~ ~ ~O ~ ~ ~ N ~1~ 4 O M ~'~p Q ~ ,~ y
"r ~ ~ ~' ~ >> 0 00 ~."' '~ ~ ~ ~ '~ ~~j 0 ~ b4 ~ a ~ ~ > ~ 'C '_' ~ ~D ~ 3
~~,r" U
;~ ~ ~'~ n,b"~°' o ~ ° ~~~~~pay o ~ ~ o ~~~ W~,~~M ~Z a o
3 ~ a.,~ a~ °~' w ~.; ~ ° o o ~ ~' ~a ~~ ~ ~ ~ .~ ~ ~c ,~ .b o~~
° ~ ~ .c an ~
~~ O ~ ~ ~ .~ ~ ~D U . ~ " >, ., ~ ~ w v~ O c~ N ~ O ~ ~ ~ cn
b N ~ R~r M ° N ~ ~ b0 ~O Q', i~ s.. ~ c~ c~ ° O N ~, wr c~ ~ :b
~
b 00
NN~~M'~'.~,~GU~~N~~i.Nr~~N.p''C~_.,~m_b-0~~
4-U c~ 'b ~ N. ~ ~ M U ~ ~ ~ ~'"' U ~ ~ ,~ ~'~ _N ,L_' c~ U 'b '~" C~ . .f-'"
N t.~.. i~ ~, l~ ,.'' ~ C~
.~'Sr., O ,.~ W O . '~~' ." ° WD ~ yn N ~ ° b°0 ~ b pOp
p~~p O~
~s.'C.n~~U ~~~O.~yt,"~~~N~.'~~~~ .~.'~ Qy,.~.p~N
~..~..i ~ ,.p ~ ~ w N ~ U O O U _: '~ ~ j U ~ w
.n a~ ~ 3U~ o~ ~ ~ ~~~ i ~~ ° ~ ~" ° c o ~-c ~~~a~ °'~,_~
U c~ >> U r~ O O ~ ° ~ > 5~ N ~ ~ ° V O ~ O D ~ W n O V~ ~
N
" c~ a.u N'.3~.1',~,(/~ ~ 'T~ O ~N C,'~°..°O' 3 U ~. ~O 0.~~ O
UMN
U ,.O b0 N G U ~ .~C ~ ~, N . C ø, ,.~ U U pp w
vlNa.U,vicbd s'U'~~t~.~~'y.,fix'-'sU-~yN.O~~~~c~.'~"~'a-~~~0 ~,S,-,~'
~ O .'~ ~ b U N ~ O ~ ,., ° v~ M y ~ > ~ N v~ ~d ~~ ~, ~ 'd ,wr O~ yn
~ U ~ (~-r ~ ~ O Q~ a~.~ ~ ~ ~ ~ ~ ~ p y"'-' ~ ,~ i.r y, c~ YC ~' 'S"" M 00 >,
d' U N
mb0~~ø''bQ\O~OU~.~~.'tncSb~'''~y~NO~
-S". > ~ ~O T~~'
M w ~-"O "b i'~"'' V Up z >, N ~ c~ ° Up., ~, ~ ,-, :~ y .~.,' y >>
~"'~, ° ~ N c ~ ""i M ~ .~ ~ ~""
° .b ~ o ~ ~ ~ ° 3 ~ ~ ~ ~ b ~ o ~ ~a~ x Wo
~s ~ c~ .~ ~» a~ ~ ° ~. o ~ ~n a\ w ,~ ~ o ~ ~ ,~ ~ ~ ,~ ov a. ~
'~ A.., cd .G U H d0 G. d .~ cd t. O. t~. c~ M ~t O .r W U d c~ cd ~ N .~ . I~
N F--i N W W
w
O
O
p ~Q,
~ ,S," x ar U ~a"'.~ . .s' V7 _
b~A O y0 ~ ~ ~ L~ ~ N N ~,
~ ~ W o ° U ~ ~ ~4 ~ ~ ~ ~ W
~ G~ ~L S"r Q y .r t-~ N N ~
M M
N N
w w
N N
W W
U U
x x
a,
N N
223
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o ~
. ~ ° °'°
'b _vWn ~ ~ ~ . c~ . C c~ ,y.~. U . ~ ~ ~ O .-~.
OOVN,L"~n7,~,U ~~~G,,~,, U ~i.Ur~y,L'Ny.U" ~(7c~41
y,0 ~n ,~~ ~ i~ d 0 3 ~ .~.1 ~1 ~ >, O d' Wn ~,.~ .~ ~ V ~ U N ii
w C "~ _ ~ U N ~, ~ ~ m ~ .C
~MCp''O ~ ~~~~"'..'~~ ~ OU~.~.° ~.~OC.~~~~ Q(n0
ao, o o a a~z
-db~°~a~:b ° o~~~~, a~a~~,:~.~,c~'~~~ ~o.o
~ ~ .~ C7 C~ ~ o o ~ ~' ~ ~, ° ~ ~ ~ ~ ° ~ ,~ o a. ° _c y
~ .a
O '.= tai ~ O V .. . ~ ~ U y ~' ~ 3 ° s., G. c~ ~ ~' ° ~
s'~' .~ '..~ 7
'"' iC N ~ ' ~ au V ,~ ~ 'b N N _.. a C-0 ~ .O C"., y
U N .~ y y ~ U ~ V ~ N ~ ~O ~ cad 7G G ry~~ a ~ U :Zj ~ ~ .~ ~ ~ GQ cUC
w U ~ ' ~ Q N N ~ ~ ~ O 7 . ~ bA V ~ W c~ ° i-v M U t. W U U 'C ~ i..
,~p~N,.~.'f~~' r~,,.,y~,00U'~. ONG.i ~-d~~tij~y~NwO~-p'i~~~ N
Gr p .~ O ~ > N ,'i;., ~ ~ ~ ~ U w c~ c~ G Q.' ~ O~ t-.~.' a ~ ~ ~c~", C ~O
~~~, .UT",
~. '~,'~o~ ~ ° ~~C~,~.b° '°M~~on.~a~ 3~k~
.~~.» W'ONM~1~.~U~ etl~NN.~'~cc3~NOU.~_~,Uc~GO O.Ow
~ OOVO~.'y ~'~~4w..i ~ ~ p'.' U OOva~ ~~.-.i ~ ~ ,~ p °
~~cd~UN ~0~~~~~.L'U yc~;-,~~N~_.~'i.~arc~.,f~" i L~r~ ~7 .~',
.C ~ ~ ~ ,'C ~_ ~ ~, ~ y ø' U i~ ,~ b-0 ~ ~ ~ ~ ~ N W ~ ~ ~ ~ ~O U O
UpN .S-',~'bppb-0i U~~'.,i'~' .r.;,~UC1~~ t~~, p~ce30~", N .:~, 3NU
..d~~~O~U~MO00.V,'~G3U ~~ ': ~~°A"' O~'~N~p~ y..,
~W ~ ~ .3 ~ o.~ °.~ ~~ ~~~~ ~ ~ ~~ N a o
t~ ~' O vW0 M U n . ~ U w b l~ y ~ N cct TJ .~' V ~O ,~-, v~ Q
3.G. O~O.-..~N°UN~." 'y~"?CP,'xt~m,~ NV~v~ j~ V~.,
U ~U ~ ~~ ~ ., ~ ~ E'~ U O ~ ._° U ~ c~ O~ N O x M ~.u ~O ~ .~~r ~ ,~
F'~ GL S,'
w cd ~OO.~~ ~ ~~~v~~U wNG
' ~~o~ iy.°'c~a~ °>G~'~~°~,~x~U~~~~ovc~o
.L"n ~ .i". ~ N L.W-U,~r '.~ '~ , ~ ~ ~ t-.~J F".~, 'C""' ' ~ .~.' ~ ~ '~" bJ0
~ ~ v~ .~., V ~ ' ~ Gyi y
~. .~ G p ~ ~ d0,~ ~ .,t",a' ,~ .O .~ ~ ~~ cd x ~~ ~ U ~ ~' ~ >
~ccSL:°UUCc~Ndw~°U° r~V...~~..UUW ~~'I~N,,.'~U'Oø'_O~Uy
,~ b w ° > ' .~ ~ 'b ,~ O ° y p ~. ..~ b ~ O~ ~ p d y :~ ~ ~
a:~ ,~ .C~r' V1 ~ ~. ~, ~' '~.S' . !n fn ~ N Vl ~ U .~ V ° ~ ~~
° ~ f~/7
vp, .C > .° y p ° ,~ ~ y~ b-0 ~ ~ O "d ._~ ,~ b '~ U ~' .... ~ ~
'y ~ ~ U ~ c~ O
~O~Up,~~yid~UN~~ t~a~~~~uUO~~pJ~.~~wOO
P, bd~t=.Ow°~~OV~~~,~ ~~N~~,s~, c~.b~(~~U ~~O °~ ;'.-
'°
N ~ N ~ N ~ ~ ~ ~ '-' ~ G~D y~ ~ .., ~ U O M N G O ~ N W
E.~NGU'b'.~~~o~~~.c~ ~°ts,~4:'~pNUM~~.~~0.~. idp
~ O N ~ O c~ ,-, '~ >, '~ vW' w ~ 'O O. > ~ .-: O p
an ~ ... oo ,n ~ a~ ~ on ~ o a ~ .~ d oy ~ °'° .d ,~ ~ ,~ ~
° .
O ,~ ~d cC y ~ N ~'i p, ;b ,~ .S'~". N ~ ~ ~ ~ ~ ~ O ~ 'Q ctt '~ :~ cVO A"
° v'
~ ~ o'cU~°~ ~ a~ o.~ ~v° N~c.~.~ ov°
v'N~ .t~,C,U°i~o0~. ~U~OwN7~~b~b'C.' '°~',~,~UN'n
cd ~' b-0 pp ~.~.' ~ C~ O fir' ~, v~ ~ N ~ !3i 7, U cd ~ .,-U, a' ' fir" ~ t~
a~
0~~~~CI,.dOvdGy,~~~~ ~~'~.yU~~,c~.b.~0~,~.-,~w ~
O ~ t~ it N ~n vo ~ ~ m ° ~ ~ >, N O ~ O ~ ~ ~ ~ N y O '~ p s..
E-~ ~, ~ . W ~ ~ .. ~ W ,~ ~ ~ Z .~ d ,.. .~ ~ ~ p p. ~s W v~ . t3, U U ~ u; d
~. o
w
w
O O N N ~ U ~ w :~ O
O ' ~ '~ .~.' N ._~ V v~ O 'O C
_° ~ ~ ~ ~ N N ~ >, c~ O c~ -~ 'y'
V by ~ ~ G c~ '~ U ~ . N
_ v~ ~ _ ~ .,~ Y s.. U b
y
p O a Q ~ Ov O ~ ~~ ~ V ~ y
i.V.n V . a ~ ~ '. i C/~ . ~ VJ ~ ~ ~-I C~
M
N N N
Cv Ov
w C7 C7
x x x
o. 0 0
N M M
224
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
° ~ .~ c a~ i
° a U a~ a~ ° ~ ~ ~s
ay ~ ~ >, °~ ~
o ~ ~ o ~; ~ .~ ~ ~ '~ E'' ~ i ° o ~ ~ ~ o
U U ~ ~ W U ~ ~ ~ ~ OU '~ ~ ~ ~ ~-~ '~, cd cd V ~ ~ ~ ~ ' ~ y 'ate
b U s~ O pp N 4. > ~ cC >, ...~ U p .r ~ .... N ~ ~ ~' s. GO
G1. ~ .~ " ~° N E"~ :; O ~ ~"p ~ ~'O ~ b0 ~ j U ~ 1', y c~ ~ . -~~. ~ ~
> U ° WO
>' O °~ ~ ~ O V ~ N b ~C ~~ ~ ~ ~ ~ ~ ~ ~ ~ N ~ N ~ V7 ,~ ~ Y ~ U N
O. ~ ~ ~ p ..~~»» .b ~' ~ pip _~ ~ ° N .~ ~ .~'.' '+~ "'~ ~ ~ ~b W N r
~ O ~ y~~~, .Q Q
U U .C _c~ N ° N ~ ~ ~ W ~ O n M U ~ U N b '~ N O ~'~' ~ ~T"~, ~
7,G ~~ U ~~ O,c~~~~..Ob ~ ~ vi ~', N~~ O U
''' vyD U ~ V ~ ~ ~' v~ ° ~ w O ~ t~ ~ b Q ~ ~ d '~ O ' c~ > N
~ N '~ V> °~ U O U U U ~ ' ' ~ ~ ~'' by \O l~ :; ~ ~ CL _O b ~
.~.~~ ~~~,~wNN,~ ~OU.~~°~Gv.r°y~~~~ ~F*:.~'~
,~, ~O°N~O,~t., c~~y~~~'~~~.,U~>~Ucdpp N:bcd~ U
W n ~ 0 ~ ~ w P.. ~ ~ V ~ V ~ ~ a ~ >, N ~ ~ .t"~' ~ .°y.,' O
y y >> ~d U t"~ ~ c~ N .~ cd ' ~ ~ N ,~" ~ G~ ~i i c~ b ~' > ..d
~ tin U ~ p N U ° ,s'» .d ,~ b0 ~ U G tn y ~ ~ ~ ,~~ '~ C/~ t..' ~ at".
~ y,~, N w N
tn ~ U ~' y, m .O ~ N ~ ~ ~d V tn O N
'~ _m c~ -b ~ O H ° ~ O ~ ' O~ ~ ° '~ N c~ U ~ > U b O
.:? N CA .~ ..U.~ ,W.U. c~C ~">', ~ '~ ~ ~ ~'~-' ,~'~' ~ ° ~ 0~1 x N ~
~ cn '~ ° '~ p O. ~
~b G ~ _ G, y~~~ E"~ c~ > c~ ~ V ,~ ~ O ~ ~ ~ ~" V _cn ~ s.. -p t~ O c~ Q" a
.b
N ° '~ ~ U >, w ~ ~ .~ ~ N cd 'b ~ U ~_ 'U E. ~d 'm U 'J, w
b ~ ,~ ~ iG ~ x G ~ N ~ O U ~ U ~ y O ,~ O cad ~ ~ °~" can
.~~,~i..~'CmL;~'~'~~ ~i.~_:ON~c~O~O"~"M'y~.r..r" ~~~,.'~yL~d4-~
_>,°'f''.~ E.~.~S".wnH p ~ U U~~," O 'S'~"" .tn»~~ 'n ~ N'~ cn~'._~
~b0~b N~ >,U
°~_ 3 >w~~~ ~~.cx~ U ~ ~ ~ ~sov
~ a~ > '~ ~ ~ ~ ~, ~ ~ ~ o ~ d .. ° ~ E~ ~, .b ar o ~ _~ o ~ c
Ob~O~..'~~,L'y~~~>,,O~OUNs.U.'~':b ~y.U.UQ~y~U°p"~'b~.i~.NO
~'~"~'.O~~Ly.U.°~;.dpp~.'r~'~n~v»~.~ed~C/~'~UO~': -f.'~"~.~Oy~"..r.
~f~-'~pU'3b-0y~V~ .r",O'd~C.'~"'b~ .rU.l~v ~yb0~ .~t'.'U~ .fU,~~~N>
.C ~ ~ ~' p :b N .b w ~ ~~ ~ N '~' ~ -d ~ ~ ~ ~ ~ ~ :b .~ O ~
_C L, ,~ p O ...~ ø, . .~"~, ~ ~ U O V7 ~ .r-.~ O ~"" N w '-' ° U ,.C
C~ p" N U ~ E.., '~ ,N ~ s.~. >' Q N 4~ ',~~~, ~ M ° ' ,~ ° U ~
W O p ',., ~ ~
U U ~ i.
~~ ~ w" a b a. ° > ~ M ~ ~ ~" ~ o .~ ~ o .F~ ~
.~ > " : a~ ° ~ i ~ o°',~o ~ ° ~~ a,~.~d°v'~ ~ a~i
~'~ ~ ~~~ o.~w ova
~ G. y ~ .~E O O _>,'... ~ >' N o0 w w ~ '~' ~b U . > N C w ~ ~G
~~~cr~~.,o>~~cwo.~NG~~~o~0~~ .c,..,>,.n°~'da~3°~~.~~;a
N ~~~TJ .~.°~~OUO°°U>~~~vly,rUU ~°i.,
OH~yO~'~7-U. >,~>~L~.~U~~UCC°Uy._~UUj,NU~a''+~~.'~
~.!".,~°~,~G~U~'~~ ~0,~'.t".>,NOt~n~U~~NN~U~'.~OE-iiC00
W c~ u.. R~ a> ~. U ~ a . U d ~ ~ ~ ~ ~ A. c~ W v~ . GL U U t-. ~' d a~ a. v~
W
° o o ~ ~
a~
o w~ ~.~'v.. GUE-
O
vi ,~ ~ .y ~ N ~ ~a ~ ,~~~ G
U ~ O
H c~ . (°'/l a, ~ d b .r ie~r N .., '.
N N
M O
w
x x
N
M M
225
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
o ~ ~ x U '~ o ~ ~ ~ ~ c .y
_~4,-d '~b_~
pv~Ua °.~n~~~ V ~~V dy~~.~.,~._cyC~i T~a"NU pOV
_ y., '~ N a' w N c~ ~ ~ ~ U V c~
E-~c~N>,.~p'nU yUv UO~ CU ~ ~'~~ V
W--. ~ ccf N U
b V~~ ': ~ V~,~,O ..o~0"~~~0,~~d~ Ot~O
~ N ~ U ~ c~ >, ~ V ~ cd Ov 'p ~ ° b0 ~ ~p ~ ~--~ ~ :.~ .,.'~. ~' ~ ~
.~ s.. 'O O t-~ .D b~ N y O_~ U ~ ~ C c_d U ~ N 3.,'' ~ rn O N y
a'-'..~ ,S" '~"' .~ O y", O 'O >' ~ 'a~.~ G~". ~ ~ ~' .. 'C ~i. ~~' ~ V; ~ U ~
~ .t~.' N J".. ~, y 3
z .y ~ p, ~ N C. ~ ,~U, N V ~ '~ ~ N N U ~.,' ° vWn ~ ~ ',~,, .~",
''' ~O N T ~n O ~ cd ?C ~ ~ V '~ c~ U Vi ..r ~ ~ 4r ~ O~ c~
~ ~W ~o~~CA ~,~, ~,°~°na,a: ~.~ ~ ~o i~~
~.
c~ G ~ ~ c~ ~ ~ ~ ~ ~ ~~ ~ . " ~ ~ ~ ~ '~" ~1 ,b ~ .,Ø ~ (y" ~O p0 ~ V W U
N~Oc~.~ ~~~~~c~3'~bOc~C~O.O~~,~.~~N yU i ~~OI~i~~
~, ~ a ~ p v~ ~ "d s.U. ~tn "Cy '~"p ~ U' -C ° -d ~' ~ ;j ~ ~ V 3 'O~'
~ O r"~'' ~ ~ ' N .~
r.'v.~" ,f.'U y'~,Uyi.,i'.'O~'c~i-,~cOU~~w~ ~N°V i.,O~MO
N ,--~ s.' ~ b H ~ ~ ' cC G U ° O ,.; ° ~ ."0.r ~ c~ U N ~.
t,_, ° l~ -d w °
N N v~ N ~'" N ~. Q' - ~, O N ~d Oa ~ pp '~ C. 'b
x_~_.~~o.k~~~~o~~~~z~o~~~o~o ~~.~o~~oW~~
NO~'G~O.~~' ~~~~0~~~~_~.'~.~'tnUU C~ ~G~~.L~°n.L~j,.LVrU
~O .~yO~c~N~~~c~'y.~°~'~
U 3 G', ~ V U y~ 'b ~ : ~ ~U ~ ~ ~ C~ ~ ~ .NO °~ U ~ b ~ ,~ ~'~''
c~
00 ~ 3 .b O O c~ cd V O c~ ~ ~ ,~ c~ V y ~ °U p Ga N ~ ~ Wn tUn N OU C
MMO~.fl,~N_ONø'c~O~~tN~tj.~~~~~'~~ ,~'y.~ON~~.Y~».~~j
NOv~O>,~N.~O~~~~b~' c~C,~',.~.,a''-'~~b~'~~O'~~'"CfU
~O U U ~. U 3 N (I, O ~ O s"' x' ", U -S", ~U" .O O ~ ~ '., _O ° O ~
~'' . ° O
Mp~~yUU~ ,~"'oD~~ ~~~~i.U,O.n.ba~~~~~~~~U~~~C
° w c~ ~ b ~ '~ ~ ~O '~ .~ ~ C c~°n ~ 3 ~ C. ~ N :~ w ~rj ~ ;p ~
~ G ° b ~ " v
N (~ O ~ ~, N p N O .~ ~ c~ ~ Ov c,.., ~ ~b ~ c~ N ~ U ~ . ~ 'b O s.. biD
.~.' y N ~ N o V N ~ ~d c~ ~ V'7 U ~ W ~ U ~ ~ ~ c° '~ > ~ ;~ U ~ ~ V
>,
7,N~ V °.~v»~'v'v~~.rw i ~~ V N~~~M~c~'n.~'~~ ~~,~~
WOO [-~i~4-,N~.~b,~N,UNnd',+-~ ~O~y~l~Mc~U ~'U~~~O m
~C~IUU~y ,f,~~~~~ux~~O~cd~~S"..,~~~~ ~ Vu~~N
'~',~~G~U~~Gtn...'S""y~~UQNVi-s~GW"~~~~~~~~~~pV~E~''~~"'..
.O '.=' ~ m .T'. it ~ Q U w y l~ ~ ~ U ~ 3 U d N b y i/7 'y ~ ° ~ y
.~ ~ ~ O 7G '~ V Ga,~ ~ ~ Q U ~~ ~ .~ U c~ ~~ ~ ~ ~ ~ V ~~ O N Qi M O
_~ ~~ ~n CL U N v~ o c~ ~ ~ ~' ~_ N oW' ° '° a~ -d ~ ~ ~ ~ s~ c~
U
~ M ~ O~ ~ N ~ U :.V., b U O U O
0 0 ~ o '-, U v ~ ~ F., ~ o ~ ~ _~ ~ ~ '~ ~ >,
WyUOyyO~G~'O'dv~00~.VCd cn 'Va..~LO
4r vW..'. ~ C~O ~ C.' f''.., ~~ 0~C. 0'a, .'T~1." ~ O
N ~-. ~ ~,. ,i:, m N y c~ .~ GL '~ ' C"., N c~ .~, U c~ O ~ s.. O '~' G. c~ cd
U N y
G ~ ~ ~' ~ 3 ~, cUn ~ c~ ~.r V U ~ U ~' ~ ~,V" s., .b .y".~ N V z ~ O b0 cn U
N
~_U'~O'~.~'~'Qdjc~n~'~~U~~c~~b~'O~VO~.~y°UU~""d~ccS~~
~ 'i' O ,~ .O >, U O ran ~ y cd ~ ~ N .~ ~ ~ c~ ~ ~ ~ O ~ ,.C c~., ° c~
U 00 ~~ N .' .~ ~ ...~ y c~ ~ ~ CL cd W N ~ 0.i c~ . U E-~ an (1r U ~ c~ c~ a~
y p. O y
Q
~V ~vl
y ,y O
_ ~ ~au U y y
~ s.U, ~' .~. ~ty "' O
O G N A.
v ,~ v~ A, ~, W U ~
N N
O
U
x x
N M
M M
226
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
a~
U ~ ~ ~ O 4j V ~ ~ ~..~ U U >> ~ bU pA bD 'b O
'"" O O ~-' by O w O ~ Vj A. N ~ O ~
C: ~, ~ ~ ~ ~ ~ U ,~ ~U., y O ~n U O U p ~ ~ ~ ~ ~ y
NO~OCO~~OVJr~Uaty "-d 'f ~~'s"""UO4.~.~'~~> c~~~. Oy._C_
w ~ C~ r-1 (~ U C~ ~' p O b0 > .O~ O~ ~ j U ~ .~C O~ O~ ~ _C~ V1 I
~_, ~ .Tr' ~, c~ ~ 'i~ O (~ >, c~ 'i' > f~,r' ~~.' t3. O ~ ,,~,
C>~~UUO~~U'''y-'~''b ~U>,C ~N ~>>~'i:.N>'~~,'Cc~
~ " ~ > wo ~ ~ , ay, ..U. ,~ ~ ~s o. > ~ x ,n ~ a~ o a~ O
v» ~~'~NN_~U' U..'''~~O'N ~JO.v~W~~~00ø,~ .p~Op~~U
U O ~~ "O ~ r.: ~ ~ ~ ~ ~ c~ ~..~ O ~ ' ;' O t=.~ U ~'.1' N 'b U s~- ~
y cd~ T c~Arx~Nfn O~ON~n>'.d0c~
U ~~'. 'O j ~ .b t-, >, ~ , ~O c~ .~ ~ ~ x ~ ...~.~ 'n U O U ~ N N N ?t N
'Ty GU .~ ~ b4 N O ~ c~ pp Ov yn '
a)cttc~'''. ~' ~UU''~ a.,Uv~~.U, c~~O~,af~~.~~~Oa)
.b . p ~ ...~ .~ U N 01 ~ cn O ~ W ~ a) N "~ ~ .-~ O U y~ ~ ~ s.. U _ "~ r.
U .T, U ~b c~ '~ N ~~-' W O ~ ~ U F, >' ,~"~4--'~., c~ ~ x ~ U ~~ ~ U ~ 4-n
o ~'G o ~-c ~~,.~~~.~ ~ ~ ~v° ~,.~°o~oW o°O ~ y~.b ~'
° U~:. °
'f~' O ~~~~ >~ O ~ ~ ~ O x ~ S; G~II ~ U C~ ~ Tr' .t".' '~ ''' "; ~ U ~ '~ O
c~i ~ b 0 ~
O . cn a3 ~ O .'" ,~ M -~ ~ U ~ ~ U ~ .~ .b
U U ~ > w .b ~ ,~ U U iG v~ '.' ~ O ~ "~ ~ ~ ~~'"i ~ c~ O U N
c~ 00~~O"UN ~ ~'.dUOc~j~..o0.y~"'b0~..i~3 OGO>
OU ~O~OA'UbOV~ V~~~~Ub~4~,c~;~o0p~_v~0 U~~bO
~ U C: ,~., V , > "Cy '~ 0~ ~ ~." U N ,~ ~ b ~ ~a~.' c~ U C'r
..'~"> NOc~NC/~p,,~~~D3'GN~'~~~UO~OvOO~aSU ~wpQ~~~O
'O ~ ~ v~ ~ 4. N p y ~' '-' cd ~ 'n Ov ~ N ~d c~ O s.~, A'' ~d 'i' N
O O >, ~ ._~G ~ G ~ >' ~ M U w ~ ~ Y (~ ~ ~ O 'n
O O ~ N ~ b ~ 'C3 U ~ ~ ~ W O '~ ~~ ~ O ~ O O ~ G ~.: ~ '~ b .~ 0
'b ~ O U ~ ~ ~ ' ,~ M O c~ .O ~ U ~ ~ ~ ': ~ ~ ~ ~ ~ a O O ~ ~ ~ ~ ,,U,
O N ~ Y y ~'~ > U ~p ~ U ,~ '_' ~d c~ U i..n O i, ,~"" N ~ 'O
O ~ b0 ,~ ~' ,~ w ~ ~~ > N O ~ ~-~ .r ~, yn f3. t~. ~ cC ~, O
~ c~ U bD ~ .~ N C4 O ~. 'y ~; ,~ N .~ :*.;' w. cd V ~ O c~ y,~ H v N U .O b O
N
N O ' .i"~. O s..~ . c~
.~ '~;b ~~N4~aS~~~~~Nypw.b~~~N~~~~.~,,_,.~c~~,
O ~', ~. t~ U U c~ ~ ~ w ~' O c~; ~ O
,s..~'" CJ ~ i:, ~ N ~ .y ~' GL U ~ ~Y' .~.~ >, C ~ G .-r ~ a i~- ~ ~ O cd c~
'n a'~O'",-,O'~v~ONON~'a. O,OUOON'~
' .~,. O ~ v~ N i., .r O ,., U a' it
0.~'r~~r ~' V7 O U~~ ~W ~U ~b C~.~~ ~'~~0~ ~ W 3 ~~ 0.'~~"~ ~ f~.
N O~'~~C~o~OI~ ~'~ v, ~ ~,V., O ~~U'C~~..O~,~
~,~~.''~ ~,'U' ObJ~~",~"Ov~,~U ~~ O O ~~'~> y ~v~NU ~ ~.'~ O~N ~O
O.' ~ ~ '~ ~ v ~' ~, H c~ O .~'. 0 ~v 4w' ~ 00 ~ ._~ ~ U U N ,~ .f''n
N~.C3v~~Uc~~'~ ~NN~'.~>,~~~O~O~~~~~~(-1U~"~~~~O
U m ~O X ~ s.. a.~ N N b ~ '-' ~ ~" ~ N G O b
'~..~ -d a., U ,'C O >, ~ ~' ~b M tn W U .W n N ~ ~ ~ ~~ N l~ ~., U ~ ~ O t, U
O
U'~~~Ar~~~~O~N~~~~,,~~p,'~~,.~ ~C"'~cd ~T,s'~ ~~G)f.~.'00
O U Aa .m ~ ~ O ~ by 3 U ~. N y .~ Wn ~' tip b ,~ y >, y O
i~ 0 r, O H YG pp y v~ G ,~ .~ N w ~ O ~ ~ ~ ,~ ~ ~ 'n N w U
N C." ~ 47 On V] W '~.," C~ U 00 '-1 N au ~ ~ U c~ . W C3~ au CI~ N ~ ... U N
~ U O f~ ...
G 'b 4--n
O p d ~ ~ O N _O G O
p .~ 'V ~ U H p >, b0 ~ ~ G
> O ~ ~.' ~ > c~
~ o a~ ~ U ~ .~ s~. ~ ~ .~
N N ~ U U N ~., ~ c~ A" 4.» U N
t.U., N . ~ U Q x W ~1 ~ ~ O cd U
N N N
d'
pp OO o0
M M M
U U
x x x
M M M
M M M
227
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
G ~, a~ 'b ~ G G o
d' ~" . ~., _N ~. N 'b CO ~ p ~ ~ N ,.~ 00 N ., G by ~ ~ O 'b ~ G
G ,L' NO '-' w ~.' U ~ b ~ c~ p, '-' y ~ >, G N ~ ~ ~'' '~ ~ ~ O ~".r", ~ n
b ~ G ~ U ~ ~',, ~ N ~ s.. ~ G ~ ~ ~ N w O N M U ~ p ~ ~ N
b N . c~ G ~,' ~ ,.., .!". O ,~-~ iG H > ~ wr
y N ~ ~ ~ c~ N O N CGU U ~ a ~d N w ~ ~ Q ,~ b.0 W M b CL .fl ~ ~ xo v M
.rt~'N~ a~ .C .~.... ~ O ~_]~Uf.~.' ~Q 'Gtn u~0
'-U'a".'V~O~.~GWn .~~'D'~tGn~r .lQ.'N'cyn~~~'Ub~._~~G. ~.fl~..G,t~
U G~~~G>WW~O,~N jo~i~.~~O~ 'bai~N
c~ o a~ ,~ ~ ~ .~ ~ G ,~ .o ~'n ° ~ .~ ~ ~ ~ ~o °r ~ ao a w ~ ~
b a. ~ ~ 1
N s?. o °c. ~ ~ ~ ~ ~ o ~ ~ ~ U ~ o ~ >, r,;~ ~'~ G ~ a ~ :b ,-,
'~ ~, a~ ~t ~ a~ a~ W o c~ ~ w o .. pa U ~ a~ E'' o ,~ U a>
O cd ~ U > U ~ .b w O ~ ~ U ~ .G ~ M ~cn ''' ~ iG ~
>, ~ pa ~ ~ ~ ~ A ° ~ , ~r,~~ ~ y a~ G G ~ .~ ~ ~, >, M o W '~' t~
~ N N ~ 'i
~., c~ ~ U 4; O_ O_ ~ ~ ,~ ~ c~ v> > G v~ N
G U ~' :~ ~"" Q N M G ~ ~ ~ .~ ~' .r ay"., ~ " p~ ,--~ ~ ~ G .~ G G O C cC
~y, ,b ." p., 3 ~ U ~ ~ U a~ w G C~. CL O ~ _~-~ N ~ N O '~ O 3 ~~ O N y O
,:, a~ U ,~ o G 'b N N ~ G -~s a .~ v .., >, a~ ~ ~ ~ >
~"Gc~_ U'-'c~GYO GN,Orn'd~ Gy-' ~,wn~.~G. Gs..U
bD .~. '~ .b W b ~, ~.U. ~ ~ b ~ 0 r-i
p O 'd x ~ ~ '~ U ~ N ~ ~ ~ ;.d W O ~ (V O ~ ~~J ~ f1 U w ~ 'fn
0 U.> ~~'G~~000 .~"'.~~Oc~C.'UL~~~:b c~0'~'v~'Y,,--.
>, ~_~ ~ ~ ~ . ~ a~ o ~ a~ G ~ G G ~ . _ .~. ,~ x U ~ o ° ~ :b U_ ~
V O b ,~ ~ ~. G w .~ c~ _'~ G ~ ~~ ~ M N U ~ c~ .J ~ N
1p ~ U ~ .~-~. U ~ .~ T ~ ~ N ~ ~ ~ ~ O ~ ~ ~ ~ '71 ~ U au '..~ i1 G
,~ ~~ U cCf y N .S-'.~ H !~' :~ N .~. G ~ b N ~ ~ .,~ ~ ~ ~a., O w ~
'~ynC. ~p~~~ ~U~s..NUOw,~ ~vN~,.-'~~i''..'Q, OObDQ'
c~.~bcV~c~ONWnNOG,NbN~~~~W n~'~~~~ GGLy,U~yN.r.7,
~n >, v~ ~ ~,~ s., 'C ~ ,~ G ~,~ N G ...~ ~ ~ ~p U W _~ ~b0 '~ G ~ ~~ O
c~ ,Sr" ~ y ~~ ,.. N A. G ~ ~' O N O O ~.' ~..; M 'L'' G .w G y0 ~.U., s.. tn
>, ~ t. ,-y"
UOUO~O~t-nb~ f..'NN~ i y,U,,N .C',NO~"CyVar 'O p",D'a~N
N a, '-' 0 'G .y-~~, ~ U O
.bN~I/~UOv'~ ,~,",ON>~-'c~0' ~ "_"UU~U.'r'.:''C t""'.',.t"";'y'Ov
NN~_r~~~O~. GO~~v~''~,~~'~~~C~ ~N~~~~~V~7G)~
UP,~-"~DG~~"~-d tU-.4:~0~~c~~,>'w'd~s:,~~~p~N Gp~ t~, U
''~' iC . N ~, ~ N ''' y U :b W N Q" i.. ~ o ~ Q ~ ~~,, ~ . ~ rn U ~y N ~ w %b
~ tn , .~._,
O C.n a., au ~ :3 N ,~ c~ ~ O ~ ~ ~~ ~ O 'C Q,', U ~ y ~ ,~U, U :b ~', O O O O
0 0 '° ,b A x b ~ ~ o ~ o ~ ~ ~ o 'b ~ w °,n ~ ~ ~ >, ~ d ~
° b
~':.'b~~~'~.r.Ur~~ >>C~U~OOU~o~GOV~~'~~>,~-'OG~m
'V'V~O"Gpncd~yn~~"i'~3 ~O~ ~~G~G~~.U.,~pnO
rx c~ a~ b ~ o w ~ ~ o ~ .~ ~ ° c.. ~ ~s ;~ U . o. ., r~.. U ~ ~ ~ ~. ~
C7
w w
o G ~ o
o '~ ~~ °~' o
a, ~ >,
~ ~ ~ -~. ~_ LQ., V
o
G~~G~" G
b-0 C ~ N p"
rx ~ O W .~ w
N N
et' d.
O O
N N
W W
U U
x x
M M
228
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
b Y ~ ~ ~ ~ .
.yc~, ~ -d ~, -d ~ °' _~ ~ ~ '' ~ as. a4 ;b o -°
_o U .~ . ~a ~ ~, ~ 3 a_~ ° -o ,~ a..~, ..., .~, a. ~ .c a~ o_~ ~
GU P.~ ~ ~ O ~ ° !3. ° ~ ~., N U w ~ U ~ ~ i,.~.~ i-~r C~, U
..U.. 'C O ~ '-'
b0 C . ~ U ~ .
~b N N ~ N U ,'~ fir' .r . ,-,
'~ ?C U v~ '~ ~,' " ~ ~ ~O ~~ ° O O~ ~ ~ ~ ~ "3 p U y.. O O p., ~'' y
".~ ~ y
W ~ ~ o.~ ~ ~.~ Y,,_..a~W ~o~''o ~C °U~ ~' p.o.'*.=~ ~~ owM
U ~ UNC~~,'~ ~U.>~u._~ V~~ >> ~~'-'°'Ccdq
~' '° U E-~ ~ ~ 3 :,. ~ 'b ~ '=. > ~s . .~ a~ ~ ~ ~~' '~ ~ o N U o N ~
w
b ~?d .n-o o ~ ° ~ ~.~oU~~n ~ ~ ~ ~ o > °'
O H .~.' y N : '~ ~ .'~.~ ~ 'b Q.'~'"-~ ~' '" c~ ~ T..J bIO
~ G 0 ''' ~ ...~ .~ N ~.~ c~ Gp ~ ° ,~ b0
U aio ~ a~ ~ o ~ ~ o ,-a a~ ~ ,~ ~ ~ X'' ~ ~ ~? ~ ~ o a, ~ .
.~ c~ ° W ~ ~ ,.~ ° O U a ~ ~ 'N ~' ~ O ~~., CO ~ ~ ~ -d v~
U~UN~~~~.U.i~Nt'.'~N .~.'b ~N~~Ny~U~ UFO
N O '~'~ b >, ~ y a' ~, ~ U O N p x '~ >' N ~'O U .b ~ ~ N "'.' °
_N .~
N ~ O ° N cd ~'O y c~ C/~ O ~ ,~ "C .~ ~ ~.~ ~ U N 4., ~ U 'd ~
° 00
T~'Ci~'.'l~.y'~y~~, ~i., O,~>~~~~' ~°U4:.o ~O ~-~'M
OO ~~cnC.°Wn'n~~O°~'ONUv~~NN ~O>>>ppF'U~G~ ~
~. b ~.~ U ..a,0 ~-~ ~ ~ ~~ .~ ,d~ c~ O 0 W .b ~ ~ c~ U ~' : N U
yn.'.~.,~Op,'nTJ~~~"~xU .f"~~~",V T.'i.U.WOQs..~°°~.c~__
~ y rn ° ~ ~ N ° ~ G U ~ OC W ~.~., ~ ~" ° .~ au .b
°~~~~~N~U 4:~cC~~~LU.~~~~ E-~~~~p~U~~ .S-'~,~cUC
U cCt O ~ ~ ~ y - W O U .a U U ~ U ~ .s.~'» ~ 1: ~ O~.r N t-U. U O °
U y ~ O
y..',~'cd ~~'L~Ur~n,L'~G~y~~ °>,~U~~ L.1~C4~"~c~~.~.,~~~,US~,.~c~
_ ~ O b N Pt C _
~.UrO~D ~Gcdc~~~'~-~.~~~b-0.~~°'bbUO.U° Uyn~~"..~,~~ .S-',~~U
N'in~OO~ V~b~p,~~i.~r0~~~'~~~;~'~p~'.~~°U.Ud
" ° ~ ~ ~ ~ .b ~ y '~ .~ c~ ,b o~o ° ~' ~ j ~ N ~ ~ ~O b ~ ~ a'
N
c~ pp ~ ~ ~ N G7 O ~ U m U .b ~ 00 ~ ~N c~ U ~ '+~ ~ ~, O 'n > b
o a~ ~ Gf ~~ ~ o. ~ ~ ~ x ~ v ~ ~ ~a o~ ~ ~
tn ~ c~ N 7, O U U ~ C ~.'. Y ~., ~ ayn
U~~ mw~~~, °c~~,_,~~~M.~~~?E'~m N'a~,~Nb00~ S".,W.dU
U .~ .~ ~ ~ ,~ ~~ ~ ~ 01 ~ t.U. ~ ~~ ~U .> .-r .~ ~ G U
W~ U U O by ~ ~ >, y c~ >' ~ ,-- ~ N y,~ ° C ~ Q.' ~ O Wr N O N N
~ ra
O ~ ~ ~ ~ N _ ~ ~ ~ N ~ ~, (~ >' DG
° p c~ O ~ p, N O "~ ~ U E..i U ~ '-' .~ w ~ 4, ° N c~
~ :~ °' >' ~ ° o ~ E-~ c..i ~ '~"' °'" w° 3 ~ o ~
o '*"p '~ -d
~' U b y ~ C~ ~ ~ '-_'~ N ~ ~..' .S'J ~ c~ w ~ v~ ~ v 'y, ,~'°., ',r
_>, U .f .'
a. .j ~ ~s " a~ ° ~ .r .
N O U ~'..~ ?G C U > N O p ~,, O~ U w U ~ C ° ~ ~ 'n U '+-i U
N c~ U ~ ~ ~ c~ N ~ cd ~ N U !3r W N 00 U O c~ x cd ,~ U N ~ U O c~ . cd cc~
~, .O ~ .b ~+-.
° y . ° ~ O
W ~ cC '. r c~
i > .~ ~ ,.., p
U ~ ~y U N ~ > ~n
it c~ [~ it
CL b Q"i y ,=-n
O ~ O i~ O ~ U
N N
0
w w
U U
x x
M M
229
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
w ~ . " y~ o
y ;~ ~ ~ ° o p ~ a~ .~ ~ ~, v ~ ,~ o
~ yes., V 'C ~ ~ ~y ,~~, N O~ ~ .~ c~ ~ 3 U ~ U ~ '+.' O ;b O
~tS'~C'~O r~'~j,0> ~~.~ ~-'~'C~~OE''~ ~U>,~"'O'~~-'OQ
U N ~''' ~ _c~ N O ~ ~ ~ ~ ~ N ..>-~ ~ c~ ..err fn CO
x .b cUd ~ p '.~C N ~ x ~ y O ~ ~b ' yc~, ~' ~ >' O
ryawOpwM j.~'J'-' ~c~ ~n~~v Gc~
>, o N ~, ,~ o ~ ~ o o~ 3 0 ~, ~ 3 a, >, r., ' ~ a~ .y a,
~,' ~~~d ~~"N4."U O y~~V,L""~ U N '~G~~~'~ ~ ~ U Gr~ ~:b c3~',.C~~"n
a'~~on~~,~~ ~b ~ U ~'o ~ ~ o
v a.3 ~ o ~ ~ . ~n ~ o ~ a~ ~ v~ .,
o o ~ ~ ~ _~ ~~ w o ~ ~ o ~ ~ ~ ~ ~ -d . ~ o ~~ ~ o
c0 c~ N O -.r ~p V >, ~ y ~ a, G"., ~ n ~ ~ :3 p, O ~ V ~ ~""O ..N. N f..' ~
~O N
~ o o .
U N o U ~, O .' ?G cn >, c~ ~q ~ ~n ~ y ~ c~ w p ~ . ~, ~ -. ~ c~
,~. ~ U "O ,~ N " w W ~' N ~ ~, N ~ ~, U O ~ ~ U O ~,.., U c~ N O U >
N N M ~ U t~ 'O O N ~ y a" ~ ~ ~ U
w ,~ E.., ~ ~ ~ U ~ w ~_ ~ ,,,_, p O ~ ~ d~ ~ y y ~ .~ i v ~ ,~ ~d p , 'C ca
O y y :~y . '~,' p ~ ~ ..~ N ., w U m ,s,~ p ,.. N .r.' ~ . ,." G ~,'
.S", 'C A" ~" D a..~ U U V'1 N N y 'y., as ~ ~ O cd
iG~v~00 ~e..~~_ Us..~,.,UO.~Q.>'.~.3U~'w
,"~ b ..gin, O ~~ >, ~ ~ 'p by ~ ~ ~ y ~ ~ O ~ O O ~ ~ ~ '-' ~ N ~ p
Oa..'U.> i'N~a...~~'UNp~G.y~' ftS'b Q'~~i N',=,,~~U
U c~ ~ ~ ~ V ~ ~ ~ b p" ~ U .t",., ~ ~ ~ O ~ ,~ .-~'. P~.~ A A O 3 ~ ~ ~ ~ O
a, cC U _ N x W ~ ~ ~ N ~ >> ~ ~ ccf ~ N U U '_' ~.Q., > U >
O~b.~~~, ~N_c~~,~~Ocd~~ ~' O~c~V~~~0.~~.'"H'n
U~ p'' pOQ~,~~~~, _~~~ p ~ V ~ ~ O~p
~U _
C. U O N c~ U ~ ~ '~ ~ U U ~ ' ~ .C .C U ~ b .~ ~ N ''~'..' ~' >~ uj au
'~ ~ ~ ~ >, O ~ ~ .b V c~ x~J" ~ ~ ~.~. N .~ .~ >, H ~ r~ O ~n ~ U w O t-. w
~ ~GD ~ O ~ O O '~' 7 b a'' .~ ~ ~ ~ ~ H R~ N O E"i ~ ~~ ~ aG
° >~~~N ~~.~~,~. Na~~ oov,U a,~+a~>A''c'~o
av~ ~~ ~~~~bo~~,~~°,.3°or'a~~c~.Uo,~e'~~~~1"
c~ ~ ~ ~b 'N '~ ~ ~ ~ V7 ~ ~ Q., ~ ~ ,~ rOn ~ ~ U ~ 0 O ~ ~ O ~
<n ~ ~ >, t'., . cd G. 'b Gj ~ M N 3 O ~ ~ ~ "'~ ~.-W C. + ø, ~ ~
'n yo ~, ~ c~ ~ ,~ '=' >, ~ ~ w ~ U U '~ ~ p" ~ ~ w ~ ~ >,
'~~. ~-' o ~ ... ~l ~ N a~ ~ ~ o a~ ~ ~ a ,~ N O O H ri ~ U
~ .~ ,~ 'b U t~. Q ~ ~ ~ ~ v c~. ~ .J .~ ~ ~1 °~ U ~ ~ U ~ o w .~
N c~ a~ ~ °~.' ~ ~ U ~ ~ E. >' ~ ~ ~ o U~ ~ ~ U o E-H ;b ~ ~ ,~ ~
;b o ~
E~ ~ ' ~ O .n ~, o a~ ~ ~ ° ~ b ~ ~' ~ .b o ~ 0 0
wx,~y'b ~O~O~"':... OO~'~ra~Cpw'b~~N w~O>,c~'-'yOs~
.O O w b p ~ ~ x ~"' > o p 0 >_ ~'.
~' 4.U. ~ I-Nr ~ O~ ~ ~-~ ~ C~ b ~ C
~,O~pvOcd~Na) ,»~3~Ot-~ .,.,~b Ncd~'pO~,~NN~
~m ~U~~~+~~U>U V~VUOp~~~NU~A~O i~~>Nfl~N
c~.' a~ ~d ~ o w U U .~ 3 .~ H . ~ ~ .~ c~ ~ W U ~ ~ ~ U ~ ~ . e~ c~ .~ U
E~ b E
o c o o ~ o
.~ ~ .o .~ ~ .o
y
A >
~.U.>.~ ~U.
o ~ v ~ o ~ v
a\
N N
00 00
M M
230
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
b y b >, ~ ~-~ ~ w
~, w ~ ° ~ ~ ~ on U ~ .~ o ;d >, ~ .~
M_ ~~ ~ ° :b o .~ ~ ., b .-1 ~
>>~M_~0~~, ON~TJ,~ ~' ~ cC. ~~y~~N b U'~pn
'nOQ\O_~.'G~,w~"'~E"~" ~ ~U Nv~Na'cynU ~~N~>NO
>-, O~ ... w>>..r~ V,~'YN~NOa-' c~~~V'"w..bD
~ '~..Zi ~ ~ ~ N
~.' .r' c~Y _~ ~' '~-' V tn ~. 0 ~ n ~ y d4 _O c~ tW c~ .D ~"' C
U ~ ~ ~ ~ 'b p ~ D >, ~ '~ U ~ ~ ~ ~ N ° ~ C O ~ ,-i ~ ~ i.U, ~~ ~
.b 1.r
O~~_c~.U>U~_N~.~~c~U~V'7 bU>
~ ~ v y .b ~. ~ ~ ~ _~ ~ w ._ cW n
U c~ ,~ ~ U ~ ~ O ~ U ~ CZ. ~ '~ O ~ ~ i"' >' O I~ U Or O O _>> ~
~~'' .. b w.. ~ ~ O cd ~ ~ U ~ d d' U c0 ,r", N ~ b0
G", w ~ CA C. ~ ° ,~ ~ a\ ~ ~ c~ c~
W C. ° ~~ ,n w t~.. ~ ~ '~~' d0 C. "'' ~ '~ ~~ ~ w -> b
ow ~ v,~ o ~ ~.~.~ ~... ~ ~vyo~ ~s >,~ ~ ~ ~ ~ ~ o ~ ~.ob
U Ov ~ ~ ~' ~ .~ ~ ~ ~ O ~ --~ ~ .~ ~ ~ c~ ~~ ~ U ~ ~ ~~ O O ° w b
~ O~ ~ ~ ~ . i3r b ~b y ..O ~ , U ~ O U ~ ~ ;~ .~ N O b-0 '~ O C. U A'' d0 ~''
'O.bDTG70c~.GC~ytiU°Qd~;O
~-' N 'G ~.' E~.'~ N '~ '-' U N cn N ~ N ~~ ~' ; : .~~, ,~ ,.; '~.." ~b y ,'>,
" ~ d0
O '"' ~ ~ y f..' ~ O s'.. b-0 ~ ~ C cyn ~'' O U ,~ ,~ O by '~"' ~~ y ;~ ect ~'
N .y".:'
~_ai~~~on.D~.-~'~~,V"°~~ UQ."~
.G r' ~ Ov O . ,~ ~ ~ v a~ OV .~ ~ N ~ cd.~ c~ ': .~ GQD ~ 'n w _>, > ~ 'in
w .~ U O ~G'~ ~ -~ H ° ~ G' iC ~ x Q ~ ~ y ~~ N U ~ ~ ~ C ., w ;3 ~ ..~
b O
OU ~i'~~ oON~"~y,a'~.~a~~N~b...~'rN~~~bOb~..~i-~r>,N~
y N . ~ O~ V tn ø' ~ V ~ O ~" ..~, _~ b ~' ~ ~~". '~ ~' '.' v> >> ~--~ y ~ u.~
~' .~"., _>> U
o _~ °~ a.
M N ~ L.mn i.Ur f.~,' ~, .O .~, : O F"» ~D '~ U iC b ~ c~ .-. ''' U f"-~. '
~A ~ ~ ~ ~ c~ ,-~'-. Q ~ ~ -y O .~ ~ '~' ~ ~.t". ~ ~ ~ ~ Q' .C N ~ cn ~1. N p
N O. ~ S'.,
~~-''~U~Vei'~~~~~ ~t,bUW~G.~°'b~'~~'~~,M~~~~'NA"'~cH"
_N ~O O ~'." ~ E~ ~ s.U, cn w U U N '+.' ~ ~ ~_' N U O X ~ U ~ ~ ~ ~ N ~ ~ 1.,
O
O O ~i ~ 3 " ~ U Q .~ ~ ~ ~ ~ ~ b ~"~, w ~ y U W U N '~ t~ M ~ tUn ~ N b U
can O~ O ° M ~ O.'O~~r~...b y ~~~ ~b ~ ~,~-.-'n.~~~ ~ N,~ .~..n
,~ .S". ~' ~ ~ .t", ~ sr ~r ~ ~O tn ~ ~ ~ E-' ~ ' ~ O ,~
b0 ~ .~ ~ w. ~ ~ '.-. pr ,G ,~ ~; ~ p ~ ~ ~ ~ N G O .C w N Q ~ ~ >,
a.~w°~ ~o~:.~a~ a~~:~yN~oo~'~~~~3Udo4_:~~.°~o
'baiA''OO V~~."UO.~vi~Ly ~'~,~N_~ bD~,~ ~Cn~b.'n~c~ f~.
a! O ~ O ~ O. Q U ~ '~ °U c~ >, ~ ~ U ,'~ -O O ~ E-' ~~ ~ ,'~,
vc ,° ~ >,',=,. ~>,U ,~ y~yN'3p~'cn~>'~ ~y
~ O ~ >'U'' U '~'.S ' ~ N yrl ~ V .~ ~~ ~ ~' ~ ,~ ~ U d N .i'~, c~ N ~ >> U
Ot~-~UaSUU~ cd Vi'~Oc~~~Fi'''.b0~ON01'''O 'bN .b
~~ c.°,~'~ ~~°rU ~ a~ o~~ ~o ~ o'~~..: ~~E-~ ~ ~~Od,~ °
~_aib
~p~c~bp00~U~.UDy'a~~~t..~'b~O~~..U~~NV'...U.i",~"'Qi"'.'~'-'A''~ V
p ~G U Q\ ~' fn ~ w m Q . o ~ ~ f~ O ~ G ,~ ~., c~ '+. ° ~ ~ p
b~U~°,'.c'3~~~~~~~~~~~~~N~~a~y~~Z~'~on~~
.~~:'y.~tns"'i,U..~cC~.'~.," i"Nv~pr,'~,O .~MUQb~UOV ~mCC
,~ G. TJ ~ U ~.u U ~ >' N 'd cd ~ ~ ~ U ~ U ~ O ~ ~ "C1 ~ .-y~ U .t'.
t-n N N a, iC G O ,~ ~ >, N O w ~ y ~ G ~ N ~O s~ N p O ~ ~ cd
~ b f3~ 0 M U O N cti d y y c~ ~ ~ C'3. of L~ G7 ~ A.r c~ ~ U H b-0 ~ d ~ cei
far U
w
Q ~O G ..V.
~ O
.O c~ :~ N U G>
_ w ~ U
. D U dp ~ '~ Gy, ;,
V
,~'~' VJ ~ ~> f3. O .~
O
M M
A
M M
231 .
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
,~ ,~ ° o ~ .~ ~ ~ °" . U c%> >, . ~ w o cc i
o ~ ~ ~ ooioow4°. ~W .~°~' HM ~ ~ °-d c<
y
J ~ " U U ~ ~' ~ ~ ?~ ~ ryn "~ ~ ,~, ~ U U U 4. ''~' O O O ,~N, N O .C
U U y 'd p c~ i' ~ a ~ ~y.' U y ~ O ...N, P-n ~ .~,' ...N. ..N~ ...'~'~
M ~ U a 'b O ~N ~~ 0 0~', ~ ~ .y '~ (~ ~' I~ ~"~ a c~ ~ ~ O w ~ '~' Q . . ~ N
O
a) ~ w ',=, .~ _~ U ~ ~ ' N O ~ W n aID O b N 0.0 ~ a~
b .~ Q~ ~ ~' ~ t3~ ~ 7 ~ N O .~',a' s,~~" M O .~ O ~ G ~ ~ cC r' U Q
N ~ ~ N 1.~" tin ~ y,~~, O U U ~N U ~ ~ U ,.yes y r+: N 'O ~ ~~ ~O ~Q ~ V.7 0~
~ b-0
_ ~ .. E.., o ~ ~'o Q a~ y
' c~ ~ ~ aW1 a~ ~, ~ ~l ~ a~
U U .O ~ ~ U N x " ~ U O i.U.~ 7, ~ ~ CL y ~ ø,, ',~' cd G'.' ~ x '~ ..U,
N N U W ~ O 'O W ~-' ~_ ~ ~a ,~ Vn ~ ~ ~ b b ~ ~' ~ b a
a~bUUCd~'~~~ c~~~~ O~~x~A''~~~ ~3'~~~ ~O~s.~,N
N~~~~~ ~ Nc~~~O.~~ o.~,~b4~~ °~~U.~~ ~O
~ond.bo°'~~o~s~'yo ~.o~°oo
,~~, '~ a~~~.oa~o~o,~~'o~'~~ooa. ~~ ~ ~a,~".
~~ 3 one ~ ~:~ ~ ~.~~~ ° ~°..°.~'~~~ ~ ~.~ ,~ ~ ~;~~ o
-c ~J ,~. ~ a~ c U ,~ ' ... ~s ~ ~ o, ~ . ~ .n .,., o. a~ ~ o ~. o ~ a~ N o ~.
°
~a,o:b~~'~~ . ° ~,a~~- ~:~°~~,~s ,~~~a.~~.~ oar
-~ ~ -~ o W ~ °' ~ x 3 0 o a~ b ''' o o ~ .~ ~ y o " .~ ~ ° y
a.~ ~, ~o o .~ y
UO~~U.dN~~ WO~~''a:~..~"O~,Q\O,s'a~ U~~T.~.'OO~,y..~~0'n'N-'y.U,O
'~~~ OUyU'-'N p .t".c~y~N~NNOUCr"t..Q p"~np,Q~vncd~~bD
G~' '_~ w ~ ~ .-. _~ o ~ ~ » o ~ ~ ~ '~ ~ on; ~ 'd 3 ° -o ~ a~ o -
o
'~ ~ V~ !3. U , 4: N C ..w.. ~~~~ cct V N O ,~ .~"~. cC ~ O c~" ',~, U ~ ~ ':,
c~ N U ~C7
.,~ ~ y ~ ~ ~ ~ p" 3 'U ~p ~ bQ ~O ~ ~
~ b~D ~ U ~ A'' ~ ~ C~) ~ M O ~ ~ ~ vn c~C t3. O ~ ~ p, ''' N w U
'~~,~''~~~ ~~0~~D ."N~wU'~cj~p~~ppcUn~~'-~%-sOai
V>'~>'N cab '~" V~VC~~NOc~~O~~ c~~t.,~>,G3~.~~,~'C
v' O U ~ ,..f,, U ~"' ~ O ~~ U ., Q ~ y N ~ .~ 'Ly f3n ~~ ~b yU., w t3' ~ ~ w
.p .~ fir' ~,' " ,~ ~ U l~ w c~ b ~ .L7 ~ U v ~ U ~ U 'b ~ ~ O O ~ ,~ O ~ M N
~
V o0 .-.' U 'C ,~ 0 cCf N U ~ ~~, '" ~' ~ O ~ .>, p, ~" '>' ~' O .S'. U 7 O ~
cC ~ ~ ~ ~ ~ ~ U .~ c~ ~ O O ~ j ~ ~ ~ ~ c~ A.. ~ p cy~d fn c~ N o W cUC
N a U ~ ~ cd y N ~ 'O Or y '.' ,f~, ' ..O cC ,,U, ~' b O 'ar ~ ,iU'n ' A.' tn
~'r ' f..' y
W Ov .U ~ U i" N p~ c~ s.. w O ~ ~U 'b ~ z C .~ c~ ~' U ~ v, ~' ~ ~ >, v, -~ ~
y s.. 'b '~ ~ Ov C O O ~ ~ .~ ~ A O ~ U .~ N . w ~ fn O
~ l~ ~ O ~ p ...U. ~ ',~ ~ ,.~', ~ ~,.~~, w ~ ~ U ~ ~ ~ bOD 4y p ~ .~ ~ P. p.,
.C ~
i-.i U ~ au O . U O ~ .~'-~ N ~ U ~-.' ~ ''.'' ,~ O y y
~ U I~ U C". .~ c~ ~y ~' A.' c~ O ~ L: c~ ,s' O ~"' O G.Wn '+, N cn w '-' _~ N
~ cd fn ~ ~.U. O ~ ~,~, -fl y0 p N b ~ .~'. r~.i ;J ~ ~ ~ ~ 'b ~ ~ O U .b c~ O
i..
.~ ~ ~ ~ ~ 7, O U ~ ~ U ~ ~ w ~b vn U0 b Ov U b 'b ~ Q,, ~ '-N' ~ O N ..'~~ O
G~ c~
~ ~ ~ ;, U ~ ~ gyp., ~~ ~ o ~ o ~ a. ~ ~ ~ ~ >, ~ ~ o. v ~ ~ v ~a~ .~ a, v Z ~
~a~
~.,~~c'~~.~W °~°~o~N~oø,~'"o°noo~°oooo
y . a W ~ U ~ . W r3. y U U v~ ~ W ,.a -d ~ U ~ ~ a~ y .~ ~ .. ~ W
w
0
.N
o y on '
y ~,
v ~ c~ U O
O
Q' x ~ .C O G~.
dd WCi~p~ WUd
N N
M M
<t
~O
z z
U U
x x
M M
232
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
_ ~ . .b
'b y y, U ~ 'b
cUn 'b '~ ~ N _~ O ~ c~ ~.-i ~ :'C ~ 'b ~ N _~
NN ~.'~.:'~ ~U.'~ 030yC'"~~..,.U.,~> ~O,~c~C ~a.U.~~ 03
~o~'~d' oo.o c~~N~~~°U'~~ ~o~ owo c~
~ ~ b ~ o ~~ o 0 ov °~ ~ ~ 3 ,..~ u. ~ ~ ~, ~ ~ ~ o ~ o av
W y pMp ''~ O U ~ U vi ~O , '~'-'' V _uj , ~ > ~ 'a:.. O~
~~ N U ~ ~ ~ C ~ ~ ~V ~> y 'r ._~ V ~ ~ ~ (~ >' U y ~ G ~ ~ O ~U ~> ~ a
GL (~ ~ b C~ y > C~ n a~ N ~ E'r U ~~,~' a 'b C~ ~ >
~a b a>
w o ~' ~, a~ . ,~ W _0 3 ,~'~' .y w o '-' a~
o°p~°~~~~ cetow~~C7,-,~,~a.'~s ~Uai~~a~~o~
o ~ o _,~ v ~' x.~ o o > o ~ '~ o
Nv~ U~.,y~'y,NbO~_bD0000 O~p ~fn U~,~Nj.'"yO~b-0
U . cC .~ ~> ~ .~, ~ ~ c~ U . cC ~"., . ~,
'dy~N bUv~i..~..rUOy~~G~~ ~N .~~~.~"V+Or
NO wc~.~pOOO~DpaN~~.~~. ~a~O_~+,ca~,~OGON
U s". ap c~ ~ w U O ~ c~ ~ c~ U ~ .~ ~ N c~ ~ w U O U ~ c~ ~ c~ U
O.~ ~b j,~N~~ ~~", ~ ~~QN ~"~i~~ ~,~ 0'b
N c~ O ~ N ~:' ~ ~ ,~ ~ ~ O _~ ON ~' >' " p b p ~C ~ ~~ O. _~ ~ ~ ~ O _c~
O _O ~ CO _~ U ~L ~ VJ ~ ~~Vl ~ '~ ~ i; ~ . y p ~yLy U
.O _U .b ~ . ,v~ y,U, .~ O ~ ,4; ~ ~ N ~ ~ .'f~'. ~ ~ .,.. ~ U >' O ~
>,C~.~y, ~Ov~p.,0 .iO,cnv~~.~0 i~V~b~N N~~ø,~~, ~~~~p0
.~,~~~ ~~NNp~~?~~c~O~~O ~~~.~ ~c~NNp~ .~~c~0
c~U~GWU~~~.'U D~~~Uv--~"C:.."~>>~~V~U~~'''U
~ G.~ ~..~J p app - c~ .r0 p ~ Up C~ 'C .c~ ~ b v ~ ,,r_-', '~~'' ~" ~ G
.~ 3 ~ ~ w c~ ~ ~ w ~ 'r'' o '~ ~ v '-' ~d .~ b o : ~
,~ -o ~ o Ei ~ o ~ ~ w no .~ ~ ° b ~ ~ a. ~ a ~-' o
o ~ ~ b a, ~ o ,~ ~ c ~ a~ ~ ~ o ~ ~ b
~ N .~ _O ' cn ~ U b ~ ~" !3r ~ i-v O ~ ~ 3 U .L) _O ~ ~ ..~ . U 'C1 ~ . ~.~'.
y ~ ~ N U
P.~,-'~.wUp~.~~b~~~~~O...U.N~T.V.I~~~' ~r-wU~';.d~~ Nwn
'~". N ~ V ~ v, ~~', N OC ~ ~ w ~ p U U ~, ,d, ~., cC~ .C ~"~ O ~ ~ ~~, N O ~
''b ~ .fl O O
NUON m~~~y, Oc~'y~~ M.~"~>yvW~~~i~y.,., OcC'f,m
W .~ ~U ~ U U ~ ~ ~ O ~ O ~ U ~ ~ x N N ~' ~ 00 U U U v~ ~ >' ~ ~ O ~ N '~
~ c~ N a..~ ~ ',.:., ~ > ~ ~ ~ N S".r N ~ ~ c~ N ~ y; ~ >
o .W x '~ U .a o o ~ ~ ~ ~ °~' ~ i ~ ~ ~ ~ w x '~ U ~ o 0
U '~ ~, U p by ,~ >y, '~ ~ .--~ V) O 't"" ,~, U ~ b0 ~r U >> y c~
W ' ~ ~" cCf cC iUr c~S w N U ~ ".~ .~ N ~ O H w ' ~, x c~ c~ it C~ 4"~ N
O U > Q'' O cU ~ O 'b p ~ N O '~ .~ N ..-. ~ 'Y .~ Wn ~ O U ~ p 'd ~p ~ c'~,~
O ,'~.,
'n U ~. 4j ~ ,..~ p ~ c~ fn Ga N O ~ V ~ " G cCd ~ N ~ N
.o c o ~ .~ N ~ ~ ~ ~ ,~ ~ .n a ~ ~ ~ ,3 ~ U U U ~ .~ ~ o ~ ~ ~ y ~ .o _..,
N ~ ~N ~ ~ ~ .~ ~' N b y ~ V7 ~ ~ !'~ N ~ ,~ ~ ~ ~ ~ ~ ~ ._'n ~ U 'b Y '-U' C~
Q"
~ ~ ~ ~ ~o ~ ~ ~ a, ~ " N ~ ~ o ~ V ~ ~ o~~n ~ ~ ~ :D :o .~ ,~
> -o ~ ~ o, ~ .r
> ~ ~1 ~ ~ ~ ~ ~ ~ v °a. w° ~ o°'o U o ~ x ~ ° ~ ~
~ ~ ~ ~ ~ ~ v °o. ~.°.
o ~ o
.° ~ '~ .° ~ '~
> .~ ~ . > .~
b4 ~ ~U U by ~ .U U
N c~ N ai
s~ ,~, .b H s~ ~ ~b H
o ~ o ~ o ~ o
M
M M
O
U
x x
a\ O
M
233
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~, c ai ;"b y 'r' ~ w
a~ y. ~ a~ on ~ ~s ~ :~: .~ o ~ . ~ on o
~~Q'C Cr-,., y~c~ y."~~~w~~NN~Y~N~ UAW c~
N V ~ ~ V V b ~ C ~ ~ c~ N O Ov '~ L: Q ~ O V ~ N
t-i '~ N ~ . 'rr.' N N . ~ ,~ ',,,, . ~ V ~ ,,U, a.~.~ ~ v~ U Y y L" '~ ~ ~ ~
~ V '~'a" ,at,.'
.f"r~U~ a ~U~V4~ >,..~.i-s'-'yU.'~O~~a~.i ~UW ~c~
W~oMO"~o~~ p~~-do~A.~ooo~NO~~v~E-''flo ~3~'='_;~~o~oU
U .D ~ ~ ~ ~ ~ ~ ~ N .~ ~V ~ W p ~ ~ oo WO ~ b O p ~ '~ ~ C ~ . ~ U
a~ ~'3 N-o 3 > o a ~~~ ai~-o~,~"'~~~ ~~ ~ o ° c~ >U ~. o
~ >W'~' ~N N '~ y ~'~ '~ ~> .~ N ~ N N ~ a ~ ,r' C: >> N y
~, ~ ,_~ V O p .,'~~ y ._~ ~" ~; w ~ '~ ': ~ ~ a\ ~O r, ~ ~ U p ~ O ~ '~ p ~
O00O~Qb~ Nw .-~. G.~-~~a0~N~~M'~U'd~.Qa arwGp,~
~' O~ ~ .s"', ~ ~"~ O ~ ?G N ~, c~ N GO V~ ~ ~ ~ ,~ V 'b ~ O s.N. ..., V ...
c~ G ~ V ~ by N ~ y. l~ N :: d U cct m
p °~o~'~p~r,~~N~>,~,~~~ ~,bG.~~o
a N .Uf.J ~ N ~,~"' b y b ~ O v~ ~ .b N v N ,s," 'fit". ~ \O O pn ,~ p., N ~ O
y .cyd
O I~ ~ x ~ .~ ~ p a ~ ~,~" ~ w y N b ~ O ~ ~ N b bU ~ U O ~' p,, ~ ~~ N
°c U ~ o pb °.>,~, ~~ o ~ ~ o ~ dd .d o ~'-' ~ o >,N ~ U ~.
~ o ~ w 'b ~ '*" ~ .a x ~ Z O o t~ ~ ~ c~ o
~ U'.'~ s..'f~>_N~"0,~~~_U~A~~y~~M'bvi ~~L~»
O .~ p b '~ '~ f3.~ O ~U p ~ ~~ ~ ~ ~ Q ~ ~ N N ~ ~.~ M ~ O ~ O
"N~s..w ~yOwOO~~~.r~~y~~~Wl~~~tVn~:rj ~~y030'O
,~ a~ ~ .c ~_, ~ o o ~ ~ c. a ~? ~. f~, :~ ~ ~ .b ,~ ~ ~ p an o °U' p
US~~oc~~a~.~;~a'' ~ ~~~~oo.~=db ~~~w.~ >,>
.' C : ~ ~ ~ w ~ ~ ~ ~ ~ ~ A " ~ ~ ~ p .~ O N .~ ~ ~ ~ w .c
.~ :r w, cn ~ o o °° ~ > C~7 ~ .~ o ,o o ~ p ~ ~ °' ~ ~ ~
.~ F"' ~ on ~ > '
j~ a~ _~ o N v a> ~"~ ~p ~ n '~ ~ "~ °~ _ ~ ~ w >,.b .~ ~ U p ~ _~ ~ -
~7
m ~ m a~ ,~ C7 ~..~ y~ .: a~ 'p _~ p ~ a> a> o
O >, O U c~ ~ cC ,~ U ~b GD ~ U ~ O U ~ w ._ N U '.~ O ~ L ,,,
'~ r-~'~ ~ 'G ~ 'd b O ~' b-0 .C V N O > ' c~ O ~ ' .~., ~ o.N. ~ O N ,~ 'y O
~ b ~ a~ O" ~ ~ .p ~ O .'~~' ,_' .~.~. > ~' .~ ,~ 0 O ~ ~ ~ V T O c~ 0 ~' Q ~
~ 'v~
~ ~ i~ O ~ '-' ~ ~ '~ ~ ..'~'r O "r..' ~.U. p~ t~_"' w 'O ~ blp ~N ~ ~ c~ ~ Q'
~ ~'_~ '~ .wn ~~ w U U
c~'G~ ,~',~.~c~CV~NbO ~.~~bppNtp-~~~pn~'b_OpUb~p~O
C: 00 O O O ~ U U ~, N O N N M _N it ,~ .r c~ ''~ ~ O O .t". >, ~.
c~ cci Q\ V ~ ~ V ~ ~ f., ~., ~ ~~ N O ~p . ~''~' ~ O c~ ~ y,V., V b ~ c~ . ~
..U.Nor.,~~~'~~>.,~,~~~.~>,.b~'~f,.'~U .~.tn'~G3"~~~>,.C'.~~cd
' ,~ .~ w ~ .~ . ~ ,~ ~ i : ~ O cd ~ V ~ ~ y.., c~ a> >, C
~.c~.~My~~'E"i~ OCR"~~0~~~~N~'y~b~~c)~p~~O~OC1"i'..~
cdxN Vcd~~C.O~O.~ V ~'~~~~~i~~~~,~ ~'~O~"O~~ V~dO
i-~~,W n.~.~NyOwU~4.'~OOwt~00 . a,~. ~Omy4.
a.Uy ~~~o~~o~~,~''~N~o~~o~~a.~.>~-'~_i~o
O 00 ~ b ~ U ~ p,'L.' b ~ ..d N w ~ p~ ~"'"~ b-0 Q' s.V, O ~., V O by ~ O c~
UN i..U~O~~~ø,N~~.~0~~.~~N~Ub~~
,~ N '~ ,_~ ~ cn V ~ 'b b O U V v' ~ V U ~ ,~ 'O ~ .b > ~ ~ v~ 'Ll ~' c~
N ~ 3 O ~ ~ ~' '~ O c~ C ~' y ~ ~ ~ ~ ~ U O W ~ .d ~ ,~ ~ ~ ~ yn
>, C7 ~ ~, ~ ~ .
-_ N ~ ,~ ~' ~ ~ Wn c~ 'b V ~. <t ~ ,,.~ , ~p w ~d ~' . ,~ ~ fn c~ 'b N r,
cW . ~ N U ~ 'G N ~ b ~, p, O a ~ N 7 '~ b ~ N V ~ O .~ ~ ~ ~ 'O .~ V M
~o°~oUo~x~°d~~°s~'Ca~C7~s~..~~'_-
"'',~C7~.oo~u3~:°d~~wc~nU
r. ~ >, o 0
p " ~ ~ ~ p O '" v p
O ~~ U ;.d ~ ~ app C
W n ~ O O ~ > ~ O G~, ~ ~,
A. .'~", ~ ~
~~.'~-'~ i°'U
.., > ~ a~ ~ o, d ~ ., ~.
M M
d' ~t
U U
x x
234
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ 01 N ~ ~ ~ ~ s.~. y ~ U ~ ~ ~ - _O ~S' ~ ~ ,_>, ~'-' i
~ O ~ vp ~ U ~ ~ (-~ .~ ~~ ~ ~ s. ~ O 'b M ~ N .b w .~ ~ ~ _~ 00
i
C~~~~~Nw~ 0~4~O.OdO ~N~ M~~ 4~Oc~UGLN
_ ~ U rn ~ Q ~
A" O .O ~ ~p N ~ ~ ~ ,~ ~ .~ ~ '~ ~ W N ~ ~ ~ 'b M O O ~~ p i~G
M
U ~ C~. a ..~ .. N U a.. .~, j~ 01 ~ ~V ~.r tn ~~ ~ O G '~". ~i.. >, ~T-~ ~"'
~ d ~ '~ ~bD O .O >, N p" aW n U ~ ~ N_ ,A. ~ y N O ~ cd ~ ~ > ~ ~D b
b~~N~NvpUUp ~~~~_~'boONb~~O~ ~'C~Cy~~U~
p b N 'Z U .~ W n ø'' U ~ ~ N O -d M ~ ~ b~D ~ ~ .p ~ cUn ~ ~ ,~ ~ W
U" ~ ,~.,~~~.~"b WQ~~Q'D i ~s..UG~."~.,r0 W ~13r..~mU
'b U ., o a~ °~ ~ ~ '~ a~ a. ~~ >, ~ U N G c~. U :b ~ " ~ a~ a~ ~ oio
>, ~ '~
U ~ ~ ~ c~ ~ ~ ~ ~ ~ ~ o o ° ° ~, ~ M C~ ~ ~
N ' 'b s.. ~ U O.~ >, ~ O, O ~ ~ m N y~ U U b ~ c~ ,~ cd O C/~
cV~~bU~DN~~b~ ,yO~bD Ri~~~~~> .i",0,~~,.L"~~,~~ c~.~~"."~
~G~"~CA~p~~~Ub ~~~W~V j~ :~~~y~ ~,c..'ti'V.~~_~.,"~rfj
O O ~ ~ ~ ~ ~ a~ .~ ~ ~ c~ ~~ N ~ ~ O a~ ~ ~. .~ :d ~ U N
b ~ p O .~ a~ ° ~ ~ ~ ~ ~ ~ ~ " W x .U y ~ O ~ ~ ~ ~ O w W WO
w N w0 ~ x Np U .fl U A. c~ Q y ~ w0 b.0 ,., w0 . .try. ~ pp ~ U ~D ,~ 3
Gl. N b O O~ p .~ y U ~ ~~ °~ ~ ~ ~' '~ O ~' .~ 'b
',~',y'Y'bOvO~~OQ'O~ O~~O~~O~ w.~~O~~~~~rn.~~~b
>, a ~ ,~. N b 'n ~ C '~ t+: bD p N GO ~ . .. ~ .:~ N p" CJ 3 U > p~ 0 ~ ~-.
G1. rn
O t1. 00 ~_.,~ N ~ c~ ~ ' O ~ :~ ;~ > L:. ~ ~ cd U b c~ O~ 3 ,G ~ .~ ~ ~ cd
'~'-'~O~MO~~~~~""~~Oc~~bc~~~~c~~'~O~ UN~Y U
N~.U.G~.nUNN,L'~"..S'~~~ G.~~'s..n~Or.rceS~y~,~>'U~''~;~n ~~~f..'~C~', >>N
,~~c,..".d~pp~NO .T'»UO~~>,O~~Oy.O~0ycd0 iGwOVU' ~'C7
O >, V ~O ~ 3 ~"'.. ~ N Oi0 .t". ~' .~~..~ ~ ~ ~ '" "d d' ~ -~ b ~ ~O ~o ~' O
w p ~ O
N j .~ N .:. w ~ -d ° .° ~ ~ ~ wp .~ C ~ ~ U ~L ~ ~ ~ ~ 'b
~ ~, '~ +~~ .~
.t".~~~U .t".pU~"'-'b0ø'Q .,Q'+.'~cdOOcCp,~~ .~".~Q~OU~U~~U~
'rc~~~ '~"0~~~.c~.b .f.00'G'~~'C MNv~O~U~ c~G.~~' U ...0
G N~~b W.~ a~ ~..d ~ ~ p ~U~ ~ ~ ~~~.~ ~_7,U ~'i-',0
v~D~jC -00 ~'O;~'~N ~...b ~,~cn~,'bb~Dc~ SON>c~~
(3, tn i-, 00
ON.~Wc~yU'baUb 7~NiC~0J00 ~c~,~~,OC', W'.~~
~,yy~U~~~M'Q~ ~'D~~~~~''~.C~W n N~~_>,O~r'Ucd~N
wpUp~N mss., Nc~y~~~~~v~yiG~~~ ~.1;
N G1 ~ ~ ~~ ~ U y N ~~'-~ v O ~ ~ eQC ~ cd c~ '~ C/~ 3 ~ W a p U s.. ~ ~ ~ ~ p
fn
.~ 's:. m ~ N U U ~ GA N s".' y..~ 'O ~ ~ ~, O ~ W GL
'''UU.'~ ~~ >,U~ ~~C~a'~ ~O~b[-~j.~wUC b0~Q,v~
fn ~n t~. ~ . >> ~ ~ ~ ~ 'b cC ~O V ~ ~ M y t.. v~ ~ O p ~ N O
~ C ~ ~ N N 'C ° ,~ b ~D .C >,
° 00 00 ~ ~l ~ s.. >, ~ d U 'b ~ 'b c~ ~" ~' ~ ~ ' 4:. O
:~ a.~~.~ ~ ~ 00 O~ .a, ~ O N c~ ~ ~ ~ Q U c~ ~ ~ vi vW ~ ~ G m ..~. c~
~a3~O~~~M~b~N .~U",b U~"N~UUT..'~,~ ~tUn>~
OU W U ~ ~ a a '~ ~ M ~ ~ d Wr ~ Cl~ ~ (~ ~.r O ~ bQ U U cC d cd .C U U v~
w ~ o
O 's"'~ s.~. C:
. ° N G '" O (1, cd
O v~ ~ ~: N ._~
U ai ~ by Q ~ U ~ ~ U N
O > ~ p O ~ O ~ . ~ U
~U
N
d b '~ ~ a~ a. ~ cn U . ° .fl
M M
v0 ~D
U U
x x
235
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
00 a' ..
c~ ~ U b4 N
N N ~ V . 7,~~' ~p ~ ."~ ,~ NN~
G~~vp~,O~O.~ ~V~GpO~yO'OU00~.-dy.,cd>, .~,'nNC~.
,.~., O
cn~.U~ ~~~~ .~."~'U~~d'(l,cdO~.,,~~s.~,
~U~pa~'lUUz ~'(~~"~,7,~~c~C ~a"~~V~O~N,~'N ~.OC4~y
s..U~UO .~ 3yn_b'b~..w~0~ .f"~.~my,U~~'NP~,~
p ~ p '-~ 0 GL '~" ~ O~ C~ ~ ~ ~G ~ y f3~ ~ ,~ .d ~ p b~Q _c~ .a
~ ~ ~s ~ U t~: ~ ~ ~ ~'~ ~ U '' ~ o 0
-dop-'U~.~°co ,a,~3°'oWw.~
U N H a ~ ~ N ~ ~ 3 ~ ~' p i:. U t-. U Ur Z ~ ~ U ~ OU ~~ ~ O ,Y y ~ y
~r~'~ Vf'c~C'b~c~d ~~N~cVnp.,O .S"~, ..VO,~'~-~,~~~~' ~NU~U V
n Wn ,~ pp ~ ~ Q ~ a~'~ ~ O sc~. ~ ~ ~ ~ v~ °~ ~, '~ N ~ O ,~ U ~
O~ '~', ..y-~ b-0 C cC ..~ N ~ ~ ,~ yn '-' > ~ O V ." M ~ O O fn ~ V c~ ~d y
cd N ' 47
O b ~ O ~ V7 '~ >> ~ b d b p ~~~~ N y ~ U V ~ U ~ ~ b0 ~ ~ 0 y
~ ~_ a~ ,~, 'd ~
~s o.~ ~~ '~.b ~ >,C7 0 ~' ~1 0 > p o U ~ a~ ~_
w ,.d ~ Ov M x ~ p Y ~ ~ ~ ,G '~ ~ w y ~ ~ N ~ '~ ~ O O ~~ '
~~LNrU.~U~l3rN ~~.T~.'M~~~.'..S"...rO~y~,b~.b'~yUE'~OQ~'b4~E"~
l~ ,i: p a O ~~ N y N x .S~', 'L.' N V y ~' ,'T ~ N
oU~~~~~~~.b'' ~~~~~~~ i°N~o~nc~°,~~~~d~w~~ao
a»o°,~.~ w~~a~o'"O~~j,"~,N~~'~
w ~ oo rn :-: ~ ~ ~ ,.~ ~ o ~ ~ o ~, ~ oyo
°' °~ ~'~ o ~ ~ a~ ~ N ~ ~ a,° ~ °~~~_ ~ ~ ~ ~
~~z.b a°na.o
'~~ W ~~ p ~ N d0 ~ ~~ U O ~ > ~ N O U N ~ "'a.~~ ~' ~ b ~ cC ~ v~
L~. V U G", ,b O cd ~ .~ ~ . ~ p ~.. -d ~O x '. ~ ~ ~ c~ ~ ~ .~ ~ 'b
b y '~ V U c~ b0 ~ U ~~ ~ -~~ ~ N ~M ~ ,~ M d0'~ O~ ~ .C c~ y ,~ tp
d '~ G '~ ~ w '~ E-~ '~ .~ N '" c°.; ~ ~ cd ' '~
~"' ~ ~ ,.., ~ O w O. ~ O ~ a ~ ~ C/~ ' ~ ~ G. ~ 'n y ~ ~ ;b 'C t-.
id ~ w p'ø,~U~.~",r-i ~M~~"L=. tn G y p p ~N ~ U y,V, ~ y .~."' 0
N~.t".~" ~ ~ V v''-' '~oO ~a v'b.'i' bU0G7 ~'~ ~"'~Ov~~ N~,.~'. ~ ~ C."
c~UyQ'~y,V,~'Ca\c~E-~~OG,_-~,~_VC>'Ot!?~ iG,~~cd~O~~~G_t~.~
Q~w'Y .G ~'ba~ ~,~ O.~ ~ y ~~.~W ~~~y~3 U >,~.U ~ G ~'w
o. ~ ~ w ~, ~ ~ U d ~ a>
'~''MNpp~~~~ ~'.,~ ~NONUQj~m C,~bV>,
~iUt~U~C~OV~O'~~OwyOw~~Of~~H'!'~'~~ ~ -(-'~.V
M y '~ > ~ ~ p O ~' ~ '~ ~ C ~ . ~ N O '~~.' ' .. O
4' ~ U ~ ~ ~ i.d > ~y i-r ..~-n L~" 'y:, iV-W ~ U ~ ~r V . ~ ~ .5~, ~,
p~ ~ ~ ~ y ~' ~ I~ O y ~ O G.» ~O,~ p. ~ w V y U ,3 O O O O 'S"~' C..c
00 y U y ~ H . ~ 00 ~ U ~b O tn ~~ M -f. ~ O .f". x" '-; .u ~ '.r .y e;7! O .
~M~~~E'i~ V ~~~a~~c~~~~b.0~~~-.~y.V.,~U~ ~.~>~~pcVn
,~ a ~ c~ ..w y . ,-, U
op, o ~ ~~j;~~~;~ ~ o a~ ~ a'~Cd7 ~~~W ~ ~~~ ~H~ ~ 3.~ bW
~o'.U ~ onxv~ 3U~H;~w~ ~
o ~ .= ~ o a d ,_~
.r.' ~o
i~ U
CL
'.=~ ~ O E"i P. ~ ~ ~ .~ ' V C O
N
a~~~ ~ ~.~~~ a~~ ~ ~.
M M
V~
U U
x x
236
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
~ ~, ° ~ ~' ~ -o
i ~ ' on ~ ~ a '~~" ~ b ~ ~ .-' ~ ~ ~ c ~. b
;n 'bY°M° ~~~ :.-'°°~ ~,4-'_oM Na~U°>' ~~
~~o>'°
O o V N M b ~ U "~ cad ~~ b N ° U ~ p y ~ .r '~ Q 3 ~. N
... ~D . -Sri, ~ p ~ U ~O ~ ~ ~~.' '~; ._..~. v N ~ ,~ c~ ~ O ~ O ~ ''' ~~ _~
U c~ ~, ~ V cC > ~ O ~'" cn ~ ~y c~ c~ O
~so i~~M., ~ ~,~ ~ ~a~c.~ ~~ow: o ~ ~o ~ ~" ° ~ ~? ° ~U
~»~~?~~ v ~'°a.3~~ov
C7 0.. ~ ~ ~ °~' a~ a~ ~ ~ ~ ,~ a ~ o ~ W ..r o b ,~ ~ o ~ ~ ov
.i~', ~ ~ ;' N w ~ ~, N ~ ~ U a) 'sue ' .~., a) w 'd N v c~ Q' v, '~ ~ N .C",
~ r,
N ~ O ,N-, .~ U ~ ,~ ~~ ~ >, ~ O ~ cd G~. ~ U ~ ~ ~, W U .~C N p., U ~U ~. WO
.S~r . CO b Y ~ N Y Vi ' ~ .-r a, ~ ~ U y ~' C~
C~ ~~U~ ~.~ ~ U G ~ ~~ O i~ ~ 00 .t'r.i.N"'~r~ 3~ U ~'Gw .r:.~ N
y ° x v o o ~ a~ >, y ~~ ~ y,.., _~ ~ o. ~ ~ U ~ w o ~ ° f-~ ~
C7
~~' '"~~a.Nr~a..~c~C ~~'rUCL N ,~~~ NU~U Nl3,.~~ V ..
M ~ ~ ~ ~ ~ ~ ~ U ~ Gh c~ '~ ~p ~", ~ E'~ ~ ~ ~ O ~
~NOy~N~ p.'°O.°cdcd~~~'t~_~_~~U~ ~ °~~Os..
'~ VI ~ ~ N ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ y Vi ~r N U V y-~i y ~ .~ ~~",' ~ ~ ,~~, b4
U°~~~~~ v~~p~7 °~~°~o~c~~,>'~onU'3 ~a~a.oa~
.~'O .b~ :'~~,~c~U,'~nN,NO~~ ~5~,~',~~b,~
ccdd -~~~,, U ~ G~ Lr. .~.~.
~ M '~ '~ ~ 'y G. C ~' ry ~ c~ O W b ~ 00 ~ ~ ~ ~" ~ ~ y N '~ s.' .° y
b
wr v~ O ~"'., N '..~ ~ ~ V7 ,Q a0 S.' w w
p .b ~ c~ ~ ~ ''..' ~' ..i"» C".r V7 V O~ ~", ~ V c~ y ~ ° 3 Q' O U
~ N Ga p ~ N U ' p 'Cf ~." ''~ N U '~ ~ y ~d v 'Ly ,+, ,~; ~ tn O ~ ~i
U ~ O M U ~ ,~ ,x N by ~ > ~ >' ~d " ~ .~G U O O ..r s.. U p U
'> .~ O ,~ ~ V; ... W U ~ x a y .~ U ~ ° O U c~ ~ U V ° ~ ~' ~_'
b0 N
~ U ~ >, ,L" N ~ ,.,, ,~ m N ~~, ~~ ~ 'b O ~ ~ O ~ °
~t ~ oo U ai ~ ° ~ ~ ° w ° o on ~ " ~ ° > ~ ~ ~ 'o
~'' > °
U~W~x~~E-~.~~ ~ O °.~~, d~UC~v~~ °O~ w v,
°? .~ ~ ~ o ~ -~ ° a~ ~ ~ ,WC r*~' '~ o ° ~ °' z ~
.~ ~ a~ ,~ ~ y.~ ° ~ N a~ b
UUOpaO~~i..'U~ .Y~~'bO~~U~U~~~p~~U~N~~v~
N~G.~~ "~ ~N ~1'~",c~C~.f.~7~~~s'~'.~"Gl~l3r~~~T~.,~~0~.~.'
OOUAMW.~°U3 U~~~~O~°U~ UN~N~y0b0d0.~y~.-,
00 ~~V y v~ .t",~,~w Qp,O~rcdU>>'b 'v' .~'" f..'f..'NU~T..'
;Woc~~,'+~~~w ~,>~.~o~a~ Oow'~U~C~ >D°.:~ ~
U ~ U ~ ° ~ V,~ p°p~ ~~v L~ ° ~;.b.~w~U~ O t~.U~ N
~0~~>>~VW n ~y~N~W.'d .f.'wr~NU,~Oc~ ,DYCf3,~
'~ O ~ W O ~ b ~~ ~~ O N O ~ ~ ~ ~ N O ~ x ~ U O ~ c~ ~U ~ ~ N ~' O
O '-' M ,--~ 'Q V > >, '° y, U ~ N U U ~ Ov '~-' ''' N N n ~.. ~ ~
N ~ y
,b~~(;~ ~~~ cC ~O~°O~ UN'd(nNM°pp~U~~ °~b.DUU w_
NO...V7° ~"'p>,v~y t3.~,.,~>';'Cc~d~p,'C~~,.'~,C>'N~~c~~~>,
b4 ~ 00 G r: c~ ~ ~ ~ ° ~ N fn ,-~ ~ ~ ~O ~ ~ U ~ b ~ ry, p
~~ '~ ~ ~ ~ ~ O ~ N Pa .~ ~ .~ N ; fl 'b pr ~ c~ '.' ~U.' O a~ ~'~" tin U 'b
'~,.1
° 'b ~ (/~ O~ U .O U ' 'C~.' ,~ U v~ b y ° fn ~' m WO .l'.. U ~
,=..~ c~ ~ y~ ~. O
.~ Q O ~ N N ~ ~ p O (n ~O ~D O U ,~ N .~
cd wr rW --wr ..» ~ au O. U E'~ d Q~ cd ctt ~ s.. O. c~ M ~ U cd a.. U U Q~
awr ~ . ~ c~
a,
O C'. ~' ~ O ~ ~
U ~ ~ ~~ N ~ V H
~ .a.. N w .O .f3..~ ~ .,., N w
n > ~ ~ O U ~ f"., ~ ~ U b-0 Q N
U ~ s..' ~ ~ N ~ m U s.~.~ ~ N
a.. y Lr N . 'r U ~ a..1 a..1 it N . a
M M
U U
x x
237
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
.b _
° '~ ~ Y b ~° ~ ~ a
M ~ ~ E'~ O ° '~ ..Or ~ ~ ~ M M m ~ ~ ~ O ~ °
N ~ ~ ~ ,i~, i1 ~ G ~ y f-.' ~ ~ ~ .y~~ O ~ C".. ,~ .~ O~ C/~ ~ A.
d' O c~ ~"", '-' 't-' tUn > t>', N b°0 d' '"~ ~ G N Q. O .O ~ -d pv '
M"'.~ y J " ~ ~~.rr,~ c~ O '~U~,~, U''~..' U yU.,,~~ U.~'.~v~U'--i C~.~,s' ~W
° .~ ~ b ~C N U ,L" ~ ,~ O ~,» ~ : ~ O V] ~, 'U y O
OONUCS~V H~O'rNN~o~0o0~!~y,U, O~ ~~~~~O~c~~~_~"~O
'~ U 4. N ~+.' iC 4=,, N O~ i1 N ~ Gtr .f.' t~ GO
~ ~c~ p O 'n y ~ .D O ~ ~ O ~ bi0 ~ '"' p .~ O ~ ~ ~ ~ N t.V..~ O U N
C~~.~," W ~ ; ~' O ~ >,T..'.~C/).°~"Cy~ c~ ~ " L y ~ ~ Uz.~ >,V
_ _" >> b-0 ~ C~ L N v~ t/~ U U ._ ~ U ~, ~ cd ~ V7
U ~.U, ~U .f"" .f, ~ y ~ ~ U ~ ~'.i ~ ~ ~ m ° >> .~.' ~ ° U
~ N
U ~' ~ .y ctf !3, "-f' U cd cd O c~ N > tn ~ > c~ , ~ y ~"~ x ~ ~ ai v~
'b '~ i..i ~ ° b T.,' ~ ~ y ~" . ~.' ~ .y CC W p a.' ~ y.., ~ > c~
a~ a~ y ~ ~ " z ~ 'b ~ o -o an ,~ ~ ono a~ . ~ ° >,
U U ,~ ~ H O ...fir 4-n 'C yr .--i ~ ~ ~ ~' ,~ ~r .r'.i N ~ ~ ~' . i.-i n U
cCf tH,
'b y O~ y b
. ~ w ~ ~ "~ ~ c~ .O N ~'~-' t-~ ~ c~ ~ ~ ~ 'C1 sue.. O t-~ 'O ~~ w, . ~ ~ ,~
. ~ c~ ~ O
y G '~ N ~ ~ H C~ .S".n N y ~' '~ V y" U ~ '~ cn O V N rVn x ~ ,rUr' N
Uc~~ "~ H~~~L.~.,~~w~Nc~;-~~cd~ c~N.~>~'b~~~V,~ ~N
ccf ..U» N y ~ ~ ~ O O~ U >> U y p°p -~ O ~~ ~ ~ O ~ ~' ~ y
° ~ '.' ~ ~d y c~ '-' ' O ~ c~ ~ ~ .t'. N 00 fir' N
._~ ~ s-~r y0 b O ~ ~ '+~ 'C ~"'., ,-~ ,~ v~ ~ c~ O '~ _ O gyp'' ~ b ~ p~ U U
~ O
~' pp C/~ cd :D y O ~ .f, i : " 3 c~ N ~ ~ b ~ ~U., yr .-w ~ ~ z t_.i
~ i o x ~ ono o ~ ~>, .~ ° c~ °~' ~ °p.~ ~ ~ 0 3
y ~ b ~ O~ ~ S,' N c~ '_' 'b y G, d ~+, ~ M ~; ~ '~ '~
is o0 ° ~r N b-0 ~ a~ ~ ._-~ ~ U ~_'., ,~," ~ ., iC O ' C/~ ,.S', vJ
:b O N ~ ~ Ov 00 pNp U O ~ ~ ~ O U U ~ b ~ b V
00~.U'G ~~~Ub~~~~~yn .5~.~ ~~GO,~~'U~~4,c~CE'-~
00 M .C ~ ~ ~' 3 .f~. ~ O ~ v~ ~ ~ ~ y ~~ ,~ " ~~ cC by U ~ N ~ O " ccf
M ~ ~ p. N ~ ~ ~ V ,~ V M N (~ ~ O U ° ~ ~ ~ 0~, ~ ~ ~ ~ ~ ~ N
N M U 'D p, .O ~ s"' ~' ~ N ~ N ~ U E" ~Y 'b ~ sy" p .O ~, ~ ~ N ,,-~, 'y "d
M'~_'Uc~c~ ~~,~~~HOUMCjOO~~~~~~~0~~~>'N~~'L',.~c~C
-~ ~ 3 ~ y ~ a~ .~ o ~' ~> ~. ,~ N '~ ~ ~ U ~ '. -o a, a~ .~ W ~ ~ U o
c~ y W y ~'r ,a ~ ~ '~, O .p 00 ~ ''~'' ~ 4"' y O V~ tVn O ~ N 'y ,~ .~.~ " 4--
n
S.' U O ~~, ~' t=i y C: ° ~ ~ U ° ~ ~~ ~., ø, 'O cd O .S'"»
U v~ ~ W U ''' N ~ O O >> C." ~ ~' 4r cd V~ ~.w
o_ ~
W ~ ~ c~ .C . > U ~1 i., y y Ov Wr O
G " 4" " N U c~ ~ ' C ~ W I~ ~ it ~ 3 ~"~ C~ y." N ;_~ ~
W ~ _o o ~ ~ ~ -d b o ~ a~ W ' _: M ~ >s..,, ~ ~ o . 4~ ~ rr~ ~ ~ ~ ... ~ ~ o
.Gy .S~.bp y~~~ U~t..'ycd~yc~~di~.': ,_~Otn~~O p~00
cn ~ '~ ~ ,~ ~ O O. ~ ~ ~ O v~ N N ,-, p" .~ c~ ~ c~., ~ p, cd y c~ .~~" ~ ~
Q' c~ cd
o°o~~ .~o~>,E-~.oo: o~~m°'~ ~,~30.v~ 'c
a..r y ~ ONO
,~ ~ U O ~ ~ y V p Vj p. p. v~ y O 't~ M U ~ N p N fn ~ c~
~~ ~ .o °' C7 U N E-~ W ~ 4° ~ '~ ~ ~ .b ° ~ ~° '*
W .~ ,o
~ U vo o ,~ ~ an ~ . " . " ~ .-: y c~. y ~ ,_~, ~ N ~-: y
~o°°oo°M~° °~'U ~ ~ a~ >a,'H ~b.~-~a~.~
° °~ ~ vi ~
~ ... ~ U y d '. c~ y w W o ~ ~ .~ N N ~ c~ ~ N s~. v~ W .~., c~ U 00 .-, N c~
~ N
° o ~' ~ ° o ~ '~ . ° o
.f.' .~ 'S..~' U ~~ G." ~y ~ C U E-~
pp~ .t'.,~~~~,~~ c~~ppC.'~~'~_- cdV
O d O. ~ ~ ~ ~ 'V ~ O A. ~
U ~. ~ ~ C/~ w~ N . ~ ~ t~., U Q a~1 ~ s.V. N . ~ U ~. s"'
y
N ~ N
M M M
N
U U U
x x x
238
CA 02441416 2003-09-22
WO 03/004622 PCT/US02/08124
a . ~ -o ~ ~o
a ~n ~ U U ~ ~ cue ~ ,.. -d can ~ ~ ~ r. o
v b b ~ .o ~~ ~ ~ ,~ o c vo ; ~ ,~ v ~ ~ ~'~ '~ ~ ~ >, ~
~. ono ~ ° ~
C ~-c ~, ,~ ~ ~'Y '°,a?M°.~ U._
° Y :, :-: .~ .r o ~ ~ a~ °'° ~, :?
~ 4"" p ~, ~..~ y ~ O~ N sc~ O U ~_ ~' w c~ O O p \O ~ ~ ~ ',~ ~ C~' O y "_U,
,., ~
~ ,.~,, ~ .~ >, b-0 ~ U ' ~ ~i s.i ~ U ~ N_ V ~ ~ c~ ~ ~ .0~.~' U ,~_. U O
N~O~r.O,'Z~'~p~~U ~.GOyO~p~pQ~E..,C1,~ aj.'t":.'O~VIOLi
> b ~o ~ o ~ ~ ~ ~ 'n '~ ~. ~ 3 ~ ~ oW ~ ~ ~ b o a~ a, o ~
,., ~ ~ id c~ M ._~ U ~ O O ~ p ~ ~ ~ .~ ~", ccs O ~' 'r ,'~,,
p~>,~NN~~c30N,~C., ~NN~~~r,~~N(,.~ ,~~>>.~~~'UO
n M O .~ V ,,.., 'b m O ~ ~ ~ U > ~ U ~ ~ ay U ~ ~ O.
~~NU~~G) U~~~~bD~~ ~p~~ ~~ jc~lqNU~ n
p ~ > U .... .-~ c~ ;.d .t", ~ ~, .--~ .C G'. of c~ ~ ~ ~ p ~ "" > ?~
c~''-' (~0~0"~'u.0'Z'NU~~ O~~~~.~W._~O
T..' N ~ y ,b ',~~ o0 ~ ~ ~ ~ V ~ CL ~~ " ~ V " O V ~ ~" >> ,~ ~O N' ~ is. p ~
p
O O ~' O ~O Ov O ~".i '_' N '~J .4i O ~ cd .C '-' '.' ." ~ N O ~ U N c~ O
.'" v' p~boo"O U~ U ~''~~~ ~ ~~ GpN ~~ y ~.U, U 'W n~+: O O.
O~~U'~MppW~>' ~ ~"U>p0>U~',~~~U N'~-' .~~~p''~p''O
c~ b4 ~ ~' ~ N ~ ~ ~ ~ ~ y .~ ~ .~ .~ ~ O Ov s ~ ~ ~. p O O b ~V .V c~
A.~M ~~~~~ ~'~~'~~~pO~~p~Op~,~r.~4 CN~O'~bW~
w UFO ~~ y ~ ~ ,SU'.' cUnw,~'YCH, N~M O~.~Z W~~ ø,iU~'~ ~
o~d..,ar~~J~~~ ~~03~oa_ ~U'~a~ ~a,Wc''~~,
N ~UNW~L~N '~ ~ppO~'~.'~~U~U~jM'~~~ cCp.,~U~yCb
~ GL.YC .Y .~ O "'~ ~ ~ U _cd N O ~O 'p ~ ~ '~ ~b O_1 ~ '~ >'-d
.L!". ~ .C ~ ~ N ~ ~ Q" ,~_ t~., bOD ~ b ~ W. oo y ...U, ,~ w C~. ~ b ~.1', '~
t~".
.u .~ T'.. a.u O_~ ~ ~ U ~. 'b a~-. U ~ ~ CC 00 ~ ~ ~ .U~. . .~., W ~ ~ ~ cd
b _N ~ 'm ~ M ~' ~~U~' , 3 ~ ~ ~ ~ c~ ~ U ~ ~ ~ U c~ 'a:~ .~S';-.-~ N ~ p ~ b
O~~~NU~ .~Ua'~~'~''~M~.~~c~~mc~O~~O.rU
_~,b ,~ ~~ y cd~~ ~U~_" ~ y,~ U w U~ O 3 cd N~~ ~ N~ P.~~'Cf y'r
.r".~~~OpU~NN".~N ypOpUpc~>>~,N-,ppr~n~ya.~'~~~'";-, C
O U Or ~ _." ,~ ~ U w r~ by ~ p O c~ .~C O w ~ ~~ ,~ ,x O, ~ O
~~ p ~ N ~ ~ p ~ ~N .~ E'" O O -O O ~ v ~O ~ U ~ O " O O ~ "O ~ ~ 'b '~'
a, cd i., . ~ 00 N U ~' ,7-~ .~, ~,' .t". N y' ~ >y--~ ~ N ''' U .~» ~ j U ~
~'.'
~ O~ v ,~ ~ ,~ i O 'b ~ O at ~ ~ N ~ N ,~ dp O at p > ~ O
'~ ~ w° ~ ~ b o M o ~ o ~ _> ~ i ~~ W ~ _~ W ~ y ~ b
,~.Ow ~p~0 ~.U.,,~~" U U~Ots.NC~N.~~~b40.Ud0~~. ~c~
w C.n ~ N ~., '~ ~O ~ ~ >~ ,.'.' ar c~ ~ ~ ~ ~ N y ~ ~. ~ ~ V 1.. 4..i p . ~ -
'~'r
O 'y:, ~ U O ~ N .~ " .D " N N cd ~ ..r U 'r-~ p O O o..~ ~ p U ~C ~n U f3m..
C
~c~~'w.~~~ '-d~'b y GN ~'O QUO ..~,~_O~'v.~..'UUw_ n
~d ~ ~ ~ p ~ U ~ ~ ~ V s.. .Zy ~ ~ N ~ ~ N U U V ~ U N
.=~ _cd ~G ~ U O ~ ~ O ~ p N U v' '~-i (~ '~ c~ O p N U O .
G. ~ N O _. " ~n ~ ~. ~ . w ~ ~, ~ ~C3 ~ _. _ ~ ~ .~ w >, ~ O
~ H ~' (~, ~ 00 ~ .3"'.r N ~C ~ .,.' >> O O ctf ~ bQ 00 I~ ~ ~ ~ 3 >' ~.,:,!
.u U ~d ~, O N
C. ~ W ~ CC .... ,~ ~ ,7-~ . fti c~ c~ ~ ., :~ .~.',. . ~ GCS ~ .r ... .~ ~ ,~
~ ~. O
E'.' ~ w
U ,~ ~ ~'' U ~,-,U" p .O , m
U O .~ ~ ~ U O ~ ~ N
.~, au
.,U. °' v
O O, ~ ~ U ~ '" ': p O C1. ~ O U p .~ pp ~, N' GL
LUr N . ~ ~ C.' U Q a~ ~ i.U, ~ . ~ a f..' U ~ i.~. w .~".' b
,r O W
M M
N
N
239
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 7
~~ TTENANT LES PAGES 1 A 239
NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des
brevets
JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME
THIS IS VOLUME 1 OF 7
CONTAINING PAGES 1 TO 239
NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:
