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 3
~~ TTENANT LES PAGES 1 A 465
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 3
CONTAINING PAGES 1 TO 465
NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
Nucleic Acids, Proteins, and Antibodies
[1] This application refers to a "Sequence Listing" that is provided only on
electronic
media in computer readable form pursuantto Administrative Instructions Section
801(a)(i).
The Sequence Listing forms a part of this description pursuant to Rule 5.2 and
Administrative Instructions Sections 801 to 806, and is hereby incorporated in
its entirety.
v [2] The Sequence Listing is provided as an electronic file (PTZ32PCT
seqList.txt,
3,411,276 bytes in size, created on January 13, 2001) on four identical
compact discs (CD-
R), labeled "COPY 1," "COPY 2," "COPY 3," and "CRF.". The Sequence Listing
complies
with Annex C of the Administrative Instructions, and may be viewed, for
example, on an
IBM-PC machine running the MS-Windows operating system by using the V viewer
software, version 2000 (see World Wide Web URL: http://www.fileviewer.com).
Field of the Invention
[3] The present invention relates to novel proteins. More speciftcally,
isolated nucleic
acid molecules are provided encoding novel polypeptides. Novel polypeptides
and antibodies
that bind to these polypeptides are provided. Also provided are vectors, host
cells, and
recombinant and synthetic methods for producing human polynucleotides and/or
polypeptides, and antibodies. The invention further relates to diagnostic and
therapeutic
1
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
methods useful for diagnosing, treating, preventing and/or prognosing
disorders related to
these novel polypeptides. The invention further relates to screening methods
for identifying
agonists and antagonists of polynucleotides and polypeptides of the invention.
The present
invention further relates to methods and/or compositions for inhibiting or
enhancing the
production and function of the polypeptides of the present invention.
Background of the Invention
[4] One of the most critical tasks a cell must perform is to respond to cues
from its
environment, i.e., extracellular signals. Some of the most important
extracellular signals
come from other cells. The ability for cells to be able to send and receive
signals from one
another is of paramount importance in. multicellular organisms because it
allows individual
cells within a body to become highly specialized and yet work in a coordinated
fashion with
other cells of the body. Cellular signaling mechanisms regulate a variety of
cellular
processes such as, for example, proliferation, differentiation, survival,
movement, and
secretion. Defects in cellular signaling can lead to a number of diseases and
disorders such
as cancers, immune system disorders and nervous system disorders. For more
expansive
reviews on this subject, please refer to Hunter, Cell 100:113-127 and Chapter
15 of
Molecular' Biology of the Cell, Third Edition, edited by Alberts et al.
(1994), which are herein
incorporated by reference in their entirety.
[5] Signal transduction requires molecules that serve as the extracellular
signaling
molecules as well as a set of receptors that "receive" the signal. Frequently,
an additional set
of proteins is necessary in order for the cell to translate the signal it has
received into an
appropriate response via the activation or inhibition of a particular set of
genes or proteins.
The signaling molecules, the receptor proteins, and the molecules that relay
the signal
between the receptor and the final effector molecules collectively form what
are known as
signal transduction pathways.
[6] To date, several common types of signal transduction pathways have been
identified. One way to classify a signal transduction pathway is based on the
class of
receptor protein it utilizes. Two well known classes of receptor proteins are
G-protein
coupled receptors and enzyme-linked receptors. This latter class of enzyme-
linked receptors
includes receptor tyrosine kinases, tyrosine kinase associated receptors,
receptor
serine/threonine kinases, receptor tyrosine phosphatases, and receptor
guanylyl cyclases.
2
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
Signal Ti~afzsduction th~ougla G protein Coupled Receptor s
[7] G protein coupled receptors are the largest family of cell surface
receptors. They
are seven-pass transmembrane receptors which activate trimeric G proteins (G
proteins) upon
ligand binding. G proteins are GTPases composed of three subunits: alpha, beta
and gamma.
G proteins function as molecular switches existing in two states: an active
GTP bound state
and an inactive GDP bound state. Ligand binding to G protein coupled receptors
induce
inactive G proteins to release GDP allowing GTP to bind in its place. Binding
of GTP to a G
protein causes the alpha subunit to dissociate from the beta and gamma
subunits which
remain associated with one another. Eventually, the GTPase activity of the
alpha subunit
results in hydrolysis of the bound GTP molecule to GDP, thus inactivating the
G protein.
[8J There are several types of G proteins that have been classified based upon
their
function. Stimulatory G proteins (GS) are involved in adenylate cyclase
activation; inhibitory
G proteins (G;) function to inhibit the activity of adenylate cyclase. Yet
another type of G
protein , Gq proteins, functions in the activation of phosphoinositide-
specific phospholipase C
enzyme.
[9J Activation of adenylate cyclase by an activated GS protein results in the
production
of the cyclic nucleotide, cyclic AMP (cAMP). CAMP mediates its effects mostly
through its
activation of cAMP dependent kinase (A-kinase), a serine/threonine kinase.
Activation of A-
kinase helps to further relay the signal from the G protein coupled receptor
to the target
proteins. In muscle cells, for instance, activation of A-kinase following
adrenaline signaling
ultimately results in the activation of an enzyme, glycogen phosphorylase,
which catalyzes
the release of glucose molecules which can be used to produce energy from
glycogen. In
other instances, activated A-lcinase translocates to the nucleus where it
phosphorylates the
CAMP response element binding (CREB) protein, which when phosphorylated, acts
as a
transcription factor to stimulate the expression of genes that have cAMP
response elements
(CRE) sequences in their regulatory regions.
[10] Gq proteins, when activated, activate the enzyme phospholipase C-beta
which
hydrolyzes PI 4,5-biphosphate (PIP2) producing inositol triphosphate (IP3) and
diacylglycerol (DAG). IP3 functions as a second messenger that causes the
release of Ca2+
from intracellular stores. Released calcium then binds to Ca2+ binding
proteins such as
calmodulin, which in its calcium bound state, is able to activate
Ca2+/calmodulin dependent
protein kinases (CaM-kinases). Activated CaM kinases then continue to relay
the signal to
3
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
more downstream molecules in the signal transduction pathway. The other
product produced
by phospholipase C-beta, DAG, functions to activate the serine/threonine
lcinase known as
protein kinase C (PKC). Activated PKC phosphoiylates target proteins depending
on the cell
type, and in many cells these phosphorylation events lead to the increased
transcription of
specific genes. The highest concentrations of protein kinase C are found in
the brain where
PKC phosphorylates ion channels in nerve cells thereby altering their
excitability. PKC
activation can be induced by treating cells with phorbol esters which are able
to cross the
plasma membrane, bind to, and activate PKG directly. .
Signal Ts°afzsductiou through Receptor Tyrosine Kiraases
[1l] The receptor protein tyrosine kinases (RPTKs) are some of the most well
studied
receptors, and the signaling cascades they initiate demonstrate two of the
fundamental
concepts in signal transduction: the regulation of protein phosphorylation and
the recruitment
of proteins into a signaling cascade via protein-protein interaction domains.
[12] Binding of the cognate ligand to a RPTK, such as epidermal growth factor
(EGF)
binding to the epidermal growth factor receptor (EGFR), induces RPTKs to
dimerize and
cross-phosphorylate each other on multiple tyrosine residues. The
phosphorylated receptor
dimer is the activated form of the receptor.
[13] The phosphorylated tyrosines on activated RPTKs are then recognized/bound
by
other components of the signal transduction pathway. One of the important
discoveries in the
field of signal transduction was the recognition of conserved domains which
allow for
protein-protein interactions in signaling pathways. The most prevalent binding
domain that
recognizes phosphotyrosine (P-Tyr) residues is known as the SH2 domain (for
Src homology
region 2, named after the Src protein in which the SH2 domain was first
discovered).
Another domain that recognizes P-Tyr residues is called the P-Tyr binding
domain (PTB).
The discovery of the SH2 domain was quickly followed by the discovery of
several other
protein-protein interaction domains involved in signal transduction and by the
realization that
most of these domains are modular in nature, meaning these domains fold
independently - a
most convenient feature for protein engineering. To date, more than 100 such
protein
interaction domains involved in signaling have been defined via comparative
sequence
analysis. Most of these domains recognize short linear sequences
(approximately 4-10 amino
acid residues in length), in some cases requiring phosphorylation of specific
residues within
the sequence allowing for inducible association. A convenient web based
database, with
4
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
links to abstracts of papers characterizing these domains can be found at
http://smart.EMBL-
Heidelberg.de.
[14] Proteins containing SH2 and PTB domains translocate to the plasma
membrane
where they associate with the activated RPTKs which, in turn, activates them
through
phosphorylation. By way of example, activation of the platelet derived growth
factor
receptor (PDGFR) results in the autophosphorylation of tyrosine residues in
the cytoplasmic
tail of the PDGFR. These P-Tyr residues then serve as the binding sites for
other proteins,
such as a GTPase (discussed in more detail below), phospholipase C-gamma, and
the
regulatory subunit of PI-3-kinase, Which are each able to recognize the P-Tyr
residues in
PDGFR via SH2 domains. The interaction of these proteins with the activated
PDGFR
results in the translocation of these proteins to the plasma membranes where
they have their
substrates and the PDGFR mediated activation of these proteins via
phosphorylation.
[15] In the previous example, each of the proteins recruited to the activated
RPTK via
their SH2 domains also had catalytic activities that allowed them to propagate
a signal.
There are proteins involved in signal transduction, however, which have no
ability in and of
themselves to propagate a signal. Instead, these proteins, known as adaptor
proteins, serve
to couple activated RPTKs to other components of the signal transduction
pathway which do
have the capacity to propagate the signal. One such adaptor protein is known
as Grb2. It
contains one SH2 domain and two SH3 domains (another Src homology domain that
mediates protein interactions). Grb 2 is constitutively associated with Sos
protein, a guanine
nucleotide releasing protein (GNRP), via its SH3 domain. Thus, when Grb2
associates with
an activated receptor via its SH2 domain, it also brings Sos into proximity
with the RPTK
which activates the Sos protein via phosphorylation.
[16] GNRP proteins, such as Sos, are one of two types of proteins that help
regulate the
activity of proteins belonging to the Ras superfamily of monomeric GTPases.
Ras proteins
are proteins that are associated with the cytoplasmic side of the plasma
membrane and help
relay signals from RPTK to the nucleus to stimulate cell proliferation or
differentiation. Ras
proteins exist in two states, an inactive state in which ras is bound to GDP
and an active state
in which ras is bound to GTP. Activated GNRP proteins promote the exchange of
bound
GDP for GTP on ras proteins, thereby activating ras. Ras, itself, is a GTPase
that hydrolyzes
GTP to GDP, and would therefore tend to inactivate itself over time. However,
ras is an
inefficient GTPase, so the inactivation of ras is enhanced by GTPase
activating proteins
(GAPS) which increase the rate of hydrolysis of GTP by ras.
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
[17] Activated Ras kinases then act to activate more downstream signaling
events,
including activation of the mitogen-activated protein kinase (MAPK) pathway
which is a
cascade of serine/threonine kinases. Ras binds to and activates a MAPK kinase
kinase
(MAPKKK, such as Raf 1, for example), which in turn activates a MAPK kinase
(MAPKK)
via phosphorylation, which in turn activates a MAPK. MAPKs relay signals
downstream by
phosphorylating various proteins in the cell including other kinases and/or
regulatory proteins
in the cell. For instance, an activated MAPK can enter the nucleus and help to
initiate
transcription of genes that must be expressed in order for the cell to respond
to the
extracellular signal, such as genes required for DNA replication in response
to the
extracellular proliferation signal.
[18] Another class of signaling receptors, receptor serine/threonine kinases
(RSK) has
recently been identified. An example of an RSK is the TGF-beta receptor.
Additionally, it
has also been recently recognized that there are modular binding domains that
recognize
phosphoserine/phosphothreonine (P-Ser/P-Thr) residues. For instance, 14-3-3
domains
recognize phosphoserines in specific amino acid contexts [RSX(P-Ser)XP] or
[R(Y/F)X(P-
Ser)XP) and may function in the assembly of signaling complexes. Other
residues such as
histidine and arginine can also be phosphorylated, and it is possible that
additional kinases
which phosphorylate these residues, or protein domains that bind
phosphohistidine or
phosphoarginine will be discovered.
Signaling hia Iht~acellula~ Receptor s
[19] Some extracellular signals do not have cell surface receptors such as G
protein
coupled receptors or receptor tyrosine kinases. Instead, these extracellular
signals are able to
traverse the plasma membrane and interact with their receptors in the
cytoplasm. Examples
of such signals are the steroid hormones and the gas nitrous oxide (NO). The
steroid
hormone receptors, once bound by their ligand, are generally able to
translocate to the
nucleus where they bind regulatory DNA elements that control the gene
expression of
specific genes. NO gas, on the other hand, generally enters a cell and reacts
with iron in the
active site of the enzyme guanylate cyclase, stimulating it to produce cyclic
GMP (cGMP).
cGMP acts as a second messenger (similar to the way cAMP functions) and can
stimulate
further downstream signaling by binding to other proteins.
6
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
Te~~aiuatisag Signal Ti~ansductioya
[20] As the effects of signal transduction are transient, there must also be
mechanisms
for terminating signal cascades. For example, G proteins are self
inactivating, and there are a
set of proteins, GAPS, that are devoted to increasing the rate of hydrolysis
of bound GTP by
ras proteins. Cyclic nucleotide second messngers such as cAMP and cGMP are
hydrolyzed
by phosphodiesterases. In the case of kinases, there generally exist a set of
complementary
phosphatases that function to dephosphorylate phosphorylated residues, thereby
bringing the
signaling event to a close.
Sigszal Ti~ansduction Pathway Componefzts and Disease
[21] Because signal transduction is involved in the regulation of so many
cellular
processes, including proliferation, differentiation, survival, and apoptosis,
it is not surprising
that defects in cellular signal transduction pathway components lead to a
number of diseases
and disorders, especially cancers. For a review on Signal transduction pathway
components
and diseases, see Hunter, Philosophical Transactions of the Royal Society of
London Series
B 353:583-605 (1998) which is herein incorporated by reference in its
entirety. For instance,
approximately 30% of human cancers have mutations in a ras gene, and at least
18 tyrosine
kinases have been identified as oncogenes in either acutely transforming
retroviruses or in
human tumors, such as for example, Src. And more than 95% of chronic
myelogenous
leukemias express an activated form of the c-Abl non-receptor tyrosine
kinases.
[2Z] Mutations in signaling pathways are also implicated in a plethora of
other diseases.
Mutation in Bruton's tyrosine kinase leads to X-linked agammaglobulinemia.
Inactivation of
ZAP70 or JAK3 leads to a severe combined immunodeficiency disease. Coffin-
Lowry
syndrome occurs when the X-linked Rsk2 protein serine kinase gene is
inactivated.
Myotonic dystrophy occurs when expression of the myotonic dystrophy serine
kinase gene is
decreased. Overexpression of the aurora2 serine kinase is implicated in colon
carcinoma.
[23] The malfunction of signal transduction pathway components, particularly
kinases,
in diseases indicate that these genes are good targets for
drugs/pharmaceuticals that either
inhibit or activate their function. In fact, some such drugs have been
developed and are
already in use or in clinical trials. For instance, an inhibitor of cyclin
dependent kinase 2
(cdk2), a kinase important in regulating cellular proliferation, is in
clinical trials for cancer
treatment, as are inhibitors of epidermal growth factor receptor tyrosine
kinases and vascular
endothelial growth factor receptor (VEGFR) tyrosine kinases. Inhibition of
VEGFR activity
7
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
reduces or eliminates the vascularization of tumors directed by VEGFR. An
antagonistic
monoclonal antibody, herceptin, against the erbB2 receptor tyrosine kinase is
being used in
breast cancer therapies to treat breast cancers where ErbB2 is overexpressed.
[24] Thus there exists a clear need for identifying and exploiting novel
signal
transduction pathway component polynucleotides and polypeptides. Although
structurally
related, such proteins may possess diverse and multifaceted functions in a
variety of cell and
tissue types. The inventive purified signal transduction pathway component
polypeptides are
research tools useful for the identification, characterization and
purification of additional
proteins involved in signal transduction. Furthermore, the identification of
new signal
transduction pathway component polynucleotides and polypeptides permits the
development
of a range of derivatives, agonists and antagonists at the nucleic acid and
protein levels which
in turn have applications in the treatment and diagnosis of a range of
conditions such as, for
example, cancer and other proliferative disorders (e.g., chronic myelogenous
leukemia),
immunological disorders (e.g., severe combined immunodeficiency and X-linked
agammaglobulinemia), and nervous system disorders (Coffin-Lowry Syndrome),
amongst
other conditions.
Summary of the Invention
[25] The present invention relates to novel proteins. More specifically,
isolated nucleic
acid molecules are provided encoding novel polypeptides. Novel polypeptides
and antibodies
that bind to these polypeptides are provided. Also provided are vectors, host
cells, and
recombinant and synthetic methods for producing human polynucleotides and/or
polypeptides, and antibodies. The invention further relates to diagnostic and
therapeutic
methods useful for diagnosing, treating, preventing and/or prognosing
disorders related to
these novel polypeptides. The invention further relates to screening methods
for identifying
agonists and antagonists of polynucleotides and polypeptides of the invention.
The present
invention further relates to methods and/or compositions for inhibiting or
enhancing the
production and function of the polypeptides of the present invention.
Detailed Description
Tables
8
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
[26J Table 1A summarizes some of the polynucleotides encompassed by the
invention
(including cDNA clones related to the sequences (Clone ID NO:Z), contig
sequences (contig
identifier (Contig ID:) and contig nucleotide sequence identifier (SEQ ID
NO:X)) and further
summarizes certain characteristics of these polynucleotides and the
polypeptides encoded
thereby. The first column provides the gene number in the application for each
clone
identifier. The second column provides a unique clone identifier, "Clone ID
NO:Z", for a
cDNA clone related to each contig sequence disclosed in Table 1A. The third
column
provides a unique contig identifier, "Contig ID:" for each of the contig
sequences disclosed
in Table IA. The fourth column provides the sequence identifier, "SEQ ID
NO:X", for each
of the contig sequences disclosed in Table 1A. The fifth column, "ORF (From-
To)",
provides the location (i.e., nucleotide position numbers) within the
polynucleotide sequence
of SEQ ID NO:X that delineate the preferred open reading frame (ORF) that
encodes the
amino acid sequence shown in the sequence listing and referenced in Table 1A
as SEQ ID
NO:Y (column 6). Column 7 lists residues comprising predicted epitopes
contained in the
polypeptides encoded by each of the preferred ORFs (SEQ ID 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 PEPTIDESTRUCTURE
(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 1A 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 1A. 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, "Tissue Distribution" shows the expression
profile of tissue,
cells, and/or cell line libraries which express the polynucleotides of the
invention. The first
number in column 8 (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. For those
identifier codes in which
the first two letters are not "AR", the second number in column 8 (following
the colon),
represents the number of times a sequence corresponding to the reference
polynucleotide
sequence (e.g., SEQ ID NO:X) was identified in the tissue/cell source. Those
tissue/cell
9
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
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 andlor specific tissue and/or cell expression. Column 9 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 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 column 10 labeled "OMIM Disease References)". A key to
the
OMIM reference identification numbers is provided in Table 5.
[27] Table 1B summarizes additional polynucleotides encompassed by the
invention
(including cDNA clones related to the sequences (Clone ID NO:Z), contig
sequences (contig
identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)),
and genomic
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
sequences (SEQ ID NO:B). The first column provides a unique clone identifier,
"Clone ID
NO:Z", for a cDNA 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 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 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).
[28] Table 2 summarizes homology and features of some of the polypeptides of
the
invention. The first column provides a unique clone identifier, "Clone ID
NO:Z",
corresponding to a cDNA clone disclosed in Table 1A. The second column
provides the
unique contig identifier, "Contig ID:" corresponding to contigs in Table IA
and allowing for
correlation with the information in Table 1A. The third column provides the
sequence
identifier, "SEQ ID 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 columns five and six.
Columns 8 and 9,
"NT From" and "NT To" respectively, delineate the polynucleotides in "SEQ ID
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.
[29] Table 3 provides polynucleotide sequences that may be disclaimed
according to
11
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
certain embodiments of the invention. The first column provides a unique clone
identifier,
"Clone ID", for a cDNA clone related to contig sequences disclosed in Table
1A. ' The
second column provides the sequence identifier, "SEQ ID NO:X", for contig
sequences
disclosed in Table 1A. The third column provides the unique contig identifier,
"Contig ID:",
for coritigs disclosed in Table 1A. The fourth column provides a unique
integer 'a' where 'a'
is any integer between 1 and the final nucleotide minus 15 of SEQ ID NO:X, and
the fifth
column provides a unique integer 'b' where 'b' is any integer between 15 and
the final
nucleotide of SEQ ID 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 ID 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).
[30] Table 4 provides a key to the tissue/cell source identifier code
disclosed in Table
1A, column 8. Column 1 provides the tissue/cell source identifier code
disclosed in Table 1A,
Column 8. Columns 2-5 provide a description of the tissue or cell source.
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 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.
[31] Table 5 provides a key to the OMIM reference identification numbers
disclosed in
Table 1A, column 10. OMIM reference identification numbers (Column 1) were
derived
from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man,
OMIM.
12
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
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 URL: http://www.ncbi.nlm.nih.gov/omim/).
Column 2 provides diseases associated with the cytologic band disclosed in
Table 1A,
column 9, as determined using the Morbid Map database.
[32] Table 6 summarizes ATCC Deposits, Deposit dates, and ATCC designation
numbers of deposits made with the ATCC in connection with the present
application.
[33] Table 7 shows the cDNA libraries sequenced, and ATCC designation numbers
and
vector information relating to these cDNA libraries.
[34] Table 8 provides a physical characterization of clones encompassed by the
invention. The first column provides the unique clone identifier, "Clone ID
NO:Z", for
certain cDNA clones of the invention, as described in Table 1A. The second
column provides
the size of the cDNA insert contained in the corresponding cDNA clone.
Definitions
[35] The following definitions are provided to facilitate understanding of
certain terms
used throughout this specification.
[36] 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" 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.
[37] As used herein, a "polynucleotide" refers to a molecule having a nucleic
acid
sequence encoding SEQ ID NO:Y or a fragment or variant thereof; a nucleic acid
sequence
contained in SEQ ID NO:X (as described in column. 3 of Table 1A) or the
complement
thereof; a cDNA sequence contained in Clone ID NO:Z (as described in column 2
of Table
1A and contained within a library deposited with the ATCC); a nucleotide
sequence encoding
13
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
the polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as defined in
column 6
of Table 1B or a fragment or variant thereof; or a nucleotide coding sequence
in SEQ ID
NO:B as defined in column 6 of Table 1B 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).
[38] In the present invention, "SEQ ID NO:X" was often generated by
ovexlapping
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
1A, each clone is identified by a cDNA Clone ID (identifier generally referred
to herein as
Clone ID NO:Z). 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.
Furthermore, certain
clones disclosed in this application have been deposited with the ATCC on
October 5, 2000,
having the ATCC designation numbers PTA 2574 and PTA 2575; and on January 5,
2001,
having the depositor reference numbers TS-l, TS-2, AC-1, and AC-2. In addition
to the
individual cDNA clone deposits, most of the cDNA libraries from which the
clones were
derived were deposited at the American Type Culture Collection (hereinafter
"ATCC").
Table 7 provides a list of the deposited cDNA libraries. One can use the Clone
ID NO:Z to
determine the library source by reference to Tables 6 and 7. Table 7 lists the
deposited
cDNA libraries by name and links each library to an ATCC Deposit. Library
names contain
four characters, for example, "HTWE." The name of a cDNA clone (Clone ID)
isolated from
that library begins with the same four characters, for example "HTWEP07". As
mentioned
below, Table 1A correlates the Clone ID names with SEQ ID NO:X. Thus, starting
with an
SEQ ID NO:X, one can use Tables 1, 6 and 7 to determine the corresponding
Clone ID,
which library it carne 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
14
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
of the Budapest Treaty on the international recognition of the deposit of
microorganisms for
the purposes of patent procedure.
[39] 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 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).
[40] A "polynucleotide" of the present invention also includes those
polynucleotides
capable of hybridizing, under stringent hybridization conditions, to sequences
contained in
SEQ ID 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 8 and 9 of Table 2 or the complement thereof, and/or
cDNA sequences
contained in Clone ID NO:Z (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 1B or the complement thereof. "Stringent hybridization conditions"
refers to an
overnight incubation at 42 degree C in a solution comprising 50% formamide, Sx
SSC (750
mM NaCI, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), Sx
Denhardt's
solution, 10% dextran sulfate, and 20 ~g/ml denatured, sheared salmon 'sperm
DNA,
followed by washing the filters in O.lx SSC at about 65 degree C.
[41] 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 incubation at 37 degree C in a solution comprising 6X
SSPE (20X SSPE
= 3M NaCI; 0.2M NaHZP04; 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.
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
In addition, to achieve even lower stringency, washes performed following
stringent
hybridization can be done at higher salt concentrations (e.g. 5X SSC).
[42] 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.
[43] 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).
[44] 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.
[45] 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
16
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
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 hems 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)).
[46] "SEQ ID NO:X" refers to a polynucleotide sequence described, for example,
in
Tables lAor 2, while "SEQ ID NO:Y" refers to a polypeptide sequence described
in column
6 of Table 1A. SEQ ID NO:X is identified by an integer specified in column 4
of Table 1A.
The polypeptide sequence SEQ ID NO:Y is a translated open reading frame (ORF)
encoded
by polynucleotide SEQ ID NO:X. "Clone ID NO:Z" refers to a cDNA clone
described in
column 2 of Table 1A.
[47] "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,
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
17
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
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.
[48] 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
signal transduction
pathway component polypeptides (including fragments and variants) of the
invention for
activity using assays as described in Examples 3 ~, 39, 49, 52-57, 64 and 67.
[49] "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 Iess activity, and most preferably, not more than
about three-fold
less activity relative to the polypeptide of the present invention).
[50] Table 1A summarizes some of the polynucleotides encompassed by the
invention
(including contig sequences (SEQ ID NO:X) and clones (Clone ID NO:Z) and
further
summarizes certain characteristics of these polynucleotides and the
polypeptides encoded
thereby.
18
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
:-:
a~
a
OA
a~
a
...
0
o a
U
~
o .-. . o
...,., i a\
~ ~ ~"',~~--i
. ~ ~ ~''~N ,-i ,-ir--,-,
~!. v
~ ~
:'Q y ~ ~ ~ O~v0O ~ ~n~ '-~d-
~"~,~
O
c ~ U _ ' 0
N
~ ~ -1 a o ~ x ~ ~
~
~ N ~ ~ ~
E ' d'M N ~-'~r;,-i
~ O ~ d:
~
y '-'~,~ N oo~ s0 ~ l~oo~j ~D~tOi ~ Cf1
O
h''O O O O O p O O O ~ r
-~
M d=
O i ~ ~ V'1l~~
N ,-Vj~ , N N N N M d- d'm
.~. ~ -,
~
~ ~ M t~
C~.' N ~-.~.'v~,~ ,~~ O -"_~,~ O 9,~ ~, ' ' ,..!,
~' C7_ ~ ~ O _ P~ _ v~'~ ~'~."~s
C7 C5 C~
Zs O
~ ~ ~ ~ ~ ~
O O ~ O O O
N
~ M d'~l ~ p~d' ~ OOO M O ~ ~ l0V1 0
-' N N d' O d- N M t~
'
' i ~ i , ,~N i M d ~ , i i i
i
O ~ b~A~ ~ , ~ ~ ~ , ~ , ~ m _~'
~ ~ O ~
.~ O v~C7 ~ ~ v y, v~~ ~ C7C7 ~C
A O ~ O O
z
O O N_
M
i
O ' '
0
FBI M V>
's
~ [~M
_
O ~ 0~0O
U '"''
r 00ov
.,
A
'"_' W
N
00
~z x x
w
a
N
H
19
CA 02395816 2002-06-26
d' M cri ni N N N N ~ ~ .-i ,-i ~ ,-i ,-i ,-; ,~ ,-i ,-i ~ ~ ~ ~ _" ~ ,-i
Q1 ~ ri ~p ~ V1 00 M ~ ~ d' l~ N t~ O~ p~ pp d' M ,-i
V1 00 ~] ~ M M d- ~ \O tn ~ M O~ 00 ~O d- ~p 01 \O l0 ~D ~O l~ V1 tn 01
tn V1 tn ~ ~ ~--W~ ~ N lD M \p V> ~ O p M d' ~ l~ l~ I~ M ~O l~
O O O p O O O p O O p p O O O p p O O O O O O O O O
xxxxxxaxxx~xxxx~~xaaaaaaax
d' M ~rj ~.rj N N N ~j N ~ .-i r.i '-.i ,-i ~ ri e-i ri '-i ,_i r-i ~-i ,-i ~-
i ~ '-i
Vi ~O p~ d: ~ ~ M pp cV M oo O O ~ t~ cn OW V 01 ~ p oo ~p ~p l~ pv
O V~ N 00 M ~p O 00 V) V1 O1 ~ N M M ~f' l0 O ~ 00
N d' oo d- ~ N t~ ~ d' V~ ~ M ~D in N N ~ N V'yp ~D ~O t~ oo ~ t~
O O p p O O O p O O O p O O O O O O O O O O O O O O
!T! "L , l rn !T! !T! !'T~ , 1 ",1.'~ !T! ~ rn ~S! "1~ ~I'! "1~ !T! ~ !T! .~
,1 ,~ .. 7 ~l , l ~ 1
M r,-~~jd'~.j~pO ~Ooo ~ O N l~~i~D 01d1p ~p p ~ v-i
N M d-~ a1 ,-WOl~oo O N ~ ~O~ Ov O M v~l~ N N d'
-i N N [~1M M M M d'd'd' d'd,,d' ~ V1~ ~ ~ ~ l0
~ N ,~N
7 ~, x a d ~ c7c7~ a ~ a c7a ~ ~7
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
M pp V7~ ~p (sl~~OM ~ M O .-,~O.-~O M p~ 00N N
r--1N M Ct'00 p M l000 ~ ~ M ~ l~Ql O ,-I l0 ~ N M
,_..~N N N M M M M M d'd' d'Ct'~ V77 l!1Vl~
~ N ~ ~ ~ N ~ ~ ~ ~ ~ ~ v~~ ,'~~ .~~ ~ ~ r~ S-~
~ ~ c~a, ~ a ~ ~ a ~ a a a a ~ ~ ~ ~ ~ ~ ~
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ,-i
cd
~ r-;H ~ '"'~~ ri~ ~i ~
00~ Q1 N O p u-iM ~ M O
fxO ~ a
'~ ,-
x a x ~ x x x a
M
N cd
i i ~
~ ri r -i ~ r ri
O ~.jd' ViM ~ ~ ~jo v0~O ~j
o
O H
O O ~ O
0 ~ o '
z ~ ~,x r-a
/1
~O
Srioo,-~,....,N N N N ~ ~ p ~ ,--~,-i, , , N , M
~
N c~ ~ ' ~ ,.r,~
s-." ;
~ ~ ~ ~ ~ ~G ~ ~ ~ ~ ~ ~ p O
O O O O O p
'
01~OO ~ O '~''~.,r~-'d- ~ ,~00 M [~ O
' . oo - ~n o
-~N d ~ .~..~ ,-y.,~O ,--,d ~ ,--,
H
N N ~ ~ N N ~ M
~ b0c~ s~~,~ tiU ~ .~
,'
_ _ _ _
C7 <C~ v~L7C'7P~ v~H ~ ,~0..~ ti~ ~ ~ C7v~,.~rn
O
N
H
d'
N N
H H
N
M
H
O
M
H
r-1
H
M
21
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
Ov M N N N ,-i~ '-'~"i'-'~-~,-i
'-r
~ ue
R~ ~Y O ~ O ~nO N d'~ oo ~
d
.
, O O O M
O d'0o l~O N O
~O
' ~ ~ x o x O ~
O
r~ r-a -~
r
[..
i
M N N .--ir"'~-'r-,-i~"',-i
r'
,~ op ,:~01. .. M ,-i\O41
a O O O ~ O ~ O O O OO
p
G7
N
M d.d' .,O1 '--~~ 00 O ~ M '"i
mn ~ N V;~ ~ y'"~ d' (~
~ ~ ~ ~ ~ CJ
p O ~ r~ p ~ C~
''-'~ ~ O O p O p ~ ~ O p O
N ~
p~~' +~d' ~ ~ O O ,-~~ ~D \O
M M d' M N d'~Op~ ~ ~,~ M lD
~ i i
i i ~ ~ i i i
~ Q, ~ j p 'i'~-'~", ~ v~
H G7~ ~ H ~ , ~ ~ G7
~
01 ~ O
O ~ O
_
M
O N M
o
o
V7 N
i
i
M ~ O N
d' ~ ~n
d\
N
D\~
M
O
U
Pa
x x
d w n
22
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
b
-i,-;~ ,-i~ a1d1 ~ M M M N N N C~j(V,-i~-ir;,-i~--;'-',-i,-i
00M '-i
O ~ dN'V-~-~n O d' ~ ppr; ~ ~ ~ ~ p vi~ ~ p oo N ~ d
O O O O ~ a O O O O O O O a a a x OCR N
a a a a a ~;~ a ~ a a x x ~ p
.-i,-i~ ~ ~ ,--i lfld'M M N N N ~j(VN ,-ir-i,~-i,-i~ ~ '-i
,-i
~
d'M ~ ool~~p ~ N d-oo~ l~~ O '"'~O~ Ov ~ ood' O ~''~'"~~
O O ~ ~ ~ ~ ~ N N ~ ~ ~ ,M-iidue'M ~ ~ O O
O o ~ o ~ ~ x O ~ O O O O O o O O ~ ~ o~ o~o ~ ~
O
O
o
O N
r;~,
N cn C7
O O
p ''-''-'
"''CfM
N
O O O
s~~, s~
dl
N
O
r
d'
N
N
O
W
M
W
U
x
23
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d- M
~-i~--i~--ir-i~--iri~-i~-i~--i~ ~--iri ~i~ 01 ~--i~ M M
N N d' O M 01 N ,=-iO ~--~~ \p O O
M ~ l~~OO 01~ M M d-d"M ~ 01
O M l~l~00 l~'~V1 M [~l~l~ ~, O lp
O O O O O O O O O O O O p O ~ d ~lO O
~ ~ a ~ a ~ x x ~ ,~,~a x ~ ~; N ~ ~ a x
.--i,-i,....;.-ir-i.--i,-i,--i~~,.-i.--i,--i,--i,--i N
_..c~ic~'i
~ ~ '-'~ ~ o
N D ~ ~ oo v'iN O ~ M 01 0ov'i ~ N o cV
d WDO ~ O v'~M '"''N d't~ V~~''~ ~ p ~ in~'N
' O O O
N
'
d ~ ~p00l~ 00O M ~ O I~I~ l~\O O O M V1
O O O O Q O O O O d ~ ,'1", ~ ''~C',Q
O
~
~ ,.
~,
d>00~ I~ ~ M ~p~D
i
rig~ O ~ b~UN br.,D
~, d w ~,d w ~ ~ ~,d
U o g U o 0 o a o 0
~ '
~ N p~ O '''d.,--,ao
-, M ~ N N ~ ~' M V'7~n
~'
a~ _~~.L_~~ p,t~ p riwi~
x C7d C7C7 d d P~~
O
O ~ O
d'
M
\OM M
i i i
N M
M
O
N O
1 ~ d\ D1
d' N
O O_1
d
l~
U
x
24
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
o '-'
N ~j N '-',-i~--~,-i,-i~ ~ r...;,-i,-~,-i,-iri ~-i,-i~ '"1r-iN ~''fx ~p
~O ~
M oo ~i~ ~ o ,-i~p op~ ~' oocriSri~ l~
1nd- O ~O'"',V1 ~j'l~00 00ppM d1 M l0I~ ~ ~IO
O O O O O O O O O O O O O O O O O O O O O '~ '-a
x ,~ a x ~ x x x x x ~ x x a a a ,~a x x ,~ ~ a;
~
N N N N ~ ~ ri,-i~-i,-i.-;~-i,-ir-ir-i,-i,-i~--ir.i~-~,-i~ O _
\O
~ uiN ~OM ~ ~i'i--~~ O o0 00 d'f~;p
I M N V'00 ~ ~ l l~~ l~OI M ~ ~ ~
V7 O1 N
~ 1 I~ V10 ~ M O
p V
O O O O O p p O O O O O O O O O O O O O O
x x x V7C/~ x x x W .-~ M
dl
~ O d
N ~p
h ~ N N N N N
o ~ ~ ~ ~.
o
~,c~ ~ ~ ~ ~ N r1j,~ ~
,
a ~ ~ ~ ~ c~
~ 0 0 0 0 0
0 0 ~ 0 0
~ ~ 'Cf'w I
M 00 ~ Cf1~ ~O M n
t~01 ~ ~ ~ N N N ~ ~O,-,
i , i , i i , i ~ i
aw'cd t.~,p cd :.,O v~byp ~
_ _ _ _
H ~ v WUP-~d E-~a. ~ ~ P.~~U
N
M
M
M
M
O
d'
N
r~
x
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d=d'M M M M N N N N N N C~jN ,--iri ~--i~ ,_;,~,-i,-i
d'~D d'O O ~ N Inl~ ooO N criOv~ ~O~.jO '"'o 'pV'iM t~,-;
p opo~ ~ ~ ~ ~ ~ ~ ~ ~ O oho~O~ N ~D~ pMM O d-d'N
a a a x a a a x x a x x x x x x x ,-;
~"'l~ ~ ~nd'd' cncriM m N N ~j~jN N ~jN ~ ~ r;r-i,=i ~O
O
x
a
d' Ovlflcnt~ - W a> ~n~--'d' O~oo~ ~ O ~''~~ cVopO ~ O d'
~ ~f'~Dl~d' l~t M V1M ~ ~OM ~ '~tnN ~' ~D,-,00 ,~l~l~
x l~ l~l0~Ol~ l~l~d' l~d'd' [~d-~O tn[~~'M ~ ~ ~ [wM 00
O O O O O O l~O O O O O O O O O O O O O O O O V1
a a ~ O ~ ~ x x x x ~ d'
a O
O
x
~ O N
,~ N N N
C~ ~ ~ ~,
7 H L~
p p O O
O M M N N
N ~O
N
v~~. tiD~ ~
~ E-~~ d ',
C~
26
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i,-i~ r.;,-i,-~,-;r; ,~~.-i,-i,~,-i,~,-ir..;,~,-i~-' ,-ic~j.~J:N N
O d' M c~jd' N ~ op l~v'jv'ioo,-iO N ~ ~ ~j ~O p ~ N ~p d:
~ O M ~ N ' O
O tryl d- ool~~n ooOv ~ ~ d ~, O ~n~
'
O V O ~ \O ~ ~ ~O M l~\O l~~O~OV7 p V'7~ ~ ,~~ ~ l~
O 1 O O O O O O ~
O
O O p O O O O O O M O O O O O
x x x x x x x a a ~ a a x x x ~ a x x
; o v~x
~ , r.
-i,-i~;,.;,-ir-;.-ir; ,--i,-i,-i,-i'-;,-i,-i,-i,_;~; ri,-i t!'jM N
~ 0 M ~ M ue M OWO ~ ~ h ~ ~l'~ cV
O V1 ~ N l0 d d'~ ~ d O o M d"d '"~ ~ M o O l~l~ \D
' \D~ ~ O ' ~ o
O ~ ~ O
d. M p l l 0000 l l O o
x x x ~ 0 ~ ~ 0 ~ o o ~
. .
-1 -1
0
o
~o,~
~ ~, a
c~ ~ 0 0 0
0 0
~ M
~r ~ cCi
_ _
M
M
D1
d'
O
N
N
N
N
r~
x
O
27
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ~ r-iri~ ri r-;r; ~ r;r-i,-ir--irir.;'-~~i~i~N,
l~ ~ O
N ~ ~ ~
d ~ ~ ~ ~ d p p ~ ~ ~ ~ 1
- ' 0
rte,~ x ~ ~ ~ ,~,r.~r-~r.~~lo x r-~~
N ~ ,--i,-i,.;ri ~-ir-i,.~r;,-iri ~--iri,..~r-ir-i,~
O N O ~ ~ c~no~od~ ~ N ~ O ~ ~ N M N in
~ ~ d'N ' ~ ~ - d'
O O t~cnO O O O d l oo D ~Dd O O
O O O O O O O
~ a ~ ~ ~ r~i
d= v-iop
d' ~ ~ N
~
N
~ ~ ~ ~ a
~ ~ a a
~ o o ~ o
0
o
~ oo ,~''"'M ~
N
' Q
s-by _~; w p
. ~ [~"N ~, _c~
% s~
C
M
O
N
N
O
d'
al
d'
01
O
a>
28
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
ri ~
(V d: N ~ ~ o0
O d' N
~O r~ O
01 ~ N ~ o r.~~ r' cad
r., N N
....
~n ~ 00~ p ~'Or'
~ R~,~, 0 00
Q' Q'C ri,''~'''~'' ''~''
ON ~ d'N ~ M ~ ohoN ~ ~ ~ ~ N ,~-,N ~O~-i
~ ~ ~ ~ ,-~,-,N O ~ ,-~,,-1..~(VN c o M ~ d'd'
~1
Q.N ~ ~, ~ ~ _ ~ ~ ~ ~ ~ a' ~ ~ ~ ~ ~'~ ~ ~
M ' ' O
i ~'C~ C7, ~ ~ , ~7,. ,s c ~'. c
,~., ~ .~ C'7 ~',~ r~ ' ,~
~ 0..H
o U p''H ''a~ o o ~"'~' 0 0 0 0 0 0 0
~
O O O O p o o ''_'.,-~.,.~~ ~ ~'-' O ~ O
O
p d' ~ ppN o0M
0 N
N ~ due.~ ~ p;, r''~ o ,-,_N..,i,-~-i,-~-~N N N N M M d d '
N -
' R ' ' ~ ~ ~ ~ N ' ' ' ~ ~ ~ ' ~ ti~ i i i d ,
~ ~ i
, s..~ . v , s N ~ ~ , ~ ~ ~,N , D w ~
, . cc3 y ~ ~ s- ~ s..
v~c~t~ ~
p ~ E-~~ ~ ~ , . ~ C7 P H C7L7 U v~ E-~~ ~ v~ ~ ~ v~v~
~ H H a
.., ~ ,
d w n
M M
N
01 N
N
N (~~
M
_
N
d\ d\
O
O d.
a
x
x
N
29
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O ~ ~ N
r; ~ ,-i..-i,-i,-~ Ov OW . M cncncn N
N
!y O ~ ~ o ~ 00 ~ G~ O ~ ~ M ~ d0-~
~o 1
r-)O O M O ~ ~ ~ '~',,O O d O O
O O ' - ' O
O ai
~
r.~,~l~ ~ r-a r; ~ .~:~ x a a i-~,
t
~.
CV,-i,-i~-i~--i '~'tcnM M N
M ~n~tvi ,-i ~' O '~ ,-i N
a\ ~ ~ ~ ~ N O
N O
O V1l0l~ O O N V7 V l~
' 0 0 0 0 t/7 ~ ' ~ ~ 0 0 1 0 00
00 ' 0 00
,2 ,
, 2
,
N wi~ ~ N ~ ~ N
O O al
~ oho o ' ~--~.-~,~N
~s~ ~ ~o ~ ca"p '~
C'7H E- ~ (7E ~ ..
H ~ ~ ,
O O ~ O O ~ ~ ~ ~ ~ O p O
+~
N l~'-'' N
N oor"'00o M ~r~ ~ N ~ ~ a\
~ p p ~ ~ _ ~ ~ ~ -~, ~.:
~ ,--~
~ ~
H _ 0.~P~~ C7 ~ ~U d ~ ~~ rnC7
C7 C7
d-
~ ~ M 00
O
O V7
i
i
O N M
M ~' V1
N N N
O
O .
O
l~O O M
M
d1
a
x x x
M 'Cf' V7
CA 02395816 2002-06-26
N N N N N N N N N ~-i ri ,.._; ri ,-i ,~ ,-; ,--i ~; ri ri r; r; ri ri ,-;
N ~ ~ M M M N M ~ ~ ~O O O~ d' ~ M ~--~ N ~ O l~ d' dW
~n ~ ~O O~ d' ~ d' O ~ ,~ N v1 ,--~ N cn
O O O o p O O O p O O O p O O O O O p O O p p O O p
xxxaaxxaaxxxx~xWxxaxx~xxxH
N N N N N N N N N N '"' '"'' r-; ~ ,-i ,-i ~ ,-i ,-i r-i ri ,-i r,; ,-i ,-i ,-
i
O ~''~ cV vi v'i ~ Vi ,-i 'd' O ~j tn ~p ~j M O l~ ~ ~ oo ~j M M t~
O V'7 ~D ~ ~ ~ M N ~ ~ O ~ N ~ in N cn Ov oo d- l~ ~O o0
O O O ~ ~O ~ ~ l~ t~ ~ ~ N ~'~' O N ~ N d- O cn ~ r-, ~ ~ O
O O O O O O O O O O O O O O O O O O O O O O O O O O
"L f~ !'h rn ,~ ,~ ~ ~ .~ J ~ ~ rn ~ rn rn ~ "T~ ~ ~ ~'h ~ 1 ~'h ~ !T!
31
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
'--i,_jy -iri '-ir-ir-i~-iri~--i'~ , y --~M
N M ,-iO ~ 01d'O O d1~ M ~ O
x
"'~ o ~ ~n d'~ ~ d' ooin~ v1
'
N d I~l~~O V1~OO ~ I~l~~ ~O ~C
O O O O O O O M O O O O O ~ ~i
x x ~ ,~a a a x ~ ~ a ~ x x
N
-i'--i,-i,-;.-i,-i,-i~-i~"',-i,-i,-i~ ,-i~
ue
N M ~ ~ ~ N d ~ ~ O
N d'~ ~ ' ~ O O
~ p d-\Ol~ ~ O p t~ l~l~p M ~
p
~ p
x ~ a ~ ~ a ,~
M
~ ~ N
vj ~ ,-i
N M ~ ~ _i~ M
H
O ~ ~ ~ ~ %
O C
~ M ~ O
~O N tn O V'1
1
i , ~--~N ~ N
-
GA t~v~~ ~;j, s.'.s~
_
~ C7 v~C7 v~ C~
d\
O O
~
O ~ N
N
i
M
N
~D ~ N
_
d w D
M
h
x
x
32
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0
_;~"'' a\ d= ~ ., ,..," .. .,
.,
-; -1 , op N N ~j ~ ~ ,-~,--'-ir,~ ,-'
~
N ~ ~n ~ N O ~ ~ ~ 0 01 v0
00
~Y~O '' N y 0
~ 1
O ~ ' O ~ ~ ~ O '~O O O p O O
O
x x ~ M a o a ~
~ x o x o ,~ x a a a a~
N ~ M
N ~
r-i
.. M c~jN N ~ ~-;ri ,-i~--i'-i,-i,-;
,--i
-i ,~ O .. d'
i M O ~ l0 ,--i'~l~ d''O'~ ppo0\O<l'M
O~
O ~ 01 p O ~ l~ \OM d' N V7~ M N d'01 O
p O
O ~ ~ ~ O O O O O O
O ''x ~ '' O 0 O 0 O
~ ,
cd ,. ,
~, ~
M
M ~ ~ ' 1
~,
r,,~0 Vi
O d' N -,
~ tip.~,--,N ,
E~~
.~va 0..~V
O ~ ~ ~ N O 4 O
~. ~,~ ~ ~ a>~'
~' ~'
r ,~ Cn C~,~ C7~U ~ C7
,
O ~ O
0 ~ d\ N
,-
~ 1
N ~ d1
' ~
M ~O
M
N ~ N ~ N
d' d'
N p o N d1
0
~ ,
,-
O
x x
x
x
d,
33
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
i O 'O N
'-- ~
-i M .. ., c .. ,--icd
C
''_'-i .., ~ N -i~ ~--~' ,-i.-.;'"'r-i,-, ~ .-i
~--iO1 ~
, v ~ , ~
01 ~ ~ ~ ~O!-, M ,--~o0
N ~ O
~ O N ~ ~ ~ O o
o
O ,0O ~ x O 0 r0 O O x x
., ,
~ a ~ ~ ~ ~ ~ ~ x r-a N
.,,
cn .. .. ,.
~ ,--i.-i.-- y j ,--ir"i,--i'"~rir--i~--~,--;~ ~-i ,--i
00 ..
01~ oo d'N ~ M ~O ,~oo~pN O ~O"' (VM ~--~ ~ ~ d'
0oM lw n ~n O oo O O N ~ ~ I~O ~ inM V1a\
O 0
O O O O a ~ ,"r,0 0 0 ~ ~ 0 0 0 p ~ 0 ~ "x,0
V
7
N ~DN l~ 01 M N O
~ 0 ~ ' ~ ~
0
~ p ~ ~ ~ ~ ~ N i 0
1
l~ i i .~.Q., j ~
a.,
H
N ~ ~1 0 0 0 0 ~ ~lO O E-',~
0 O
+-~ +r
p O O ~ M N ~ O O N O O O 0
d1d' O N l~ p~ o ~p ,-~O N N d1 ~O
r, d'~O ,-~,-~cVN N dw D ,--~,~N d' ~Oo0
~' O ~ ~,~"'~ ~ 'i' O ~ ~ r~~ ci W b
'"~A
~ ,. ~ , ~
C7 P 'J 'Uv~Q',Q,'~l P ~ 'U CiQ',ra H
..i -~
M
O
O 00
d>
i
N
O
M d. M
d'
N
O
O
N
M
x
x
O
N N
34
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0
~ M M M N N N N N N ~' ,-i~-i,-i'""'
'-'
IxO '-'~ O~d- '_'~O lp~ ~ 01~ ONO'~~'~ M
O N O ~ O
O
p M x'~ x ~ '~'x ra~ r~~ x ~ W -x E-~
H
--i ~ d'c~iM ~jN ~.jN N N ~' ,-iri~-i~
vD pOVp~ '"'0100v0 ~ O N M oo,_-iO d'~O(V ~
N ~ d'd1l~ M V1N M
O O O ~ ~ ~ d'O d wo t~~ '"',~M N ~
N
O ~ C/~~,O O ~ O O O O ~ O ,,~0,O ~OO ~,
O
M
~
~ v~~ ~ ' ~ N N M
ri ~
_ ~ cd ~ ~ ~ N N p,
bp
~ ~ 0 ~
O O O -'O O
~ +-,,~ N r ~ O +~
W p ~ ~ ~ N ~ ~ O
--~dwo
O' v~r~ bA~ ' ~
a ~ H d ~ cC 5 ~ v a
~
, c c ,
0
0
M l0
\O O
N N
N
M
V~
N
~U
x
N
N
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
-i,-i,.._;,-ir;,-i,-i'"',-i.-i~ ,~ ,-i~ ~.rjcn ~'i(V
N ~ ~ y 0 d' ~ ~ 00 0oO ~ O W O M M ~ ~ ~
O
M ~ ~ ~ ~'' ~ ~ ~ ~
~
~O~O d-~p~ ~ ~ v1 ~ N ~ t
W
O O O O O O O O O O p O ~ a O O O O p O
O
x x x a ,~a ~ x ~ a ~,x ; ~ x x ~ ~ x
x
~ ~
-i,-i,~,-i,-i~ r-i'--~,-ir;,_;'-.;,-; cncri~'1~'1N N
ri
00
~i'i~'N oo inl~cV d',=ioo ~j ~ dwn o0 ~ ~ N O
~O
O
O O p O p p p O 0 0 p 0 0 ~ a O O O O O OO
O
x ~ x ,~ ~ x x ~ ~ a
M
"
N d~ ~ N d' O 01.--,
~ M
i M i ~ 00
C7x
d
O ~ ~ ~ O O O p O
O
d op ~ O ~ N y 0 a1~ ~j~
' ono
_ ~
~. ~ _c~ _~~'-' _cd~
v~ ~ld''~ ~U-~-.f~ d'ra!~~U
E-
due'
O ~p
d1
v0 d'
l~ M
N i
M
M N
M
M ,
N v
d\
O
N
x
M
N
36
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O N
rj,-i,-i,~r-i,-i'~~ ,-i,-i~ ,-i,_;,-i,~-i~ d1 p oo \OV'7d' crj
viO ~p~NoMO~N ~ ~t v0~ ~ ~ due-~ O ~ ~ ~M ~ M v0
O ~ d'
-a~io O ~,r~ x x r~ ~ x,r~~ r~r~~ p" N r~ ~ ~i ~
r~
-i~-i.-a'-~e-1~--i,-~~ ~ ~ ,-i~ ~ Ol \O~OV1 M
M
N ~ N oMO~ d.d'~ O ~ ~ M d0'o O p d'O ~ 010~1~
O p O ~ O O O O O O O O O O O O ~ ~ O O O O M
~ O
O
G7
0oLp,-;vDy D dv N l~op"O
N N N a WiM ~ O ~, ~ ~i O
I~~ x v~H U an.~~, j ~' ~ ,-~lC5 ap
0 0 0 0 0 0 ~ o o ~-'o o ~ o ~
O~ ~ N o ~ d' oo o
N O N N O ~ ~ O1(VM oo O ,.-~~ N
~ v~d d v~vo 0.. ~ C7~ ~ ~ v~~Cx NO
f~ N
Hd
N
O
M
01
O
M
N i
d'
M
N M
N
N
d'
x
w
a
x
N
37
CA 02395816 2002-06-26
m N ~j N N N N N N N N N N N r'' '-' r'' '"' ~ '"'~ ~-' '_'' ~ r' ~"' ,-i
'", V1 ~p ~ M_ O~ l~ d1 \O N '~ '~ t~ ~O O ~ ~ ~O ~ l~ ,-i
d'
d' d' ~ N ~ ~ O d' ~ ~ ~ ~ oo ,--~ ~ O N ~ °~ ~ ,.~~ O M v'1 O
VO'7 x '~' ~ x '~' ~l '~-~ ~l ra vp7 ~ x ~ ~ x ',.~'' ~ '~,' x x x H
M M N N N N N N N N N N N N '"' ,-; ,-i ~-; ,-i ,_; ~-i ,-; ,-i ,-i r.; ,-i
01 O d' ~''~ oo ,-i ~ ~O 0o ~O O o0 M O ~ ~ 01 01 d: M p~ 0o V1 p o0
'~' N V1 O M V) ~ ~ lD ~D ~ V> O1 ~ ~ ~ ~O V1 ~ M M p ~ V~ 00
I~ d' M l~ O l~ ~O l~ l~ V~ O O O M
O O O O O O O O O O O O O O O O O O O ~p O O O O O O
!T! . 1 rn rn !T! . 1 rn !T! !T! . t . 1 . 1 . 1 . 1 !T! !T! !'T'! !T! !T! rn
!T! Lr !T! !T! rn rn
-iN O O N cnN ,-i l0d' Q1N urn
in~ ~ M M ~ ~OQv M ~ N 0 M p~ M
N N , , M M 00 d-d-due- v1~n
i ~ C."~ _ ~ O ~ ~ ~ _ _ _
_ ~ _~M 5-~p ~ V~~."v~ ~
p ~ O O O O d' O O ~ O O O
a~ dN~' i
s-..t'.,t ~.Q, ~ ~;_cd p a., yipri wi~
N ~ cnv~ vo,--~ y",.s;~
H v~, d Q; d C7O I~H
N ~
rn M
~
v~
~
,Wn
~.-a
~
38
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~ r-i~-ir.;~--~~-;ri~--ir-i~--;'"'',~.~.-i~-i,...i,-i,~
0o cYi~ ~p d'p d'l~ O a '"'01OvN l~N t~p
N ~n~ ~p ~ ~ O V1 a1~D~ r"'oo~n M ~ in~p
r~ r~x O '~~ ~ r~ r~~ x r~r~O O ~ ~ C~
-i ~ rir-.;~ ,~.-ir; ~--ir-.i~--~~-i,~~-i~--i'.-;~ r; ri
o~oN cN~ O ~ ~ O ~ ~ ~ trjN ~ N oOoM c-~n0
O ~O ~ O \O ~"~l~~O00 ~D~Or''M ~ ~ V1l~l~O V1
O O O O O O O O O O O O O O O O O O O
~ x x x x x ~ ~ ~ x x ~
N ~
~ a;
, ~ j,c~N ,
E-~ U
0 0 0 0 0 0
00 ~ ~to 0
'
~ o
~~ x
M
O
O
O
d'
M
M
N
M
D\
39
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
cd O N cd
r-i .. ,-, ~ G~.., .. .-,
O
O ~ p ~ O
,~ O ~ N '-' ,.~ O
-i d' C/~ . d' O V7 .
~jj ~ ~ N O o~o
01 ~ 00 ,-~ P~ O ~--i o0
O
x ~ O ~ x
O ~ ,-i N o 0 N ~ ,-i ,-i Vj .-i r-i
N N N N M M M ~p Vj ~ ,-~~ oo d- ,-i ,~-~ ~ Vj ~ .-~-~ ~ cn
oopoo000~;~t~oo~;U~0..o~;~~oo U
-, N ~p ~ ~ ~ 00 0o O O ~ ~p ~ O O O O ~ O O ~ ~p
N N N N N c~n M ~ 01 ~ ,~ ,_, ~ ~ ~ pMp ~ ~ d\ ~ ,M-i ,-~
N N ~ ~ ~ ~ N ~ ~ ~~ ~ ~ ,~ j~ ~ ~ ~ ~ ~ ,~ O _~
H ~ H ~ ~ ~ ~ ~ ~ r~ ~ ~ ~ ~ ~ ~ H P
O ~ O
N ~O N O
N N
due- M ~ N
N
M .~ M
O ~ O
d>
r~ r-a
x x
N N
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O ~ O
a\
~p~ ..~' r''
O ~ p ~
. rno
M H ~ v~ ~
N ~
H ~ H ~
H ,~ 00
O M M ~D ~ d-V'1~O H
O M O
~ x o o ~ ,~~ oo
M
O N ~ _ ' ~ ~ N N O
.-..~ d1~ \p l~'"~l~ ~ ,-iO d ~ ~ '
-i
N in ~ Srid'~O' ,-,N ~n l~oo4j~ ' , ~ ' ~ ~ ~ '
" ~ '? J
~, s W ' i H i , m , ~ s~cat , ,
~ ~ ,
o ~ ~ ~ ~ ~ ~ ~,~ ~ H ~ ~ ~ a ~ ~
H ~ ~ ~ ~ a x ~ x ~
0 0 ~ 0 ~ 0 0 0 0 0 0 0
0 0 0 0 o o 0 0 0 0
O N ~
~ M M ~ ~D ~ ~ O O CI'N M ppO [~ O ~ o ~ N M
O '
d;,~ ~ N d' tn ~ cnv7,.-~~ N d' ~O~ ~ H ,~,-,N N N M cnd
0 O ~ O ~'~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~' j ~
;.,s.. 7 i.. ~ ~ , ~ 7 ' x , , ~ ~ N , ,
s ~
~ C I C ~ ~ ~ U C C ~ Q, ~ A.,U C7c~,~ C7
, 7
O
N
N
, M i
i
O H
d.
M ~. M
O
O
H
~
H r1
H
U
x x
N
41
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O ~ ~O
N
d\ U7 ~ .-i
ri
p ~ ~, cn
O ~' -~ O ~
p ' ~
~ x ~= .~ a ~
0 ; a
N o v~o N
'--i.-i N ~ ,~
.-i
~ d O
d'M 0 ~ ,-~
O O ~ ~ O
~O O
x
00V~01 O d'l~ O ~ M
~'O ''_'~ ~ ~ ~ O o M ~ 'DO ~ =
O
" ~ - N N ~ ~ , N N O~ ,. , '"''N l 'd~
d . O -, O ~ -~
~ ~ ~ ~ ~
~'~''a W ~ ' ~ ~ .~ ~ ' ~ ~ . ~ ~ ~, '
i ~.
-, ~ b N N ~ ''~.,~ Ga~ N N ~ ' ,,.~,~ , ~-'cn~
A ~ G.i
p ~ ~ ~ ~ ~ ~ ~ ~, ~ ~
Q
'
O ~ ' O O O O O O ~ ~ O O ~ O
~
M ~pd. d"p .~'~ o M ~ .d.,O .~'-~.~~ M ,--~d.-~ ~-'\D
l~ ~''' ~O M .N M
-
.-~N O~ ~ d> Ol~ d lflOl~
M ~ ~ ~ ~
O ,~s...~',P, ~~'.~s: i~~ ~' ~''~ "~S'"~3's~~, ~ '~..,'~'m p'~ Q
a~~ ~ ~ ~ c~a ~ v~H c7 ~ d c7. v~ci H C7~ U w t~ a,
i
o ~ o
M
r t i d.
d'
N ~ N
d\
O
01 O
N M
42
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N i
,...., ~i C~jr r; ~-i,-.~
O O N ~ O M N
O ~ ~ O O p O p
x ~ x x H x ~
N .
riri N .--i,-ir;,-i,-i
r-i
p ~ p O N ~ O O ~
o ~ ~ O
o r1
p
x x x x
~..
.~
o ~ ~ ~ M M ~ ~ ~ ~ ~ M ~ ~ M
~ dl O 41
M M Q w --W--iV1 l ,~~p M O M ~ V1
op N N N ., d- pp O N N
, ~ N ~ ~ v , : '~~i ~i ~ N ~ i
~ ~ ~
al~ ~ ~ ' j,~ ~ s. Q. c
~' ~ d; ~ ~
, ~ ~ H ~ a a ~ a c~. ~ ~ ~ ~ ~ ~ H ~ a
~ H
a ~ ~ ~ ,
E~0 0 0 ~ ~ 0 0 0 0 0 0 0 0 ~ 0 0 0 0 0 0 0 0
o ~ ~ ~ ~ M inp N l~~ ,-,~ p N p ~ ''J''~M ~ p N l~
.,... N N 01 ' o ~ N N d '
.N d'( p l~,-.,d ~p0 ~ M ~''Ov.~ <h \ O (~,-,d
M ~ i ,~ ,-iN N N N M ~.r~i M ~.,~,~ [~,-,,--~N N N
b~A~.b~A~ ~ ~ ~ ~ N N o ~ ~ ~ b ~r b
A O
c~ ~ ~ ~ ~ ~ , ~ , ~ ~ ~ ~ ~ ~
~ ~ ~ ~
~ ~ a a ~ w ~ ~ a
o ~ o
0o N N
N M M
M
O
d>
O
H
U
Q,
x
M
43
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
O~ CV ~O V'i d' M ~''~ N N N N N '~ ,-; ,-i ,-i ,-i ,~ ,~ ,-i ,-i
O ~ l~ ~O l~ ~-i d' ~ M 01 ~-i d1 d' pp p O M_ t(j O t_n M
~'~~~~O~M~000~~~NV>100O~~1fl
M o a a °a ° a ° a a a a x ° x x x x H x x
d' M M N N N N N ,-i ,-i r"~ ~ ,-i ,-i ,-i ,-i
O 01 ~ M d' '~1" ~ M V1 ~ O O '-' '"' ~--i O N
l~ M d' l~ M O ~ ~ 000 ~ l~ \D O d- ~ M p ~ '"'1 M
O O d- [~ [~ ~ pp [~ M M V1 O O
~~O~OOOOO~OO~OOOO,,~O.,,
M opd= ~ .-i 01 ~ ~ M m N O~o0
- W ~ O ~ O ,~ V~ O N ~ 00
O
M M M d'~ ~'iV7'~ ~ ~,N M M M M
i
. M OZN O N s.,~ b ~p~ cd
N ~p
a ~ ~ H ~ ~ ~ ~ a a H ~ ~
~ ~ ~ ~ ~ ~
0 0 0 0 0 ~ a ~ 0 0 0 0 0 0 0 0 0
0 0
_ ~ ~ M
00,--~M 01 V1M O ~ d. O~.-id'l~ Ol
M M M M ~ N l~'~ rl'~N N M M M M
~;O ~ ~ ~ s~.~ ~ p R.~~ t;~ ~ tip
, ~
M
O
N
d'
O
d'
O1
N
M
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
ri .-ir-;ri r,~-i~ '~~ ri,~ r-;~ .-i
N ~ ~ ~ ~ ~ ~ N x
O O O O x
'-a~l~.-a~l r-a~-1,- , a rp : '~ ~
j x'
d d
r-ir-i,--i,-;,--i,-i.-i,--i~ ,--,,-i~ ~ . ,-'
r;~
r'N iriN ~ ~OaiO l~01~ op VOvpd~
O d'~ oo ~ ~ ~ d'M 01N ~p~ N N
0 O
~ O IO~ M I~~ ~ ~ ~ ~ O M N d' ~x 0 rx
~
~ ~ ~ 0 0 0 ~,
~ a ,~~ x x
O ~ h
N o
N j o
V ~ ~ ~ ~ ~ N o0
~ p ~ ~ ~ ~,~
b0, , , ,
N ~ ~ ~ ~ ~ ~ ~ pp~
O O 0 O O O o ~ _
Ur
O ' .'-.~,~,~,
.,~,."~ d"M 01'N ~-'p O
~OO
,-,~.,.~~ ~O~O M
,Lp,N ~' ~ v~~
Qr~ ~ r~x ~ ~ ~..'r~~
N
O ~ O
O
' ' '
'
d' ~ N
M
d
'
O
O~ O
d>
A
W W
x x
M d'
M M
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M N N N ,-i,~,-ir-i,-i~;,--i,~,.._;,-i,_;~-i,-i,-i,-i,--ir'',-,
pp .. _.. ..
N ~ ~ dN-~ o~pN oo~ ~ ,-N~ ~ ~ ~ ~
a 0 p ue'~p~ ~ ,.,M ~O~ ~ l0 ~ O
0 0 0 0 0 0 ~ p p o o p o o p j 0 0 0 0
M a ~ a ~ ~ ~ x x x x ~ x x ~ a a 0 x x x ~
N N N N ,-i~ ,-i,-ir;,-i,-i,~r-i.-~,-i,-;a ,-i,-i
,-i
pp .... .. .. ..
M~N Vi00M o000V1 ,-rM Vj~ O p 00 CI'~--~M M O~O '"iO \p
N O ald' Vlp~l~ -~,--~p N VI~ N ~ d'O ~ O M N d'
O ~ O inI~ l~N ~ d'O ,--~d' O M ~O N ~ oo ~OooM ~ l~N
0 0 0 0 0 o p p p 0 0 o p o 0 0 0 0 0 o p o 0
x x x ~ x ~ a
M ~
N V'iN d'~O
00 d.ppO ~ ~ d-
0 O M
0 ~ 0 ~ .~0~0 i
+~ p0pp 'U0
N '~ ~D~ O N
in ~ l ~ ,~,-,
N N N ~ N O
a a v~~ ~ x w N
~
a
a
M
O
d-
M
O
d'
d'
N
46
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
-i~ wi~~cnM cncncn cn~.jN N N cVN N (VN
O ~ y p ~ N 000oOv oop oo ~ ~ p Wi Ov~'
~ O M '-'~ ~ ~ ~ ~ N O N ~ ~ ~ ~ O
'~ O O O O O O O O O O O O O O O O O
a G7x x a ~1r.~~lv7',.~,'~''~-~-~,~~l r.~ N
O
O
O
v1d'~''~M cricriM cn~j N n1N N N N N
-i .... _..
00~ O c-~n~ N ~_''~~ ~ ~ ~ O ~ N ~ due'O O
O O ~ O a ~-1~la o O O p O y
O
v'i..N 01,.d'~,-'
V7~ ~ Q1' ' 1
W_,
N '~ ,~C7 ~ O
O ~ O ~
+.. .,.,~ O p
M ~ l~N \O'''
C~~ rigx A..,C7
a\
O
d'
U
x
M
47
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~;,-i,-i,-;~--i.-i,--i~ ,--i,~,--i,--iri~"i-i '"r;~-ir;,--i,--i,-.i~-iri
dM'O dN'~ O .~ N d'~ N N ~ ~ i p ~ ood'O WEo0r-i
~pV1 ~ O O O O p M O O O d"~ M O t~j~ ~ ~ ~ II1\p
O O O O O O '~ \p
~ x x x x x x x x x x ~ x x ~ a a a a a
~;~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ x ~;~; ~ ~ ~ ~ ~ a
p vjO W l~01 uiO oo l~O ~-i~ p N ~ ~ ~jN ,-al~oo ~ V'i~;~
N d-d V N 01 ~ d\,-,O~~ ~ V'~~ N ~ ,-~O l~O WE l~~ O~
d'O ~ 01d'v1 ~ V~~p V1~ d-O N l0~O ~r1,-yn l~d'M l~V~O
O O p ~ O O O O O O Q O O p O O V1p O O O O O O O
~ ~ x p x x ~ x O ~ .~ ~ ~ 01
x x 00
O
O
48
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
a1
ri~-i'..''r-i~i~--i.-;r-i,_..;,-r 01 N r-1,~ ,-ir-, .-ip~ tncri~'1N C~jN
~OV7 .~~O~ ~ p l~wj O O V~1~ ~1'd'l~ O ~ d1d'~ cn ~p,-i
O ~ ~ ~ O ~
O O O O O O O O O O ~ ~lO O O O ~ ~ O O O O O O
a ~ x ~ x x ~ ~ ,~ ,~ ~ N a a a a ~ I~~ x ~ ~ I~
-i,-i~ ,-i,-i,-ir;,-..-;.-i,.-i ..,-i,--i,--i,--i,-i ~fid'cnN N N
00~ oo O t~'-'N o0
O O O ~n~ ~ M ~ p ~ ~ O O O ~ ~ V~I~ O O oOo~ ~ ~ N O
O O O p O O O O ~ x O O O O O ~ ,~ O O O O O
x ~ x ~ i~ ~ a a x ~ ~
a;
0
0 ~ ~ ~
O , ,U. "'v~
O '~'O .~.~0O ~O .a.~0O
O 00d'~ ~ InM
M Oi~ N N N N
.~,a: f~~.j,>. ~ cn
v~', v~vo...,
V7 r~x
O~ O
I i
M M
N
N
O O
O
N
N
W W
E-i E
x x
M M
49
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r-i,--ir;'"'r; ,-i~ .--ir;ri
N v'iN
M ~ ~ O ~ ~ ~ O d'~
,.
~
~ x a a x a a a ~
a a;
~ (V
-i r-i,~r-;,-j~--i~--iri ri.-~r-i~-i
N 01pp,-i ~ M V1
\O d'd'M 0 ~ o ~ ~ ~ p ~ r~
O O p O ~ 0 N O
0
O p O O O O O
N oo~ ~ N N N N O N
~
i ~ ~ ~ ~ ~ ~
y ~
. ~. ,--i~ ,~i
H ~ ~''N U'~ ~ ~ ~ W ~ a>
' , ~j [ , ~ ~
-
O G~Q~ C/~O O O O
p O p N ~' ~ +~O .~-~E-~O p ~
.,~ O
M ~ O M
N (V N ~ cnN
a W ' r~ ~,Q.,~ N ~ ~ '~
''
>, c~~, W o 'U ~ x ~, s-i C7
~C '~d ~ d
E-~ v~,~ , H P
d' r.,
00
O
in o0
N
N
''-' 00
N
N
O
O N
N
O
H
M
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
.-i~ d'cfiN N N N N ''1'-'r.;,-i,-i,-ir-i,-i,.~,-iri'"i
.. " .. ,-i
O I~M M O1l~00 [s.~~ ~ ~j~ ~ O ~ ~ d-1nO
O O O O O O O ~ O o O O O ~ ~ O O M
M W x a x a a a ~ a x ~ x x x x a a a a V7
n ~''~M N N N N ~-'--~,-i.--i,.-i,-i,-i,-i.-;r-i,-iO
O
xx
~
,-i
tipp1d' ,-i01,~ p1~p~ v yp~ ~O ooO M ~jd'a1~
l~~nN OvM N ~nl~l~oo p ,~00 0od'~--~\OI~O 00
O l~~ V1p ~ ~O\O'"~~p d-d'v7 \OO d' \Ol~00d'
O O O n-1~ ~ ,~'O,O O O O ~ O O O O ~
OO
O ~ d-
(V~1 M N ~
c- v
~on '~
O O O N ~.
V~H O
O
oMON ~ O _
r-,
cV M M N d'
H ~ H C7~ C7
00
N
O
N
M
N
N
due'd'
N
O
a1
O
al
GO
N
x
M
51
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
,..., N
-i'-i~ d1~ M N ~j,-i,-i,-i,-ir.;,-i.-i
p "
0op ,-~~ O d ~O O ~O O oo~p wtl~ 01
'
O O O O O O O O
O O O 'C d ' p O p Q 0 O
~'
a H a x x x x ~ x x ,~ ~ x
~
,,._, M N ~.jN ,-i,-i'-;r-ir;,-i,.~r;
~O~ Vj ~j ~ ~ d1 cnp~~p cric_nd'~ N ~ wj M O tri
N ~
O ~ N ~ ~ O n
o N x O p ~ ~ ~ ~ O o O l O o 0 0 0
o O o O 0
O
p O o ,~ O O
x ~ ~ ~ ~ x x x x x x
" n 1 ~ ~ N ~ M ~ ueo 0
N ~.c 0 ~.,~Vj ~ d d'
-
~0 00N ~ ~ ~ ~ ~ ~ ~
~
bD~.~ ~ ~ ~ ~ ~ ~ ~,N ~ j '~'S" ~ .~~, N
r' ~ G
~.a~a , -~
a~d ~ ~ d C7..a~ d ~ ~'. a vaU
.
~,
H o 0 0 0 0 ~ 0 0 0 0 0 0 o
0 o
+.~ O N ~ O N ~pd. ~ M
- N ~ d'~ ~ M I~ 0 N l~~ M ~ ~ 0 ~O~ d-
0
Ol M d V~ p
p
,j~rigR~Gr v~~;c~bi0y~.,'~v~ ~ ~ ~-~ ~ ~'~ ~ .y-~rcd
c~ a ~ ~ a H ~ ~ ~ c~x c~~ H ~ ~ ~ ~ ~ ~ ~ H
M
O ~ O
~D C~'
~O M O1
d' 00 O
i i
l0 ~--~ M
O
d' V1 d'
d\
d'
N ~ O
d,
x
H
x
O
~h
52
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r-iM C~j''~~ ~ riri ,-i~--i,-i~ r-i N N ~j ~--i,-ir-i~--ir-iri
N ~--i
~D 0 i h h
N ~ p ~ O ~ ~ ~ ~ ~ ii~''~ue"n ~ O O o
1 t o
O
~'O M ~D~ v1 ~ d o ~DO N
o
I~ ~ 00I~ ~Dl0\O O ~ V1d'M
~ x x a ~ x x x x xx
~ a a a a a ~ x a x
M N ~ ,~ ,-i,-;,-i,-i,-i,-;~-, C~1N N ,-i~ ,-i~ ,~
~--i
00 O~~O~ d',-i~.jcnV~0001 i _ ~ '"'~O M
V1 ~
p ~ ~ ~ ~ o
0 p o
V
1
O O lW h ~ ~ V~~ ~D 0 00I~l~ O O ~ '~f~ p M V7~ V~
0 . V~
O O O O O O O O O O O ~ ,,~O O O O O O O O
O
Q' ,~ ,~"~L~ "~,~J ,~,~~7,~ Q' ~ ,~ ,~rn5._,'""~'i
d'
'
N ~ ;' ; ;'.-~,--~N N M O r-i
00v~ ~ ~ ~ ~ ~ M I i
~ . N ~ ~ '
, ~
~ ~ ~ ~ ~ x ~ H H _~,
~ O O O O O O ~ ~ ~
O O O
O
~ ~
~'V)lD 0 M 0
0
p
-, M o0~ ~ ,--~,-~~--aN N
~
~ b tiJ~~ ~ C~.vwi W, j,~
0
~ ~ ~ ~ ~ ~ ~ H a '' ~ ~ ~
~
r a c
M
i i
O
M
M
~ N
Q M
d\
M
N
C7
x x
53
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O ~ o
N ~
-i,-i~--i.-~~ ~.-id ,:-i ~.,,jM cnM cVN
' N
~
~ ~ ~ N O x O l ~ ''iv'iO ~Ocn
0 ~ ~ ' ~
G~ ~2!voin d n V~
d in
O O _ O O '~ ~ ~ 0 ~ ~
O ' ' r ~ ~ 0
-1
-1
~ x a x r
~ ~ ~ =
-i,-i,...; ,_; d M M c~ c~N
N
N ~ N '"'N M i ~ ~ ~ 01 d'01d1 pvcri
~ ~ p O ~
p
p ~ p ~ O ~ p ~ O V1 ~ O
O O fx fx O O O
O O O O x , ,,~O O O
O
~ ~ x ~ ~ a x x x
~p ~ N ,-i N .-iop~
~O
O r'~ ''~ N l~d' l~'~;' ~ N
i' N
~ ~ ~ ' ~ '~
~ ci~~ j,~ ~ ~,~, .~... N
~, N
N ~,, d U' ~U,.~C7 ~, ~~a~ ~,H E-~~ v~
.- c~
-) r~C~ ~ ~ a
O O O O O a O O O O
O
O O O O O O
.~ .,~.~.~ ~ Oy O ''"'''-'''''~ V1 0101
O
~ ~ 0 ~ H ~
~ N ,-~ 1 N
0 N
i ~ i , i i ~ ~ i ~ ~ ~ i i i
bD ~ v~~ c~i~ t~~, ~ Gp~, byG~.W n v~
s-.~.-y,N ~ N ..~i~ _ s-,v~ ~.,v y, ~,~,
~a
C7~ ..-a~ ~ E-~C'7 C7 ~ ~ ~ ~ U ~ ~
C7
0
M
M N
'-' d'
N
i
M M N
dl
a>
M
N
a>
r' O
M ~p
W
U
x
dM-
54
CA 02395816 2002-06-26
N N N ,-' .-i ~-i ~ r-i .-i '"~ ,-i ,-i ~ ~---i ~---i --i '-i r-i ,-i ,-~ ri r-
i ri ri ri
~01N~ OMO~d~"c~j~'~..~O~OON~dd~O~O\D~
OOpOO OOOOOOOOpO00~~00p0o000
xa,~~x~,~,~~~xxxxxx~,axxxx~,,~a,~
N N ~j N ~ ,-i ,-; r"~ --i r-i ,_, r-i .--i ,~ '--i r-i ,.~ ,.~ r-.i ~--i ,-i
~-i ,~ ri ~-i ,-i
M '"'' d' N N o0 ~ '-' ~' ~ O N ~ O N ~ d~ d' '-' ~ l~ \O ri
N ~ N l~ ,-.., ,-., ~ V~ d' V1 M 00 ,_, V7 01 r-, ~ M ~D p~ d" M d' l~
N N ~- '"'' ~ N ~p M O M d- d' O p V) O M O N N 10 ,-~ ~p ~O l~
O O O O O O O O O p ~ O O O O O O O O O p O O O O O
!T~ !T! rn !'r! ~I"! rn rn !T! rn n !'T! h'! ~ ~'7~ ~1'~ L. M ~ M 1 1 1
N ~ [W,.-i~O M M .-iVj
'
O M d l~M d'd-a>~ N
M ' ~D l
M ~ M d ~ ~ ~ 'p~
~
cd~ i.,f~
c~~ ~ _ ~ ~ ~ y~" '~~~
~ ~c~c~ x
O ~ O O O ~ O ~ d O
V1o N M Ov ~ ~ ~ O
N
0...., O
~ ~ a ? ~
N ~ N N N ~ ) ~ ~
~ ,
v~ v~v~v~ A,~ ~ P,U
~
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O M
-i,-i,-i~-~r''~-iriri,-i,-i'"'' O\~ ~ ~ N
_ _ _ ooO N
O O ~ ~ M OOOM M ~ ~ '~ ~ ~
O ~ O O O O O o ~'~' ~ rx'00
a a a x x x x a a ~ x o ~ ~ ~;O
O
a
a
~;~ ~ ~ ~ ~ ~ ~ ~ ~ ~ a
N
N
M d' 01d'~ O o00oN oo~nM ~ N ~ N M
OOOl~ 0~0~O~ M M l~l~ l~~ ~ o O H O O O
O ,-1O a O ~ C/~a ,~ O O O fx''x ~r ~'~'OOO
l~
O
O
p1 M
~ x H ~ 00 O~~ ~ 00
~ a ~ a ~ ~
+~O.~-~O~O+~Op -NO.NO.~.~0+~O.NO
M
~O t~M ~ ~ p~d' ~
b4~ R..~ ~.~- p Q, N p
~ a w E-~A.,~ P-~Q,
O ~ O
s
I~ O
O ~O l~ a1
00 ~ d' N
N , , 00
' O oo
N v0 0o N
v~n1
00 l\ M O
N
O
a
x x
56
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
(vj~' ,-i'-i,-i,-iO O ~, N ,-i~--~~ ~ O
n ' ,--~,-,00
v o ,N-,O M O
~
~
O O O O O O 'C3 ~ '-' xrO
x ..~~ ~ ~1~ ~ ~ x x ~)a t
N , N s
N i i ~ i , ~ ~ d
~~ .-,- .--~ ~ ~ C~j'"r-;,. ,--i
N ~ O d'N d'~ ~ ~rR.iO~~j ~ 1pM ~O
O ~ ~ O ~ N ~O v~
O O 0 O O ~ p x'O O O O O
O
a ,, o ~ ,. ~
~,
M v'i~O ~ N ~ ~ ~ O
-i oo~-,~ oo N N N N Ovoo O ~ ,--~,.~-~ooN
,-;~ a ,-~ ~ ~ , Q.~
-~
~
~.. ~ c , ~ a ,.~, ~ ~ ~ ~ Q ~ E-~~ C7
n n H l ~ ~ ~ '
~ ~ ~ C ~ ~ ~ ~ , ,
~ e~ O O O O O p O p O O p O
p '~'p ~ O ~ ~ M l~tn oo~ O O N d' oo\pa1
~'M ~ 01O N ,...,~p~ ~ d~~po0
N
N ~ ~ N ~
v~ by,~ ~,~,~.~ bybyc~ v~~!,~ ~.tipbyc~ci~
_ C%C~C/~ ~ ~ ~ ~ ~ J V ~ ~ ~ ~~
~ E" , , r-C C 7 ~ t
~
O
O ~ O
M
M lp
i
~
M
d1
M
d' ~ lfl
d>
M
W
x
_- ~~ - . _ .
_
57
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ,-i M
-i ~ ,_.; ,_; l~ tlj d= ~,,j ~.,~j c~j N N fV N N N N N (~j N N N
p~ ~l Ix O d' dwo ~ oo ~W p oo M
O O ~ ~O O ~ l~ l~ \O ~ ~ ~O ~ ~. ~ M ~-' l~ in ~ M ~D
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
M N ~ Vj ~ a a a a a x x x x x x x x x ,~
'--i ,..~ l~ trj d' d= M crj M ~,j N N N N N N (~j N N N
~ O vp ~ ti ~' l~ d' p1 ~ ~p v0 ~ M (V Vi CO ~_n c_ri O N O (V
[~ O In ~ [w N ~ ~ ~ l0 l0 d' p M O !I7 O l~ d' ~ I~ M (~
a o o ~ ,°~ 0 0 0 0 0 0 0 ~ 0 0 0 0 0 0 0 0 0 0
Q' "S,'' ~l d' ~,' ',L ~ .~ .~ ,~ '', L'~ rn ~ ',1,'i '~'i r~ '~ ~ ,~ ,~ rn
r; r;
O1
N M M
~ x ~ ~ c~
~,
p ~ O O O O
0 0 d'M M N ~--~
-~ ''~~N M OO~
0..C70..P.,E-i
N
O ~
M In
M M N
O l~
i
O
N ~ ~O
d'
M V~
N
dl dl
N
W
w
x 'x
a,
58
CA 02395816 2002-06-26
N N N r-i ,-; ,-i r.; ~; r; '-i r; r-; ,-i ~--i ,--i ,-; ,-i ~-i ~--i ~ r-i ,-
; ,-i ,-i ,.~ ,-i
d' O ~ ~ a1 v--i ~ ~D d' d' 00 01
~ oho N ~ ~ ~ ~ ~ M N oo O v0 N oo d' ~ ~ oo ~ M v0 p
O O O O O O O O p O p O O O O p O O O p O p O O p O
,~,~,~xxxx~~x~,~xxxaxxxHx~xxHx
N N N N '"i ''i .-i r"~ ri ~ ~ ,-i r-i ri .--i v--i r-i .--i '--i ,~ r-i .--i
,-i ,-i ~-.i ,_;
~t ~ oo csj O v~ d: N p a Vj O~ O O~ O v'i oo ~ dv M d= cn vri 01 Oi
t<7 I~ tfS ~ l~ al M ~O N l~ ~ ~--~ l~ O tn M ~ N Lp O\ l~ M l~ tn tn
l~ l~ h N '~ N ~-'~ ~ d' ~ O ~ M O N l~ M V1 O r--~ Vl ~ ~ M O M
O O O O O O O O O O O O O O O O O O O p O O O O O O
1 . 1 . 1 rn !T! ~T'! rn !T! rn !T! rn !T! !T! 7 !'T'! !T! !T! !'T~ !"I"! . 1
h'! !T! !T! !T! !'N . 1
59
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ..,--i ~ .,00
r--i~--iriri'--ir--iri~-ir-iri~--i~ ~-;.-~,~ri V~ '"'i ri
V'iN Wit'M ~n ~"'~O W ,-.M O O o M due'~nO
~ ~O~ ~ l~ V100lfl~O~ d' ~ ~ O N x ~, d-
-a ~ t~W o M vo vo~ ~ ~ w o d- ~ O ,- mo~ x
O O O O O O O O O O O O O O O O '~ x O O O
a a a a a a a a a x a a x a x ~ ~ N a x a
M ~O l~~Od'M a V'iN d'(V~ cYiO oo~p N ~ ~ O ~i'M
N M d'~DO l~V100 ~ V1~ d'~ 00[~ N O V>M lD~ ~
0 d wD~Dl~oo M ~DM ~OO ~ l~f u~N d' O O N ~DO
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 ~ ,'I,'0 0 0 0
~ a a ~ a a v~ x x x a
N ~p
O ~ M O
~
O O O ~ ~ ~
~ O
~ O
O ~-~M d- N d'w ,-~
d'(w --~ M
i i i ---~
d'
i
i i
w ~ ~7c~ a ~ d
c~
M
O ~ O
r1 r-I
'.O
d' l~ l~
.--~~ d-
i i
O
d.
0~1 _N
d\
O
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i N
(V 01
M ....., N .
O N N N ~',--ir'r"',-~,~',-i,--i,-i~ v1 .
O cV~ ooON~p N O N 01O ~ 01p , ~
O O O O ~ O O O O O O O 'd O
M C~~ r~a ~l1~ H G? a r-~~ r~~ N
M N N '",,--i~--~,-i,~ ,-i,-i,-i,-i,-,
01l~ (V~ O ~ '~N v7t~~O d'l~ ~ O
O O o00~ ~ ~ ~ dNO O ~ ~ ~ ~ ~ O O O
~..ao 0 0 ~ o ~ ~ ,"o~,0 0 0 0 0 ~ v~ O
N a1 d'
~n u'it~~ ,_,,.-~~ ,~~ oo r.,,-~~ O ,M~N
' ~ o0
~p ~_~ 'i', ~'~ i,~ d ~,~, ~ N ~ l
~. ~
O~
''
U'~ '~3~ a ,i~ r~ ~ ~, ~ C~~ !%~~,O~"'C/~'~
~ l ~ J f3 ~~
r ~ O O O O O O O C ,
~ ' ~ '''' '~ ~ ~
O _OO '"' ''-'~ ~ O .,~ O O O
~ O i N N O
d' O N N d't ~ o 0o p ~ d-~ N o0
n o
l~W --yr"-,,~ '~~ M ~ '_'i~ ~ M ~--~Vl
i i i i ~ ~ ~ i 01
i ~ i i i i , i , i
i
C7C7 C7H C7 rn~ H ,..~h, C7 P-.~ v~~ C~ x C~
f-
o ~ o
N d1
0o M l~ N
~r1 v"~
, ,
i i ,
O
N
N ~ M
~ N N N
O~ ~ ~ ~ N
O
M
61
CA 02395816 2002-06-26
~O vi tn ~ d" d- M M M M M M N N N N N N ~j N N N N N N
01011~~~ ~.~.~ ~rM-~,N-,pNdM'~t~~ M~o~otj~
l~ M l~ V'7 ~ O d' 00 ~ V~ '", \O M V1 V1 O V~ O N
O O O O O O O O O O O O O O O ~ O O O O O O O O O O
~aa~x~axxx,~xxxx~xxx~xxxa~a
00 ~p vi Sri ~' '~' d' d' M cn M ~ej cn N N N N N tV N nj N cV nj N N
~f' ~p O ~ ~ "'' ~ oo l~ O p ~.j d' d' d' ~' N oo O p oo ~-i
V7 N ~O N ~ ~' v1 0o M ~ ~ M d' N M v'7 ~ ~ ~"' N ,-, N O~ d- 01 N
~ M O ~ ~ I~ ~ lp U7 M I~ ~ ,.~ M M d' l0 ~ O ~D ~ O l~ V7
O O O O O O O O O O O O O O O O O O O O O O O Q O O
1 rn rn rn !T! !'1"! . 1 . 1 !'1'! !T! !T! rn . 1 !T! rn rn ~I'! !T'! !T! !'N
C.~ !'t"! !T! C... . 1 . 1
M ~ 00O
dl
~ ~ a ~ ~
0 0 0 0 0
O N dM'
i i r
,
'V~C7~)r~C~
62
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
N N N N N N '"~ ,-i ~ ,-i '_'" ,-i '-, '"'~ ~ ,~ '"'~ ,-i ~-i ,~ ,~ '-i ~; ,~
~-i '-i
~ N N ~ O ~ ~ O N °o N o0 N ~ ~ d- O O N O ~''~ N tn °o N
O O O O O O O p O p O p O O O O O O O p p O O O O O
axx~~ax~x~x~xx~xxxxxxxxxxx
N N N N N N N ,-i ,-i .-i ~~ ri ~~ ,-i ~ ,-i r-i ,-i ,-; ,.1 ,-i ,-i r; ,-; ,-
i ,-;
V7 ~ ~O ~ M M d N 0o O tfj O d1 ~ M !~ O M ,-i ~ O tfj ~p h o0
~ M l~ d- V1 O ~ ~ ,-, d' d- I~ O M ~ O~ V'7 N [~ ,_, M V1 ~O ~ l0
l0 d' ~ l~ l~ ~O ,-i N d- ~''~ O M ,--~ O ~ V1 ~ ~ d- N O O M <f' N
O O O O O O O O O O O O O O O O O O O p O O O O O O
1 . 1 !'1"! !T! . 1 . 1 . 1 rn rn rn !T! rn !T! L~ !'T'! . 1 !T! !T! h'! 1 rn
!T! 1 rn !'T~ h'!
63
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
i i
-.i,--ir; r;,--i~--i,-ir-i.--i~--i~ir.;r-.ir-r;~- ~;r.;r-i~-i'"'~
N cnp ,-i~ ~.jr-iv'iM OvN oo t~ooN oo ~ ~-iO V'i~ N ~ y O
N M ~ ~OW O ool~v'~ooO~N ~'~ ~ V~ '-'~V~o0 ~1 ~ ~ -'-C,'
O O p O O O O O O O O p O O O O ~ p O O O O O O
x x a a a a a a a a a ~ x x x x ~ a a a x a x ~,
d'O l~~DM ooM ~ M ~ M o001O 01 v0p t~ nj~ M l~~jN
V1~ M d'I~ ~OO ~ 00Q1\O M ~ l~M M d-l~ 1n 'CI"~O
t~7~ ~ ~O~ l~ l~00~ l~l~~D d-~ ~ V~ d'l~l~ l~O M l~O O
O O O O O O O O O O O O O O O O O O O O O O
G7G7 ~ ~ ~ ~ x ~r~ ~r x ~ G7x
O
O
M
d'
M
N
d\
64
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M lp
[W ~ ~ V"1 Vj d= d' d" d' ~: d' M M M wj
O ~ M ~ ~p O~ 00 ~O Vj wj ~ M l~ 00
O ~ l~ d1 ~ l~ N tn O ~ O ~ d- 01 V1
O ,..~ ~l Cl1 ~ ,~ ~ x ,~ ,,..] ,~ ,~ ~ x r~'
--i oo ~ ~O V'i trj ~i= d= d' d' d= d' d' M M M
d~wo 0o d- M '"~ ~ d. l~ N ~O ~n a\ M d' d' so
Op~~~OvNl~pp~~~ ~~v~ION
,.~ ''OZ'' OO OO 'pz'' 'O~' 'per'' n O ,.O~G, O O O ~O ,per.., ''O~' p'~,''
"O~'
M
~
d V7M ~D ~
; ',~Q.rig~ ~, ~ N
_ ~ ~ ti ~
~
L~ o ~ "~U "~ v~
o 0 0 ,
0 0 .~ o
~ O O
''~~OOOM O M O ~ .,J
M ~ O N d- I
d'
-~,-,,-, ~,
O O
F-~E~ C~C~~ a c~ ~ 0.~ ~ a
r-. ~ ,
a\
N
N
N
N
N
x
d'
CA 02395816 2002-06-26
M M M M M N N N N N N ~.j N N N N N N N N N N N N ~j N
N ~ a t_~ Ov O v'i ~ O cV ~ ,-i cn N ,-, t~ M ~ p ,--i M d' O c'1 0o Yj
d- ~ 000 ~n ~ ~ ~ N N p O ~ ~ O tin O dM ~ ~ l~ V1 ~O ~ ~ N d-
r~ a a r~ ,~, x x x x ~ C~ r~ x r-~ ~ x ~ r~ rW -.a ~ r~i O CW.-a
M M ~j ~j cn ~j ~j N N ~j N ~j ~j (V ~j N N N N cV N N N N N N
r'' ~ 'd' ~i ~ oo p O O ~ M ~j p ~ ~p d' d' ,~-i ~j a1 d' ~O ~n N d'
Vl d' \p tr7 d' t~ d- 00 O e--~ ~O \O ~ M M M ~O d- ~/' \O l~ l~ ~O ~' O
v~ ~O ~ \p v~ l~ O ~n ~ O N ,-~ O O O ~O N p ,-a t
O O O p O O O O O O O O O O O O O O O O O O O O O O
!T! 1 ~ 1 !T! 1 rn ~'h !T! rn !T! , 1 G.r !T! rn !T! ~'h G~ rn , 1 .1 ~ 1 ,1
~'P~ rn _ 1
66
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
N N N ~ ,-i ,-i ~"'' .-i ,-~ ,-~ ~; " ,..~ ,--i ,-a ~ r; ,-i ,-i ,-; ,-; ,-i ~
,-i ,-i r-i
00Q~d'_l~N V1~O~0~~~~~M~OOl0~0M~MOl~
O O O O lOp O O O O O 0 ~ O O O ~ O O O p p O ~ O O O
aaxx~xxxxx~~,xxx~xxx~xx~,xxx
N N (wj N '"a ,-i '"' r-i ~"'~ ,., ,-i ,-i ,.._, .--i ,-i '..._i ,-m-i ,-i r-i
,...1 ,-a r,; r-i ,-i ,-i
v0 r.i ,=i l~ ~ d' ~ N ~ '-' ~n O N t~ N vp r"' oo M cV p~ ~D ~p O ~n
V1 O~ ~ d1 ~ ~ ~ 00 ~ ~ O \D ~ ~ ~O ,~ M O~ M M M M <f. ~ V~ V'7
l~ V1 O l~ N ,.-~ ~ N N ~O p M ,-i ~ d- O d- N M l0 O O M V> O M
O O O O O O O O O O O p O O O ~p O O O O O O O O O O
1 . 1 rn . 1 !'1"! rn !T! .n !'T'! !T! . 1 rn !T! . 1 !'N rn !T! !'f'! !T! !T!
CJ !T! rn !T! !T! !T!
67
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
f-i ,--i ,-i ,-i r.i .-. ,-i .--i ,~ ,~ .--~ ,~ ,-; ,-; ,-i ,--i ,-. ,-; ,--i
.-i ,.~ ~i ~-i ~ r.; ,--.
Wit' M Vj Ov o0 00 0o c~ ~j O ~n ~ M ~j O (V O ~ oo ~ 0 ~ °~ p 0
~0
01 W tn ~D O Ov M ~ ,~ oo N ~O l~ O ~O v1 O N N ~ ~ M oo d'
V1 V1 p ~ l~ Vl O ~f' ,~ N ~ M l~ [~ 00 l0 l~ 00 1n ~ l!7 ~ ~ M M
'F.~' rx a i-~' 'h.-~ rte' x '~-i ~ ','Or, 'i--~ ~ ,,.py-O.l ~l r0--1 ~O-1 r0-
1 ~O-l-~' ,"'0"[,a'' rte, ,.~, ~ O O
-i ~--i ~-i .-i .-i ~--i ~--i ~-i ~--i ,-~ r-i ~.-i '-i .-i r; .--i ~-i .--i ~-
; ~--i ~-i ~~ ~-~ r-i ri ri
a l~ ~ cn d' oo vi ~_o v0 ~ 'd' ~ oo ,=-i ~O cri 'd' ~ d' M w' N O oo Oi o_o
M l~ ~O M O O ~ ~O O i~ d' V7 ~ ~ ~O l~ ~ ~ ~O \O M ~ ~ M V~ V)
O O O O O O O O O O O O O p O O O O O O O O O O O O
!'N !T! ~'! ~T'! !T! !'t'! !T! !T! !T! . 1 !'T'! !T! !'T'! . 1 . 1 . 1 . 1 . 1
. 1 . 1 rn !T! h'! rn !T! !T!
68
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
ri
~ ~ N oo p
O O ~pN ~ ~ M O
x
O
O ~O
~ ~ x ~
~ a x a a N x
~ N
-i ,-i,-i,-i,-i,-i,-i ,-~
N t~N .=id'v'id'N ~ N
~ d v
M N ~ M ~ ~ Ol ' 1
d' O l~ O ~Od' V1d'O O O O [w
O O O O ~ O ~ x O O
~ ~ ~ a
p N
Ov ~ p O
1
~ O i~N N
..N M ~ ,
01 ~ O >,
~ N N
o ~,'~ ~ ~ C7 d ~ ~ C7U s~ .~~;,
0 0 ~ C7
0 0 0 0 0
p.., 0 , ,~.~.~,.~,.~E-~ .,..,o H
.,.
o 0 0 . o o
'
o ~ '~ *~~ ow o 0 00 ~nd-o ~ ,-~~ o
N ~O N N N N ~ ~
-,~ ~ ~ ~ d' ~ ,-d'
-,
O O bU ~'O t.'i.~ v~ a~~ ~ ~ ~,'O~
,
_
P~~,~ ~ a,H E-a~ ,-~~ ~ ~..~H C7Q,,-~
E-a
O ~
O
N ~
1
0
, d' d'
, ,
N d- d~
N
~ ue
d' d
'
N
d'
w
H
x
69
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
.-i ~O ~ M M ~rj N (wj C~j '-~ ,--i ~-i r--i ,-i '-.; ,-i r-i ,
~~i~d~.,~~Ne o~ONNO~~o~N d c'~ d ,.Ø)
x o 0 0 0 °o 0 0 0 0 0 0 0 0 0 0 0 0 0 o O o
No~xa~xaaxxxxxxxx~,~~~~a~
~,,j M M M ~j (y e-.~ ~ ,~ ~ ~ ,y-, .-i ~ ,-i ,-i r-i
op ~ p d; ~ Vi '--i M ,-i N M O O~ 00 ~ l~ d1
O ~ N d- ~n try op O op N ~p d' O ~ ~ N M O ~p oo V7
O ~ O ~ l~ ~ d' h ~ M ~ ~D O ~j- ~O d' ~ l~ l~ O ~ O dM'
O O O O O O O O O O O O O O O O p O p O O O
G !'f'! rn !T! .1 ~ 1 rn ~ 1 !T! rn !T! !T! !T! ,1 !T! !T! !T! . 1 . 1 rn
!'T'! rn . 1
N .,c~
''-'
O _
p N
~ .-M-~o s~
o
~ H
C7O ~ O O
O O
d' O ''JO 01
~-1'~''00M 0O
Y,~r ~ri~.nbA
0
N ,.c;..~"~s., y~
O
O
a>
W
x
~o
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
01 N N N N N N ~ r.; ,-i ,-i ,-i ~; .-i ,-i r; ,-i ,-; ,-i r-i ,-i ,-i
00 ~O .. .. .. .. .. .. ..
~-t M M 00
ON~~~NNMN~l~NV7Nt~N~oMONNM
O d' d' \O ~ V1 ~O ,~ O N M M V1 ~ ~ ~ ,-, l~ ,-, M V1
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
~x~~xx~axxxxxxx~~~~x
M N N N N (wj N r-i ~ ,-i ,-i r; ,-; ri ,~ ,-i ,-i ,-i ,-i ,-i ,_;
''-' ~ iV M_ N O ~p ,-i ~p O_1 ~ tr'i ~:rj tn ~p d= ~t a\ ~ ti'i p
O
p ~ O ~ V7 ~ l~ M ~ ~ ~ O ~ ~ O N d' v7 ~ d- M
O O O O O p O O O O O O O O O O O O O O
C ''~L,'' '.'~L.'' rJ~'' ''~L.'' rn ,~ rn "',1,.'' '"~L,' ''~.' rn '~"' '~''
rn ',Z,'' ".'~'. LT' ~J"! !T' rn
O M
M pp
M ~ ~,~ d' ~ i
_ c
p C7 ~
U
a E'' ~
0 0 0
0 0 .~+,o .~o
y n
00 N cn ,
,w0O ~ ,
~ ~
U E d p,C7 .lv~
-~
0 0
0 0
0
d '-'
d-
M
M
M N
al
~G
W
x
71
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0
,_;,-i,-i~i ,~ M N N N ~jN N N N r-i'-i,-i,-i,-~,-i~-i'~ri
a>
d'in Vi~ N O in~ cVdyd Ov ~-io0N M '"~O ~n N V~H N M
~nd' N N ~y,~n~' ~ ~ ~Ooo inm ~n oo~ ~Dd- ~ O N '-io_o
4 0 x 0 0 d ,.x'O O O O O O O O O O O O O O O O O
~ ,~ ~ x ~; x x x ,~a a a x x x ~ x x ~ a x a
.-i,_..;,~,-i,-ii ~ M N N C~jN N (V(V ~-i''~'~,~ ,-;.--i,-i,-i,-i
01d: p v'icn ~O ~ ~ cT ~--~uip 01 W n d' O '-'N I~ '"~~ ~ tnd'
~ dN"~ O p O ~ ~ ~ oOOdM'~ ~ O ~ d'p M V~'~,~-m~n0
0 0 0 0 0 o x ,~o ~ ~ O O o o a O ~ o <o 0 0 ~ O
~ M
M ,-i~ N
N'd ,-1t~.v~
.~~ '-'~d U w
H ~' d o 0 0
O
N
M ~
H
~ 1
W ~ d ~ d
M
O op
H
H
D\
t r
d'Q1
~OO
H M
.~'~D
N M
M M
dl
N ~
a1H
d
W
W
x
72
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
b
c
d
-i,--ir-i~',-i.-ir.;,-i,-iri~.--i,~ r-i,-i,_;,-i~-~,-i~"~'-i'-;ri a
,
d' ~ O N O p~,-i~ oo~ncn criv0~.-;O_~~''~oo~ oopy
N M ~ O p V~..~ ~ ~ ~ ~ ~ ~ ~ p ~n ~ c~n~ 0 ~ ~ 0
x x x H a a ~ ~ a a a a x x x a a
p oo N ~ ~-iiri~pt~l~ ~ d'~O ~Ov'ioovp c'10000 00~ p Oyc'>
00 V1H V1N N M ~D l~l~O l~d'N H Do~ H l~
O H N M t/~~ ~ ~O~D l~t~oo l~in~t'N ~D~Din d'~ ~ ~ d'
O O O O O O O O O O O O O O O O O O O O O O O O
O
d'
d
O
O
O
N
H
~r
O
H
H
M
O
H
N
_
d'
H
d'
H
N
H
al
73
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ~ ,- m;
., cat
N N N C.jN N '"~~-i'~'""~., .,.,,-~,-i.-~ 01 p
~ ,-i,--i
O ~ ' ~ ~ O ~ ~ O ~ ~ h ~ ~ O
M N d " M ~ 1 o
O o
O ~ 00l~ ~ I~d V1 l0 t~~'Ul V1V~
~
x ~ r-~x r-~x x x x ~l r.~r-~x r~~l N
N Vj .,.," .,... .,.. N N
N N N N N N (V H H H H r1r-1, r-Ir1~~
,-.~
r1
~ O i h O w ~ ooM ~O ~ON ~ ~ M
O O n o
t o
o 0 o o 0 0 ~ ~ o o ~ o o
,. a ~ ~
.a
M ~ ~ M
N ~ M O M N cn O
~ ~ ~ ~ i d-
~" v~~, ~ ~ ,-
x _ ~
'UH a~ ' ~ x ~""x ~ '
U .
0 0 ~ o 0 ~ ~
0 o o H o
~
00~no ~n o
d- .~ O
~ ~
H H ~ p1 M ~ ,~ ~O M
~
i i i m --~r i i
0..~ ~, ~ ~ i Q,
_ ~
O . M
M
O
d' O
i
i
M
N o0
O
M
\O O
d\
N
D\
D\
V~
U
W W
'
x x
a
74
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
00l~ t~~Ov'i~n~hd= d"M M M M M ~''~N N N N N N cVN N
N
O V~o~ M ~ v~ ~ ~ u~~ ~ tin~n oo ~ due'N ~ ~ Ov
p O p p O O O p O p O ~ ~ 0 ~ N M N p O O O o0
~ ~ a a ,~~ ~ a a x x ~ a a a o o o x x x x a
a
0ot~ ~ ~pvCiV'id'd= d'd=M cnM M c~ N N N N (VN N N N
N
d1~ M (V.:-ir-i,=-ir-i~p t~tnO N ~ ~ ~ N ~ \O d"r"'~ N oo~j
d.~ '"~V1l~N 01~f'l0 ~1'00~D N N ~ ~ d"O [~ I~00~ M M M
l~l~O I~l~~ ~ ~D~D V~d'M d'~ ~ l~ M O M ~ u1~O O O [~
O O O O O O O O O O p O O O O O O O O O O O O O V1
a ~ x x ~ ~ x ~ ,~~ x x x x x [~
O
O
M
0
~s
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N N N N N ~ ~',-w'"',-;'"'i,-i,--i.-i,-i,-i,-;,-;,~ ,.._;'-i
\O (Vp p r-iN dv OvO ~ d: O tnl~ ~ r"'~ ~ O tn O ~ O dv
_ _N V_o00~p O N N d'~ <''~ ~ d-,~ d'M oo t_nalO d'd'v1N O
O O O O O O O O O O O p O O O O O O O O O O O O O
x ~ ~ a ~ ~ax x ~ x x ~ x x ~ x x x x x x .~x x x x
N N N N N N N N '"'~ ~",-i~ ,.-i~ ,-i,-i,-i,_;.-;r; ,-i,-i~-.;r; ,-i
~fiO O o00o dvN ~ O ~ ~-"oo ~ N M ~ '-'~ 01N O ~ I~,-i~n
~f'V~ O d'(~]h M ~O~ M M Q1 M O~ M 00~ ~ ~ Inl~
~O~ ~ l~l~ lfl~ ~ '-i,-WO~j-~O,~M d"~ <l'O O O ~ ~ <f'M
O O O O O O O O O O O O O O O O O O O O O O O O O O
x a x ~ x ~ x ~ ~ x x
76
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r;
-i,~,-;,-i~;,~ ~ d1r.;,--;,-i,~,--i~-~;~ r'r-i,.-~,~r;.-;
O p 001~n~ ~ ~ eMn p ~ N ~ ooO v0 "
O O M d-ood-a\ '"~p dvO
O O O ~nd' ~r1~ ~O ,~~ LD~Dl~O ,~~ ~ N oo d_-,-,O
O O O O O O ~ " p O O O O O p ~ O O O O ~ d-
x x ~ x x x x ~ x ~,~ ,~ ~ a a a O ~ x x ~ ~ ~ ~,W
O M oo Wit'd'd W ~i'iO ~.j~ O ~OM cn~p x ~ N O o001 (V~ p
01,-iN l~M ~O 1'N M d-~ d' d'I~O N l~(~~ ~ d'M N O O
N N l~ ~D~ N 01~O,- y, y0 ~pl~oo~ d'M M W O ~ V1d-aa
O O O O O O d'O O p z O O O O O ~DO O O O O O p ~p
x x x x O x ~ x ~ ~ O ~ x x ri
a O
N
l~
p
O
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N M ~ d' O
--iriri r-i~.--y -iN N (~jN r'-~.-iri,-i,~ ,-ir;N .-io0
M O O N ~ ~ h ~ h ~ ~ O O cano ,--ia1
O ~ ~ d ~ x o ~ o d- ~
' o o
0 0 0 0 0 o o ~ o o o o o o o ~ ~ a o o o
~ x x x x ~ a
a a ~ x ~:~ a a x a
-i,-;,-i~ ,-i,~ N N N ~ ,-i,-i,-i~ ~ ,-i,~ ~ l~V'~Vj
crid'~.j~ ~ O Vjp~~ ,~,-ip~~h ViM pp ~ l~O y i'i
V1
~ 01~n ~ d' oo~ M v0 N l~l~~O O~O u'~ ~ lflN d-M d-
'
l~~ M ~ ~ ~ O V lpd'N O O V~N ~ 0ol~ O ~Ol~r''
7
p ~ ~ ~ x p p x
~ ~l x d x a ~lx a x x a ~l ~ x
N (Voo,-i ~O o0
O N ~
M ~ N
N '",~ N N N i
011 .i.'~ i M , ~OO~~
s ,
U ~ ~ ~ ~ ~ v' U
~ U L7,~
0 0 ~,
0 0 0.. 0 0 0
O O O O O
~ ~ N ~ ~,.,._,O .-i
d' ~n- ~ O ~ 01
p d O ,~opM N
-' "' N ''~ ~ ~
' 01 ~ ~ N r l ~noo N
bDcd ~ a~c~t~, byj, ~ N cd~ c~
~.,-i~ '.,,-.v~ ~ ,~ ~,,.~,-iN
~ C7 U I~d a
0
o ~00
~ a\
. .
M
M N
N dN-
M
N
N
O o0
d\
d
w
x x
N
78
CA 02395816 2002-06-26
d=.d.,~cf:d:wj~.,~MMM~rjwj~jNNNNNNNN~jNN N
N N
N ~ N ~ ~ O d- O ~ ~ ~ ~ M ui N ~D oo ~ ~:,,j d' 01 N l~ ,~ o0
'"' ~O O l~ N N O o M ~O M tn N ~ O N dN' ~ ~ I~ O ~ M tn V1
O O O O O O O O O O O O ~ O O O O O ~ ~ ~ O p ~ ~ p
x a ~ a x x x x a x x x x x x x x x a ,~ a x ~ ,~ ,~ x
d' d' d' ~ d' cri M M ~rj ~rj ~.rj ~j N N CV N N N ~j N (V N N N N CV
O N ~i'i o0 0o p ~O d' O N ~ oo <''~ ~ ~'w' ~O (V oo p p o0 t~ O
~O N ~O d' oo N d' oo try oo ~ ~ M oo ~O ~n N ,-, ~ ,-~ 'd' l~ N ~ O
M O ~O l~ ~ d' O N ~ M l~ N ~''~ ~ O N N ~D N ~ v1 ~ ~ O t~ l0
O O O O O O O O O O O O O O O O O O O O O O O O O O
rn rn . 1 . 1 . 1 rn !T! !T! . 1 . 1 1 rn !T! ~T~ !T! !T! M !'T~ r 1 1 M ~T'~
r 1 1
79
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
-; '"' ,-i ~--i r; ~--i ,--i r; r; ,--i ~--r ~ ,--i ~-i ,--i '--; r; r; ~-i .-
i ~--i ~-i r.; ri ,--i ,-i
O ~ in ~ ~p O o0 01 l~ o ~ V'i ~'1 ~O O O ,~ oo d' d' ~O M ~j vi
00 Q~ M ~ pp ~ ,~ ,~ V1 00 ~ tn d' V_~ V7 ~ 00 M M ~ d- ~O I~ O
O o O o Mp O O ~p O O o 0 O O O O O p O O O O ~p O O O
xxxx~x~~xaxxxxxxxxxxxxaa,~,~
c~i ,--' .--. ,~ ~; ,-~ ~--~ r; ,--~ ,--~ ,--~ '-... ,~ ,--. ,~ r; ,--~ ~; ,-
... ,
'd' ~ O r'' oo ~ Uj (V ~ a1 ~ ,_; ,=-i Oy~ ~ cn ~ ~ ~ cn N dv ~ ,_-i
V1 <j- d' ,~ ~ N d- M d' d' 00 N 00 O V1 d' l0 ~ M 00 M [~ ~O ~p V1
O O O ~ O ~ ~' O O O ~ O O O O ~ O O O O ~
O ,,,, O ~ O O ~ O O ~ ~ ~,, O ~ ~ ~ ~ O ~ ~ ~ ~ O OO O O
8O
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
o cho 0 0 0 0
01 M O O O O l0
N O .-mn tmn o0
d' ooN O O O O
-i M ~ l~l~h
N
O
i N
rt~-iri,-i,-i,- r;~ r; ~-iriri O r; ,-i,-i
~O O
~DM OvM d1O ~jl~~ ~ ,-;~ O O ~ M ueN ~ a1
V100 0001~ ~ ~ ~ M V~~ON x ~Y., d ~ . V7
- .
O O O O O O O p O O O "O ~ ~ ~ ~ O
O O O
O x O
a a a x x x ~ x a ,~,~~ ~ ~ x x ~ x ,~
, M
M M O ~ M ~ 1
O
p d ~ 00~ N , 'dO O ~ 00 .~, ~ ~ N M
p ' -~ l O _,
l~ ~n~O~ ~ l~V~~O t~in~O ~ p ,--mn m1v>
O O O O ~ O O O
O O O O O O O O O ,~ O O
~ a a x x x ,~ x x x x ~
d= ~ Vi ~p in
M ~ ,-i~ N O N ~ O ~ N
O~~; ~ O t'~ a~~ ~ c~
W
, ppap~ ~ O ,--..
~ ~,
O ~ a ~ C/~ ~,
sw r-,~
,
O O
~ 0
I~01~pN O ~ l~d
'
~ N ~ N
~ ,-,~ ,~ N
~, ~'a)cC~ ~ tip~',~ ~
v m, w . a ,
'
C7 U t~~ ~ ~ d ~ C ~
7
o ~
N
M
l
N dN'
O
w
x
M
81
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O O O O O O O O O O O O O N O M
V"1O O O O ~ ~ v> V7V1V7 00M
O~ d'
l~
l~ 000000 00000000 000000 ~nO ~ N
-i ,-,,--i.-~,---~.-~,--ar, ,-,,-i~ ~pM
,-a O
O
d' d'~ d' d'd'd'd' d'd'~n ooOv O O
O
M
M
a
c
rid
O O ~ N N M N O O ~ 0
0
Ix O ,-,M ~f'd'V7 0
h ,O0~ O , ,.O~i~ H O
, ,0~ N
o N rb,r ,
o ,
ri ~ ~ ~ ~ ri~ ri~ r;
d;
-i t~~ M V'iN oop~ ~ d'
00
~ M
O ~' x O 0 0 0 0 p a 0 0 p
~ x x
,..,~ ~--~ O M
~D N M
,_,-,~ p
, , ,
a ~ d C~
n
~.,~ ~ p p O ~ O O O
~
O O p ~ M p r-'l~00
O
--i'i M l
'
H W ,L~.ii , i~ f/~"'~'V7
~ .~.~~
_ H ,-~~ r~
DD
O
M
, ,
,
M N M
d
N
M
N N N
O
M
x
x
x
s~,
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~n
0
N ~ tn
ricat
01 ; ,.- W 1 .. (~jf~j~.j,-;~--~~-i,--i~ ~-i,-i~ ,-;~ ~ ,--i
r.-i
~
O ~ M O N l~~Ov0 d'~ ~--ioo ~ v'i'-''"'~ -iwt'~
cV
.
0 0 ~
,'2',O ~ ,~,O O p O 0 0 0 p O 0 p p 00
: x x x a ~ x ~ ~ x x x x ~ a xx
~ ~; ,~~: ~ ,
.. (vjN N r'',-i,-a,-ir..;r;,-i,--i,--i,.,_;,-i,-i
,..-;
Vj ..,_,
~ O d'~ ~ ~
O ~ O O O O O ~ O O O o0 M
x x o
o x ~ x ~ ~ x x ~ ~ o
~
N ~ ~ N ~ ~ ~ o O ~ ~ Ca.
p
~ ~ ap
0.~ . ' 0
~ , 0..x a~E~''[~U o 0
~
O O O O O ' ~ O O
-'
~ M
~nco ~ ~n oo ~ oo~OO ~
p
O p''O s-~O
~-. ~"
C7 H H C7 H H P~~C H G,v? 0.~
0
N N
O 01
a1
O - _ _ _
M
U
x
x
83
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r;
r-i~'' ,--iN ~ ~.-i~ d=criN ~j,-i.-i,-i~-~r-i,-i
,-i
~ ue
d
'
O O ~ ~ ~ ~ ~ p O O p O O O O O O
O
a x ~ ,~x a a x ~ ~ x x x
~ N x.
'"''"'i N '"' ~ d=wj N N .--i~ ,-i,-i,-i,~
,-i
N pip~ O M ~ 0lw(-
O _ ~ O O ~ 00oO o00
O
~ ~ ~'~ '~ ~ ~ ~ ~ ~
x x ~ a ~ x x xx
d\
M ~ ~ ,--~ ~ ~ dN-~o,d~-
N O ,--a,~ N N ~ ~ ~.j~ .-~01N
m ~ dpi
' ~ ~ % ~ ~
~ ~ ~.1C ~ f/~'
r ~
U o 0 0 0 0 0 0 0 0 0 0 0 0
~ w --~ M I~O M ~ O
~ ,-~ooN
~',v~ ~ ~ ~ ~ ~ ~ ~ r..,i
a ~ ~ ~ ~ ~
~ c ~ H a a c ~ ~ H ~
_O ,-r .~N
i i ,
i
r, ~ M M
d'l~
N O N N
O
U
O
x
a\
84
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
,.--i,--i";.-;,.-.ir;r;,--i~-',-i,....;,---i,--i,-;~ ,--iW rid=
I~O (V~t p cj-1p N ~ 01O Q yjO O d~-
0~1~ .~~ d'DO V~OIr~, ~''~ O V~'1
x x ~ x x a l~l~ I~tn O l~
a ~ x x a ~ a a ~ ~ ~ x x
a
-in-~ opN O oo'd'~ 000oO vnd'oO ~ M a oo
N N O ~ \OO ~ N N tn v'1M ~ O I~O t
0 0 ~ o ~ o Q a o 0 0 0 ~ ~~nx tx ,-~o d'
d'
0
o ~ M
01 ~ ~ N~i
O _~,Nv~
O C7L'7v~
O O OO
0'~ 0 ,-N~oNoN
_j,~ ti~N
H
N M
a>
lfl N
i
i
O
M
N O
N
M
G7
8s
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
ri
M N N ~ '-''~ '''~"''-''"'i~ ~ '"~,-i,-;,-;,-i~ d1~ ~O d=c~M
N
M 01~ oo'-'O d'v1'-'~O d'01~ (jd=N 01O O ~ wlr~ cV
l0V1M M t~ ~ ,-~~ ~f'l~O _ ~ tnV~ ~ C/~ (Z!I~V7 V1l~~
O O O O O O O O O O p p O ~ p O O "O ~ a O O O tM
a ~ a a x x x x x a a ~ x ~ ~ a a ~ ~ ~ a ~ O
M M N N ~'r''r.;r-i,--.,,-~,-i~ ,-i,-i,-iri ,-i~ ~ ~ d W O
n a
~
wj
cn
O N ~ 01~ M --id'~O ~ fVM ~ N I~~O ~ ~ ~ ~ ~ ~ ~ M
p ,-~-~~ ~ ~ ~ p N ~ ~ ~ ~ l~0c~O ~ ~ ~ O O O O O
O O O O O O O O O O O O O O O O O O txa O O O
G7~ ~ ~ G7 O
O
O
d-
v
a,
M
N o0
~ d
N
O
O
N
0o N
N
d1 d\
W
x
86
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N N N C~jN r"~,-i,-;~ ,-i~---i,-i,-;,-ir-i~--i,-i,-i,--i,-i~-i,-i,-i
a\~t ~ OvM vp ~ ~ oo t~~ 0~1N ~ oho_OM due'~ due'p ~ dN"N '"'
O O p p O p O O O p O O O O O O O O O O O O O O ~
x a ~ a x ~ x x ~ ,~x x x x x x a a ,~ ,~,~,~ a ,~o0
N N N N N N N ~"~,-,,.-i,-i,-i,-ir-;r-i,-i,---i'-;,-i,-i,-i,-i,-i,-iO
l~ M N d1(V iiid'~"~ O d' d'cnV7 0100~jVj ~tvd'~ O enO
M ~ I~00-~V~ d1~ ~O ~ l~M N V~M V1M [~Cf'\Ol~I~ 'CI"~ ,~
M V1l~ V1N ~ M N O ~ ~ O V7[~~Q M (~I~ ~ M x
O O O O O O O O O O O O O O O O O - O O O O O O ,-i
~ x ~ a ~ ~ ~ ~ x x O ~ .~ ~ ~ d=
a N
\D
~O
O
O
~
87
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i o 0
c~i
h N N '~~-i~ ~ N N N
N
tip~ o c~j ~ ~ ~
o
O O O ~ ue ~ O O M ~ N M
O ~ ~ d ~
'
~ ~ ~
~ x O a
x r~t-.~x x x ~' x x r~
O O n r~
c~ N V1 ~ ~ ~ cd c ir'1
M N .-;~ ,~~'~ , ..N N N
N
01 _. ,-r
. ~
M M ~ O ~ l~ M d'M M ~ ~O ~ l~~ O O1
O
d' O O O O l~I~,~,O O N ~O O O ~ ~ ~
Q ~ ~ Q o ~ 00
o x ,~ O O a ,~~ O O
~ ro ~o
~ M
7 M 1 Q ~ C M O M
V 0 V ~ _,N
,
~ ~ ~
~ ~, '~aj 'p,~ r;ci~~ .~,
e~ ,
~ ~ ~. ~ ~ ~,x ~ ~ x
-'
' ~ O O ~ , O O O
~ O O O ~ O ~ O
,-iV~ O ~
.~--~ ,..,
O ~ 00 ~ M
0 v
00 y 0 pi Oi ~
0
p. Q v~ j~~ .t".~ ~~,'~ ~.t a.,' ~ i
by ~ p,
_ _ _ _ _
00
V1 O
'~. O
r t
M \O '-'
N
. N N n
d
, o
~ o
N
O ~ O
Q
N
a\ a1 ~ a,
M M
x x
N M d'
$g
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
Q
00
N N r;r;'"~~ r;ri,~ ririr1 01 r-iV7
l~oo d'O N ~ N O d' ~ 01d1 O due' O 0
d'v1 ~ in~ ~ 01~D ~nooa1 p~O
V1M ~ l0l~~ V~V7lrl O 'C3
O O O O O 0 O O O O O O ~ C/~ ~
x a x x x x .~a a x ,~~ O (~j N
N N N ,-i~ r',-i~-i,-iri,-i~--i~--~ ~-i
M
Q W v'iO ~ M ~ ~ ~ N ~ ~ o ~ ~ N 0 O
000t' d'~ 0 M h ~ ~ l~U1 ~ 0 0 ~
O l~ O o~~ ~Q-1,~ ~nO O Q x x O
~
~ M
N M oo cna\N oo rM.,
oo r~ooN c~ ~ cd
~' ~/7
'~'O ~ O C~x ~ O O
O .~,O ,~,O O O
d' ~ N ~ N ~ O M
N ~ d'oo d'oo, y o ~
a>d R.~ R.,~O ,~ ~ ~,
~ P~ C~ H
O
O
M ~ M [~ V1
i i i i
M M M i N
~
O ~ O ~ O
N N ~ N
N N v7
N ,--~ oo M
\
N '"'
C7
W
x x
89
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
l~ ~ d= d' d' d' M M M c~i M rj (V N N N N N N N N N ,-i
~. O ,-i M~~N
M ~ N \D d' V1 ~ d' O [~ ~ ~ [~ M 00 In ~
O ~ 0 0 0 0 ~ o o O ~ p o 0 0 o O O O o o p O
~;oaa~a~axxxaxa~xxxxaa~~ax
l~ ~ d~ d' d' d' d' cn M m M cn M N N N N N ~j ~j N ~j
O o O ~ ~ l~ oo p ~ O N oo N cV cn M (V oo p op N op
p M v1 N ~ ~O d' l~ oo N M ~n oo N in Ow1 N_ ~ N ~ ,~ oo N
O O O O O O O O O O O O o O O O O O p O O O O
Q' J ''S' v, '7 J ,~ J rn "',.L'" J ,~ rn 'S,' ',I,' 'J..,'' '',1.'' '~'' ''~'
,~ ,~ ',7..,'' rn
O N v-i
D\ N d=~ d,-,ooN
r, ~ i ~ , i
_~,~,,~ N j,
~ p
~ Is,C'7' .,
0 0 0 o
~'-'o I~ ~ 00
N ~ ooO M l~~
_
tip N cC ~ c~
-, a~
~ C7U A.,
0
0
0
m
0
N
N
d\
d'
x
x
CA 02395816 2002-06-26
,W-i ~ ,--; ,--i ,-i r; ~--~ ,--i '-; .-i ,--i ,-i ~; ,-i ,--i ,~ r; ,--i ~-i
~-i r-i ,--i ~-i ~--i
O oo v'i ~ O ,-i ~ ~ ~-i d' ~ ~ oo ~tv p cn N ~i'i v0 ~ cri a\
00 ~ d' ~ ~ N O ~ d' N ~p oo N M r,
O O M ~1 d' O l~ ~ O M d' O O N ~O ~O M N \O \O l~ 00 \O M I
xx°x°°.-°~xaxxxxxxxx°aaaaa°aax
so iii ~ os o0 0; o; ~ W o 0 0 ~.-; vi ~ ~ M ci wt t~ ~ so ~i o~; M
Ol ,~ ~ N O ~ d' 00 00 ~f' V1 ~ ~p ~ M 00 M [~ ~O ~ In l~ 00 Cf'
tn N d- M N ~O V» V> V1 ~ O ,~ l~ O O ~O ~ t~ I~ ~O l~ t~ ~n ~O
O O O O O O O O O O O O O p O O O O O O O O O O O O
!T~ rn rn ~'h ~ !T! !T~ !T! !T! !T! !T! ~I'! . 1 !T! !T! !T'. !T! . 1 . 1 . 1
. 1 . 1 . 1 . 1 . 1
91
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
-i,~,_;,-ir.;,-i,-i,-i.-ip r-iM N cVr.;,-i.-.-ir' ,-w
,-i
h ~ ~ N ~ N ~ ~ ~ ~ ~ ~ ~ ~ 0' O
N
o ~ v ~ O 1 d
o 1 0
~ O M
O O p O p O O O O "d ~ O O O O
~
x x ~ x a ~ ~ ,~~ ~ N x a ~ x x x
i i i i ~ ~ ~
r ,-,- ,-~;,-i,-i.-i ,_..., ~jN ~j ~ r; ~
,-i
cYid\01 .-;p1N cri~--~oo d: ~ p N ~ cV ~ d1'-'d'
r;
O~V1O N M V1 01O ~ O1 ~ O N '~~O O d'M M
O O O O O ~ ~ N O p O O O Op
p O O O p p p
x x ~ ~ a ~ ~ ~ x ~ x~
O N ~ 01 0od'O ~
d' ~ N N M V~M ~O oo
O~ " N
N ~ ,-~,~ ~ p O ,_..,,~ ,~N (V N
cn
~ ~ ~ ~
'
~,>, . '_"'
a ~ ~ a ~ ~ ~ x ~ x c~ ~ a ~ ~
~
0 0 C7 0 0 0 0 0 0
0
0 O M ~ ~ t~N ooO M d'
00
N ~O~ ~ ~ ,--iM d'N
~ V'yD ,--i,-~,--i~ V1 d1,--i~--~~ ~'1N c'1
, M
,'i~~ N ~ ~ ~;~',~ ~,~ ~ ~ ~ p.
U ~ ~
C7 P ~ -1H H ~ v~~ ~ C7C7 ~
..~ C7
a1
'-' o
0
N
M
O
M N
N
dl
M
r~
x
92
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ,-i
~
.-i'-.;,-i~--~-i~--~ p1
M v1~O N 01.-~ O N p
N
~
[~l~M M p O
.,
O O O p O O
r~i~ ~
M c~
rir-i~ ~iri~i ~
lDM ~ d'O~l~ ~ ~ V~M
M O
0 0 0 0 0 o , ~ o
-,
O
0
~ M ~ ~
~ ~ o ,-.. ,-. . .
o ~ ~ ~ a . .
. ~ ~ ; ~ ~ ~ ~ ~,~;~
~
C7~ ~ ' ~ ~ C7 ~ ~ ,~ ~ C~~ E~H ~ ~ ~ ~ C7
0 0 ~ C7 o C7~ ~ 0 0 0 0 o c7 ~ ~ o 0 0
0 0 ~ 0 0 0 ~''J~' ~'~-'0 0 0
,d-N ~p ,'-',-'d-01 ''"'''''r-'O '"''v0 d'd-a-'
M ~ N 00,-,N O~~ ~D '"~M d' ~ l~d1 tn~D,--iM
M '"1~ 00~ ~ d'00
,t"~, b4 s~cd~,~ ,-;c~~ ~ ~Lvw ~ ~.~ ~'~ ' ~, ci~
_ _ _
p N
a1
' d~ d-
N N N
N N
d1
O O
~
N
O
N ~ N
O
N
x
d\
93
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M ,~ a1 '-' O O
D\ ri ri~ ~ ~ N ~ ~-i~ 00 ~p
dr
O O N O O ~
o vp o ~id' O O ~ o~oO
o
N O ~
~
t~ ~ M cT
M cd '~' p1~ O t
,--a ,...~ ~ n
,~ ,-,.~ ~ ~ ''~'o d1 (W
~p
M O V~~ o ~ O ~ ~ ~, pip~ ~ 00
fx N V1
~
',.1,0 0 0 ~ ~ ~ ~ N ~ ,~I',o 00
O oo N
N ~p ~ oo N
ue o
d ~ ~ ~ ~ ~ d ~ ~ p; ~ ~no0
' '
i ~ _J,a.,~ , g Q-,_~ b4~ C, _~,p
~ r.. ,
o H C7 ~ ~ a ~U~ ~, ~ ~,~-,C7 Q ~ ~, C7p
'
''' M O ~ 0 ~ ~ ~ o ~ ~ ~ , ~ 0 0 ~
~
~ O 0 ~
~ N M ~ 00 ~ ~ p~ M ~O(~ 0
i ~ i ~ i i i i i 0 i i ~ i i
i
i i i i ,
~ it _cCi."3.~ p .~3_.S-',_.~S p N _~,'b4 ,~~_.x"rs'-~_~_.~1_~ ~..
~ ~ te
E v~ ~ -1~ f~~ C7C7 ti,P C7~ C7C7H C7C~C7 v~
-~ ...
N
O
N
d1
0o N
O N d\
N~ ~ d' N
i
N N N N
O
d
00 N 01 M
_
O1 O o0 O~
V7 M
N
O ~ N
94
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d'~rjM ~,,~N ~jN N N N ~,jN N ejN ~ ,-i,-;~ --i,-i,-i,~,-i,-i
d'p ~ ~ M ~ \Oc~id'O ~ ~ ~ ~ l~ d'\O01 O ~ o0r--i.--i~p~p r''
N ~ M N op p~ooV1 ~p_OO _ ~ ~ O N v7,- W~M O_0o M 0oO _~
O p O o p ~ O O O O o O O p d O O O O O O O p O O O
x x x ~ x ~ax x x x a x ~ a x x ~ x x x x x x x H x
M M M M fVN N N N CVN N N N N '"',-i,.._,,-i,-i~.-.i,-~r.;,-i,-i
W d: cnp~,--io0N o0 w1'oo,-i~ ~ O l~ v'i~'O ~ v'iv'ioo p op,-i
d"v~ N V1M O ~ ~ N ~ t~O ~ v1I~ 01d'~p ~--~ooN ~ ,-,M l~
M '-"'~lpl~ 00~O\D d'd'[~00 ~Ol~l~ V1M M d"'d'O M ,-,l~N O
O O O O O O O O O O O O O O O O O O O O O O O O O O
x ~ x ~ x x x ~ ~ x x x x
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
'"',~ '-i,-i,~,-i~-i,-i~ ,-i,-ir..;,-a~ O~ V'icriN N N '-''"~,-i~
'-'
~ 0 ~ ~ O O
\DO V~ O ~O~ l~01M 0 ~ O ~O ~ ~ ~ ~ p M
O 0 p
~ ., a
O O O O O O O O O O O ~ O ~ O O p O O O p O
O
x x a a a ~ a a x ~ x ~ a x ~ O ~ x a x x x ~ Hx
,
-i ~ ,-i,-i,-;.--i,-i,-i~ ,--i,-i,-i.-;,-i M cnN N ~-i~ ,-i,-i
.-i
d'l~ ~ O ood' oovpV'id'O D1a ~O'-',,-~1M d10od W d'~j~i'i
'~t
N ~p d'O vDt~ l0\O~O ~'oo M ~r1Ov~ ~OM ~nd w0 ~ ~ N d'
' O N
'
O O ~ 00~ l~ M ~Ol0 d M O d'l~V1~ O M [~\Ol0 ~O~O~pV1
O O O O d
O
O
O O O O O O O O O O O O O x O O O O
x x a ~ .~,~ x ~ ~ ~ x ~ ~ ~ x x
-ioo ;'N N
In M d' p.,
c~
O O
O O
O O
N M
~
i
, , ,
~
r~ C"7'U ~IH d'
O
M
M
d\
M
O
Q\
M
O
d
x
M
96
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-.O ~ o
-i,--i,-i,-i,-i,-;,-i'"',-i~ r-i ,~ ,-i d."N N ~.jr-i,--i,-i,_;
M r.i
0ocrid: oo,-ic~no0o O O o '-'~ O O O Q ~ oo ~ N _oo
~ dM'~O~ '~P!O d. ~ O ~ ~ ~ ~ ~ ~ d-~j
x x a a a a ~ x a ~ ~ x a ~ '~a x a a x x M
.--i,-ir; ,-i,-.i,-i,-i~ ,-i,---~ N ,-ii ~ trjN N N N ,-i~ N
d',=-icn~ ~ Q1d' Vj~ ,-~i~-ip~ ~ M a1 N ,-i,_..;pp~jN cM
O_OO\[~ [~I~V1 00~ O V1~ ~O i~M ~ ~'M ~ N M 00OpO x
O O Q O O O O Q O ~ ,."L,'O O R~a O O o O O Q o r;
,---i
op
N
Q
O\
O
Q
M
O ~ O
N
N
00 ~--~N
O
O
N oNo
O
~ O
~ a\
a1
a
x x
97
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~ 1 ~ ~ i i
,.~,-;,-;, ,-~ ,-,- ,-,-,-i~ ,-.
h0 0
t~M ~ ~ ~ ~ Ix o ,-~1N ~ ~ p ~ ~ ~ ~ R~ ~d
~
x a a x '~x x x x x x ~
a a a N ~
cri
ri~ ~ rir;~ riri ~ r; ~ ~ ri~ r;r; r;~
01~ iV~ N l~~ ~ '"'d'p a1~n N ~Dp~~n pp~O~
O O ~ ~ ~ O _ O O ~ p ~ N O N ~ ~ ~ ~ O O
N O ~ o o O O O t O x
o r1
O
O O O O O O O ~ O o o
a ~ ~ ~ ~ x ~ x ~ a x
.-iN d 0 ~ ~ ~ ~ r-iI~ ('1
~ ~'' ~ ~'v
, ~ ~
G7~ ~''E-~ v~ j,~,~ ,~U.
a H
O O ~' r-l C/~O
O O
O O O O ,_,,~, a O O O
0 ~ O
N 00O d- ~ " [~00 \p61M Ol
d
.--iM [ ~ ,~,--~~ ~ ,-~M d-
i
i
~.c ~ a ~ ~' ~ p,
D
d . ~, c t c O N
n .. C G
7
O1 O
O
l~ O
_
V~1
i
N M
Q\
00 M
O l~
ue
Y
d N
'
d\
W W
98
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O .--i
i i i M
O W --;~--~'-;~-'--~- ,~rjN
d N ,:..;~ ~ ~ N 1~a10 O
, (~
_,
p p O O O O O '
t3
o ~ x x x x x a ~ ~
N ~'
i ~--i,-i~-i,-.ar.i,.._,
'-i 01
~ ~t010o d'(V O
- ~ ~ N a1010o N t~~ ~
-r
O O ~ l~N ~"''M ~ ~ ~O~ O O
'~ O 0 0 ~
W ~ x
.-7~l x x ~.7
M o0 o u'icfi
M
N y n oo O ~Oo0
N N ~ i ~ d' 0 '';;' ~ ,~,--,N N N ~
Yi
' w i ' ~ ~ O ~ ~ ~~ ~ ~ ~.i
~ V~
~ i _cd, O ,-~c~i~..-ra~N R.~
~
~. s., s
~ '~~ ~ ~' w t~~ ~ a ~
~ ~
0 ~ 0 0 0 0 0
0 0 0 0 0 o ~
~
' ~ M O N ~ ~ ~ ~ ~ ~ N ~
d ~ N ~ 1 ,- ,- N
0 ~ -r
by~ ~ ~ ~ ~; p ~ cit~ p ~ ~ ~ ~ ~ 'S..~"
p
_ _ _ _ _ 7 _ _ 0.'~_ _ _ ~ _
C7 C7 ~U C7~U ~ ~U ~ ~ ~ 7
0.,~. ~ G U U C C
-~ A,
~ ~ N
_
ON
M .-v
N '
~' O
i ~
M M M
M
~
_
N
N
O
0
U U
x
a,
99
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O O O O ~ O ~ O O O
tn V1 M M 00 00 N 'Cf' d
O O O O 01 M 00 O O O
M M ~t d' co N oo O O O
O O N N M o0 0o O~ 01 01
N
M
Cr'
c~i
-i ~ N
ri
'_'O ~ ~ ~-.i~ncricn
N ~O N
N ~ N ~
-, vj N
N
d' M
O O O O O O Vii'cn
~ ~ ~0
,"'.f~.,,OO ~ ,'I',~ ,..~O 0
,.N~
O
O
01 ~ ,-iO Sri(~N p
O
~ ~
c~ i3 ~ ~ ~ ~,~, ~ ~ M ~ ~
'
>,_ . O ,-~cd,-~~ N ~ lp~ ,.-,v~
y.,
~',H p~C7 ~ C7~ ~ ~ j~a~~ ~,N ~
U
O O O O O O O 0 'UO ~ O O O
O
O ~ O
J
d' v1M ~ O N d' N ' O .a-'O .~'.~'''''
.-,
ooD1 N M O
N
~ ~ i ~ N ; d ~--,d-,--,N ~ p
' p
~
i
i ~ , ~ ~ ~ ~ y ~ i ~ i i ~ ~
~ O ~ O c~p cd~
~ _ G~0. C~C7~U ~ ~ _ ~ _ _ d
~U ~ ~ ~ 7
~ I~ G L
M d- In
i i
O ~ N
O O O
ue
d
'
O
a1 try
0o O
N
1~O
CA 02395816 2002-06-26
N N N N N '"~ ,-i ,-i ,y-i r-.i ~ ,_; ,-i ~-i ~--i ,-i '-i .-i r-i ~-i ~ '-' ,-
i r-i
~ M M N LO ~ ~ t%j ~ ~1 'Cf' M ~p ~D tn v~ ~ ~ M d"
\O M l~ V> ~ ~O \O N N O N O d' M ~D \p h ~ ~O ~O ~ ~ d- I~
O O O O O O O O O O O O O O O O O O O O O O O p O
xa~~.~xxx~xx~,axxx,~a~~~xx~~x
N N N N N ~'-i ,.-i r-i r--i ,-i r--i ,~ r-.i ,-i r-i ri ,_; r-i r-i ,-i ~-i ,-
i ~ ,-i r-i '-i
O OW 'i ~O QW"' cV ~ r-i ~ tij ,-; O~ O N ~ p ~p M oo M N ~'1 0o O l~
~D ~ ~ in v'W~ O d' V1 0o d' tn M Ov N ~ ~ d' t~ ~O ~ 01 N N d' l~
M l~ ~O l~ I~ '"~ d' M M ~n v~ O O O O V~ [~ \D l~ l~ ~ l~ ~ O l~ l~
O O O O O O O O O O O O O O O O O O O O O O O O O O
rn . 1 , 1 . 1 . 1 .~T'! !'!"! .tT'! .~T'! !'!'! !'T'! rn !T'! !'T'! .~'fi
.~T'! . 1 . 1 . 1 . 1 . 1 . 1 !T! rn . 1 . 1
N ~
'"_'~Ooo N
~Cci7~ ~l
O O p O
O
r., N
i , i
N ~ N ~~"' .
a ~ ~ w
101
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
M M
-id '~ N N N N N N ,-i~--i,-i,-i,_;~ ~ ~ ~ ~-ir.;
'
p O ooO ~.j0100~ ~ M ~O~n a1Vjoo ~-id:
x ~ O ~ N ~ ~ ~ O O
p ~ ~ ~ l ~ ~ ~ O
0
O ~ x O O O O O O O O O p O O O O O
" x ~ a a a x x x x x a x ~ ,~~ x a
,
-i~ M (VN N N N ~ ,-i,-i'-i,-i,-i,_;,-i,-i~
O ~ M ,-i\Ol~~ l~
N
I~~ oo M ~ V1d' V1l~lflN ~ ~ O
O d O l~I~l~ l~~ l0M d'N N ~ l~~O l~
'
x x x x o
x x x a a o ~ x x
.. pp.-iO O d' ,-~N M O
N ~Q Q1~ M ~ l~ ~p''~
ci~~ ~ ~ ~ ~,J~
~ ~~
~ N U ~ a~ N C~
C7~ m
0 0 0 0 0 0 0 0 0
0
N N ~ ~ ~ M ~ ~
;' d 0 1
' ~ 1 0
p. ~ ~ 0 ~ ~p p. ~:
b
~ ~ c~ ~,a ~ ~ ~ ~ H
~C
N
r.,
0o O
N 01
i
M
M O
M M
O
M
M
N
a1 D1
Qr
x
M
102
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-a ,-.iM ~j N N N r"~,--;~ ~ ,-i,-;,-i~--i,-;.-i,-i,-i~ '"',-;'"i~ ,-i
01 O N '--i~ N M ~ ,-i~ ~ O ~ ,-i01p1M l~V
tn p~ O l~ N O lp ~ O \pl~ ~OM ~ lp O I O O
O O p O p ~ O O O p O p O O O O O O
a ~: ~ ,~ x x x x ~ ~ x x x x x ~ a ~ ~ x x ~ x ~ a
-ir-i ..~j N N ~j ,-ir-i,_;,--iri,--i.-;r-i,-i~.-i,-i,-i,--i~ r-i,--i,-i
cri~ I~p ~ ~ p~ O ~Oop O d'~p ,-ip ~O N cnO d W000\O
p d p -vp M d'tn l~V~~ O 01~ ~p tnV1Q1 ~OO 'd'~ ~Ol~N p
O fx x p O O p O O p O O p O O O O O O O O O O
~ x x ~ ~ x ~ ~ ~ ~ x a
O
O
O
N
M
N
d1
O
a1
d.
N
w
w
x
d'
a\
103
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0
-i ooV'id'M ~rjN N ~j~j r-i,-i,-i~;,-i,~,-i~ ~ ~ ~ " "
.. '.-i
j O ~ ~ O ,~~j ~O~ ood' t~'"'~ d'~ ~i~ M
l0Q~ 0000.-~ M M ,~~ 0 M !~ 1 ~O
O d x N ~ ~ ~ v1l!7V1~ ~ d' ~ O d'~ ~ ~ OQO O N
O O O p O O O O O O O O O O O O O O O
,~ ~ x x x x x x x a x x x x .xa x ,~a ,~ ,~a O
O
xx
-;~ V'7~ M ~rjM N ~jN ~.j,-i,-i~;,-i~-i,--ir;,-i,-i,--i,-i,~
,-i
trjdM'~ ~ 00od-~ ~ M l~YjN ~ cn O r.i010001 ~py 1r ~ N o0
O ~O d'01tnN d-01 V7N l~oov7 N ~OO ~ OvN
p V1 O V1 \OO [w Ind'~p~ [wM N p ~ d'M d-~p00 l~
~ P~ x ~ O O p O O ~ O O ~ O O ~ O ~ p O a O O O
O
Vj\OO 00 O M
j M d0.,~ ~pooV~Ov N d' M
0 ~ ~ ~ ,~ ~ ~-iN N M M
_ ~ ~ ~ C/~~
G7O O O O ~ O
'U ~ ~ O O p ~
N d- N M ~ ~ ~ ~ 01 ~ M
M M
~ oop~ ,-m--y.,~ .--~N N M
i ~ i ~
r~ i ~ i i i ~,i ~ ~ i ~, C/~
r~G7 ~,(~C/~ H (~
N
O
N
N
O
d'
N
M
x
d>
104
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
b o W '~ of d
O ~ O
,-i ..
r"' -i'-i ~ N N N C~j'"~,-i~-i,-;,~r-i,-i~
tn ~ ~ , ~ ~
M
W rj ~ N ~ ~ ~p ~ ~ ~ o M
O
d M p ~ M ~ ~ ~ ~ ~ I~
O '~ x O O N x O O O O O ~ O O O O O OO
x ~ ~ ~ x o : a a ~ a x x x x a ~ ~ ~.a
a
.. N . ~ ..~
_ '..''~ ''..~ O _ ' N N N N N ,-ir-i,~ ,_;,~r...;,-i
~ ' ,-i
01d-O ~ O ~ N '"''oo~ fx O N N Ovoo~ N M l~Ly p v'iSri~
01
N ~ O ~ 0 ~ ~ ~ ~ ~ ~ N
' O a' p ~ ~ ~ ~ ~ O d ~
d '
O O ~ N ,'2,'O O O ~ p" " ,."L~,O O O O O O O O O O O O
O
G7 M V1 G7~ ~ x V7~-.~~ ~i
N N M ue
d
'
Ov M ~ '-' ,-iVii''-~~ "'
~ l~~; Q,r~ ~,
~"U' a ~ ~ ~ E-.,_
C~
v' ~'o o . a o 0 0
E-~
0 0 .~ ~ o o
_
l\O O N ~
M
_~
~ A, ~ C~E~ C~
O~ O
N
M
N
N
O O
O1 M
M O1
d- d'
a
x
x
a, a,
105
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d- d'
' d'criM cncYiN N N N
h O N
o ~O .. ....
o x O ~ ,~~ p ~ O yj ,-~~--ipp N
O o0
l~M V1pp lfl~f'~ ~"'~l~Ol ~O
~ M
p p O p
,~O O O O O O
~ O
,~a ~ a ~ ~ x a a~
wid=cn cnM cn ~jN N N
N
,_; ~ ..
V1O 00.~ O I~~ [~~ d" 00
M
O O O ~ ~ M O
O l~1 O I~l O O ~O
,~O O O O O ~ O [~
O
O
C ~ ~
i d' oo~ ,~N ~ ~ ~ ~ ~j~ O
~ ~ ~ M ~
s~,J-,p, ~ ~ ~',-~"~,~, ~ .sue
~ ctt~ '-'~" x N '-'_'
C/7'~[~r',~ ~" (~C/~[7 [~C/~~ ["~
O O O
'J ~
O O O O O O ' ''J O O O O O O
M N ~ ~O00 M '"'~N ~ M N ~ O M d-O
M V \O ~'~ ~ M
1 00 ~ ,~ M
i i i i i i i
~~-_cd~
H
N N
d'
' N
O
00 ~ N
O ~ O
N oo
O
O
a\ a>
N N
O
x x
a\
a\
106
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-;~n
'
N N N '"''r-.w'""''-',-ir,1,~'"'i~ ,-i,-i~ '"',~,_i,~ a1' ~ ~ ~
~ l<1
~ ~0 ~ p M ~jp ~ d' ' lxo (x p
h0
l~V7 l~l ~Olfl~ ~ O~ ~OO O ~O00'-,~D d M O x \O
l~ '-WOO ~ ,~ M l~ ~ ~ ~ a
O O O O O O O , O O O O O O O O O Q O y '~ O
O O
~ a ~ x x H x ,~x a x ~ ,~~ x x a ~ ~ ~ ~ ~ ~ ~x
N N N N ,-ir'-',.,,-i,-i~ ,-i~--ir-;,-i,-i-i ~ ,-i,-i.-i'-~'-"''~ ,~ ,-,
0o viN N ~' ~ O a1 M r-iM ~p~Ocrit~ N p m M ~ p ~ ~ ~
00
lfl~ ~ ~ ~ d'_ M N ~ ~ ~ ~ ~ M ~ O p ~ O p
O t l t N O O O O O O O O V1\DO O p O O R;a O P~ a
O O O O O O O O O
~ a ~ x x ~ ~ x x x a a ~ x x x
~ ~M
0 0
0
M
N
G7
M d'
N N
d'
d'
O
N
d\
N ~O
M
r~
x
x
O
O O
107
CA 02395816 2002-06-26
v'i d- d' d~ M M N N N N N N N N N N N N N ,-i ,-i ,-i ,-i r; ,-i ,-;
O [~ ~ d- ~ o O ~ .d- Ol l~ d' [~ ~ O d' V7 M 00 00 ~ ~ ~ l~ ~O _l~
O O O O o O O ~ O O O O O O O O O O O O O O O p O O
~aaax,~H~Hxxxa,~~x~a~xxxxxxx
v'i <j= d= d= d' cn N ~j N tV CV N N ~j N N N N N ~-i ~"~
~D 01 l~ ~n d' d' ~O O cn O oo 'd' ~j ~ oo d' N oo p O ~~ O l~ N Ov
V1 ~f' ~ I~ N ~ ~ ~"i V1 M O1 ~p (~ M V~ V1 ~ d' ~ d' 00 ~--~ tn O
~O ~ l~ l~ l~ ~ ,~ ~1 O O O d' ~O M d' l~ l~ l~ O ~ M V1 ~ O O
O O O O O O O O p O O O O p O O O O O O p O O O O O
1 rn . 1 . 1 . 1 . 1 !T! rn !T! !T! !T! !T! !'N . 1 . 1 . 1 . 1 . 1 1 rn !'N
!T! !'I-! 1 M M
O
_~
O
O .'_'
''-'O
m O
~'.
H
C7
1O8
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
.-t'-',-i'-'~',-i,-;,~,-i~--i,-i,-i,-i,-i'"r''',-i,-i~ O N
0oO j ~ ~ ~ N ~ N N
~O o o0
~ ~ ~ O ~ ~ x
p ~ O M [~l~ l~l~ l~\O ~ l~~ O
p
O o O p O O p O O O O O O p p p O p
H x x x x ~ ~ ,~a a ~ a a ~ x x a a a
; i i i i ~ ~ N
- r ~;r ,-r; .-,-;W -iriri ,-i,-i~ r;~i~--,-~
d'O ~pd W0~ N ~jo0 N 'd'~ ~OcriM ~ l~~ o0 p
N '~ M ~ ~ ~ ~ O M [~l000 N ~OO M V1 O O
p ~ ~ O
O O O O O O p O p a p
~
dl
..O
~
v
'
1
~ Q"~ N
H j N ~ U Q'
~
r
~
O p O O o E''
~ op~ O
~ l0
~, ~.~.
_
C7 rigH H C7 v~
in
N
N
O
d-
~n
M
N
v0 d'
N l~
0o N
d> a>
M
h
x
N
O
109
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ~ ~ N
~ ~ '
,.:~ ,_; d c'nc<7~rjN N ~j~jN N N N ,-i,-i
,-i
N ~' M l~ 0 ~ N ~ O
1
~ ' ~ ~ ~ ~.d ~ ~ ~ ~ ~ N ~ ~ ~ ~
' "
N n
,x a ~ x ~ r~a '~ ~ r~a
i i M ,--~ M ~; c 1 = M N V N N N
- ~- .. ~ trd nj c ~j~j nj
M
d:~O oo~ ~O ~ ~ O ~ ~ M p~ V'i~ l~00 00~jM M
O d O O O p x O p N ~ N ~ ~ O ~ ~ ~ ~ ~ ~ M
O
O O ~ L~ fx O O M 0 0 M
O x ~,~ ~ O a ~ O h,O O ,0.,O
, ,.
~ ~ ~ ~
d=
N riN ~ ~ m
~ l~
~ i ~ ~ '"',-m--~d.d-d. o v~
I ~ i
~ ~ a c~~ v ~ ~ ~ c~
~ c~
~ 0 0 0 0 0 0
" 0 0 0 0 0
l~ O j ~ ~ ~ ~ h ~ m ii
d- l~,-,~ ~'~'d-d'o d-V~~?
o
d-
~ ~ ~ ~ p ~ ~ bya)~; s~~
-.a_ H ~ p~~ ~ ~ 0.~v~ ~ _ d
'U ~U
N N N
d1
N ,-~ M
N
N
M ~j" l/~
O
N V7 O
O 00 M
l~ N
M ~O
dl
dl d>
a v
x x x
o ~
o
110
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
,~.-;,-.,-;,~ ,~,-i'-..,-i,_;~ .-;,-i,-i,.-i.-i,--~r'.-i,_;,~,-;
0 dl ~ M ~ N_~ O OlO 0~0M ~ ~ M ~ . 00~O M M Ol ~
O p O O O O p O O O O O O O O ,~O O O Q Q O O O
~ x H x x x x H x x x x x a ,~ ,~O ,~a ,~x x x a p
a ,~~,
a1 M M ~n ~ O ,-il~l~ood' p ~jOv ,-i W100 Sril~N ~ ~j"
-rO M ~ I~ 00V1l~ 00~ M Ol ~ d-M d'O V100 \Od"N O 'CI"01
~O M O ~ ~ O O ~ ~OO d' ,~,-,~O l0~f"l0(~ ~O~ ~ ~ l~~I"
p O O O O O O O O O O O p p O O l0O O O O O O O M
x x x x x x x x x ~ ~ ~ O ~ a x ~ ~ t~
. d-
O
O
~~
111
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
O ,--i~ M ,-i~ l~d=cn (VN N N N N (Vri~',-i,-i,-i,-i
,-;
O O ~ ~ O ~ ,-ioom o_o~ p cnU'iO (V~ d'dW V d_'~
O cn
"d~ O 'C1 ~ O ~ ~ l~ d'd'N ~ ~ ~ ~ M ~ d' O ~
O O O O
O
C/~~ ,~O O O O O O O O x O O x O x x xx
V~~iC/7~lr1 r~~ ~
'-' '"a ool~d'd.,M (VN N N N N ~"'r',."~r''
a1 oo
p~ ~ .. .. ..
N pp o M op tnl~d1.-~M O O N M 01 ~O~ ~ ~'i~-'d'~
M t~~ V1 ~ ~O-1 N O oo V1~ O M o0N O
~
01
O O O l~~Ol~ ~OM O d'00l~ l~~ N l0 V'7O M
O P~ ~Ø.,O l~ ~ p O O O O O O O O O O O O O O O
O
O
G7
., O
opN
,~,
~.~
' C~CJ
O O
O O O '"''
.a-.,
,.._
-, ~ l~l~ O M
,~ O M ~p
s.,i ~ ~ v~cn
G7 ~ ~ ~
r
O
a\
d'
N
N
N
N
a>
M M
D\
N
M
a
x x
O O
112
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
a'o
'"',-i,-i,-i,-i~-;.-i,-i,-i.~O Q1 ~ M ~rjN N N N C~jN N N ~' ,-i
..
N -~a\ ~n~ O v'iO ~ p ~ O N ~ O (V~ ~ ~ t~~ ~Dd'~ pv
~ O v00001 d'ir101 o
a ~ ~~-l~ a ~ ~~-1~ ~ ~ o ~ o o o o Noo o o o 0
~,~; ~;x ~ ~ ~ x x ~ a a ~ x
'-m'"'~"'~'_'~,'~ r'r-''r"',-~ ..d'M criN N cV(VN N N N .-;
O O v0~p~ O O~~n N '-'~ '-'_ ooco vpp ~ ~OcVdv 01I~v'ip
O N ~n ~ON d' d''d'~n ~ M N d' t~~O~ M ~OV1 d'l~Ov M
V1~O ~ ~ ~ l~l~l~ M O O O O O l~ N M ~ O ~Ol~ l~l~~ O
x O O O O o O O O O ~ ~ x p O O O O o O O O O O O O.
~ ~ ~ ~ a ~ x ~ a ~ ~ x
.. N
..N
d>~
N v~ ,!,
cd
o O O
a1
[~M CO
H H C7
M
N
O
M
O
M
r~
O
113
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r;
..cri
.-;r; ri~--i~ ~-i~ r; ~ ~-i,-i,-;,-;r;,--i,-;,~;r-i,~V~Ov N N O
I~ '~N O ~ O M \O~ N ~ cn O 0101 M O O
p ~ ~pN l~00 ~ ~ O~ ~ M I~ d>~,'~~-!O ~D (yy
~ O O p O p O ~ O O O O p O ~ O O O
x a x x ~ x ~ x ~ x a a a ~ ~ ~ a a a N
--i-i r"~~"'-i,--.iri'~ ~-i'~'~ri ,-i,~~i ,-;~-iri ri--V --~i
i
0oO O '"'O N 0oN ~ M N ~ \O~O~ I~M O Qvl0~ ~ ~ 01pip
tnO ~ M ~O~ N ~ \OM '-~O ~ON M d'V1 Q~~OO '~ [~O
M M ~ d'O O O N M ~ ~ DO ~ ,~M O l~l~ V~M O N l~O
O O O O O O \pO O O O O O O O O O O O O ~ ,T,O O O
G7 G7 O
~
C/~
N M
M M
O~ M
'd' ~O
M ,
i
N M
N
01 O
N
O~ M
~f' M
dl
G7
x
O1 O
O .-i
114
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N O ~ ~ ~ lD
'"'op.. ~rj ~ ~ ~ ~ ~ ~ ~ ~ ~
N N ~ H r1 '-iv--I d' O1
i --i ,--i,~ rj ,~ ,~ ~--.~,~r.,,-i--~--,
O N O O O -~a~jv0\p ~j~ M ~Od'' d'cnO~\O N l~ O O
r.~',~, ~ ~ N ~ ~ O O N O ~ ~ ~ ~ ~ ~ Ix L~
N '~ Z',-ci~ a O O O O O O O O ~ O O O O O O
O ,-i~ d= ~ ~l'r~,r~ v7~irx'r~ir~iO ~-.l~lr-1r.~''r.~,~l ~ M
~iM N N ~ ~ ~ due",~ ,-i,-i,-i'-i..-i,~1
,~r;
(V _
p O p ~ ~ ~ ~ ~ d0"O due.~ ~ l~O ~ due.'l~~ ohoN ~ ~ p O
~ r~O ~'~~ O O O O O O O O M ~Ol~l~l~ .--W~l~
O a ~ a O O O O ~
cril ~ a>
C/~~ ~ ~ ~',_~
O
O O O O O O
,~,
d_ ~i.~ ~ ~ N
~ ~ N ~ ~ a>
~ a~ fs,a~ U C'7
v~ ~
d' ~ W O
M M M M
M N ~i
d ~ opo
i i
H N tn
00
N N N N
H H
N m d- 00
H
l0 ~ M
-t
_
Q\ ~ D\
M 01
00
N
N M d-
115
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
..-; o
'-'~~M ,~ ~ l0Yj m N N N
N
O
~ ~ p1 ~ ~ M ~
r-i
o o ~ ~ o 0 0 0 0 0
a 0
,. ,..
. .a
x a ~ ~ x a a x x a
a
~,N , ~
v0wi M N N N
N
~ 01 ~ ~ 010o N ~O,-,~O
L~~ O O p ~ ' O O O O
'O
, O O O
.
L;
N o ~ ~ ~ ~ ~ ~ ~
a\
d in~ v001 N ~ M ~ N v
' '7
~
~O~ oo.~'_"'N N N N M M M d'~ ,-i'-' ~ ,~ N N
' ~ N
~ Oi~ 'n ~ ~ ~ cCc~cc3' O v~O M ~,d ~ ~ ~ i ~ ~
; i
, ~ _ ~~--~~-.,-.,-.-~~ t-~~ '_'ii ,.c,"M i ,~ . ~ Q''~
N 7 cad N
U H ~ '~ C7C7C ~ ~ ~ I~ ~ ~ ~s ~''~ ~ ~ ~ ~ H H C~
L7 0 0 0 0 0 0 0 ~ ~ 0
0 0 0 0 0 o ~, o o ~ o o 0
~ M ~ M ~ o ~ N ,--~ 01r
o d ~ o in
~ O~~ ~ N N N O cn' M ~ ~ ,-~~ ;',~ o0op~~ ,-~.,~ j N
N M
O O ~ r.,~ s.~ ~4 ~ m ~'~ ~ O ~"'~ ~ ~ N a..~
~ 7 _ ~ ' d ' ' ' ~ v ~ " ~
' c '
~
C E~~I E-aU , C ra, ~ d P..iE-i~ ~ ~l H E-~~ U ~ U
7
d\
N
M
M
N
O
N
M
d'
N
O
N
M
N
N
~ N
M
d'
d
W
x
116
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
' O
\O , ,_..; cd
i ~ i ,
- , ,-'-.;,-;,-.,-~,~,-i,-;,-;,-i~-',~ ,--i,~o ,-i ,-;,-.;,-.
~oo
_ _
o~oo~o~ d- N ~ ~ O ~ ~ ~ ~ N ~ ~ ~'~
d ~ x ~,~'ll~o o
' o o
0 0 0 0 p p 0 0 0 ~ O
0 0 0 0 0 0 0 ~ '' 0 0 0
~'
~ x x x x x a a a a a a a x ~ a a a a a
~ ,-i,-ir-i,_;~-iri ri,-i,-;r-i~--i~ ~ '-iri~ ,~~ ,-i~-iri a
~
ue M d ~ N '~~ V'i01a\N cnN ~D ~pVjcn Ov
dp ood'OW ~
d N N a\ l~v~0001 l0O l~ ~ ~ d- oo 0
'
~O ~D~ V1 ~ ~ l~ l~~ l~t~ l0~ ~ I~l~~ O O O ~ 0 ~
0
O O O O O O p O O O O O O O O O O O
C/~O p
a x x x C/~ a a a a a x a a x
-a V'i N r.id'
N
M ~ M ~ ' ' ~
'
M d d V~
M 01
~ ~ M
H ~ C7H (~ H H C~ H Q~, ~ ~ ~
. _
~ ~ (~ i C7
c
M ~ M ~ ~ O O
p ~ ~
p
N M M M M ~ ~ d' Ct'~ ~ pp 00
i i
i"" ~ ~ N ~'"t-~~ ~ O z.
v~ a ~ ~ ~ ,-, ~ ~
~
G7 H ~ H
O
M M M
O M M
r
N
-, ~
~ \p o0
N
~n ~ ~n
00
O1
O
O
O1
d\
x
x
0
x
117
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
N
N ,~'-',-i,--~ .-.i ,-i~ 01~ N N ~-~,-i,-i,~~ ~~
,-i
O d100 ~p~ \O o0 O O ~ O M 0o,-id' O d'M
~ ~ ,.. ~
O ~ p M ~D ~ ~ O ~ ~ ~ ~ N ~ ~' '-'i
O
~ ~ ~ ~ x o 0 0 0 0 0 0 0
0
a ~ a x x x x x x~
N M ,~ ,~~:
N ,-i~ ,-i,-a.--i .. M N N ,-i.-i'-i
~ M O '"'\O d1(j~ M i ~ ,,~ d\l~O d'l~l~
O~ ~ N
h p ~ t
p
O o O d'~ ~ ~ o o ~ ~ ~ O v~~ N O , O i
o -r
,~O o ~ ~ o ~ x ~ x ~ x O O o o O O
O
~ ~ ~ ~ o ~ ~ ~
0
M ~ ~ '-'
O M ~ ~ l~N
p ~ j ci~~ Q.
d ~, E-
~
C7~ ~ ,~. ~lU
O O O ~ ~ O O
O O
M
N ' N ., ~ ~ ~
d d '1 ~ l~
~ V
a3v~v~ +' .~-'~. s~co~ c~
N .
~ _ ~ ~ x _
~ ~
a a ~
O ~ N M
d' d' d' d'
~O \O ~ O
~ M ~
O d' V
O i i '1
i t
O ~ O N
01 01 O
N
a1 O
N N N M
M 01 V1 O.
01 ~O N o0
N ~ O .-
Ol M I~
V1 N
a\ ~ ~ at
G7
x x x
0o O~ O
N
118
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~ M
'"' ,-i ,-i ,-; d1 ~ M ~j N N N r"' r., '~ '_"i ~ ~"' ,-i
,-i ,-i N oo d'_ N ,-i .-; '.-i
d- ~ _ _
~ ~ p
M N
h
O l~ l~ ~ l~ O M ~ o
l0 x ~ a l~~ N o
O O O O O O '~ O M V'1 ~ ~ ~-" O M N
d' l~ l~ tn d' d' M ~' O O ~ ~O
O ~O V~
O O
r- O O O O
x~~aaa ~ ~: ~ ~ ~~ x x x x C/~ r.~, x, x
aaaxx
-i ,-i ,-i ,-i M M N N N ,-i ,-i ~ ~ r-i ,-i .-i
,-i ,--i '~ ~ ~ON ,---i ,-i ,-i
~O oo \O N ~ ~ ~ O c'~j 01 ,-i ~y ~j ~ N ,=i \O
\D ~ O~ al ~ oo wfi
~ ~ \O O d1 M ~D N l~
- M O M
~
d p o '"''~O O I
l ~ x p M N
~n l~ l~ V~ ~O O M ~ N
N O oo l~ O N N ~ ~ O V'1 N N M ~O
O O O O O O O p
O O O O O p ~ o O O O O O
xa~~ ~ ~ x a~~~ x~ x x
M ~O
'~
M
~
N
O
O
00
d-,--~V1
~ O
N
~
C7_ _
U U
M
M
M
d\
d.
O
G7
x
N
119
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~C N t~ O
-i,-;,-i,-i,-i,-i,-.;,-;,-i,-;,-i,-ir.;~ O\ O O\ r-;
N a O Q W1cri0op ~O~Oo0 ~pnj O ,."L,' O N
l~t~ in~nO ~D N a1~ d'~n~n O
i~l~ lD~D0010 M M h (~t~l~ N ~ N
O O O O O O O O O O O O O O a
a a a a a a ~ ~,a a a a ~ ~ n , \
-, ~
ri~ '-i~-i~--iri ~-i~-iri ~-i'--ir; ~--i,-.;~ _ ~
M d' M ~Dl~lW n O cV Vil~l~ oo~p ~ cVi -'O d'
00o~ ~ ~ ~ O ~ ~ ~ ~ ~ ~ O O O O O
i0-11~-O.lO O ~ O ~ O O a O O O O ,0~,~ "~L,' ,T, ~ "r~,
O
a''
,-~
~ D\
d' N ooN
0 . >,
H a ~
0 0 0 0
d ~ ~ N
~
a ~ a~' O H ~
w
N M
M M
N -~ ~ ~ oo
N M ~ due- ~ ON
M i i i i
i i
N ~ O ~ O
N
N Q~ M d- O
M ~ M M N M
v--1 I/'~ r-I r-i ty -1
0 Ol d'
O ~n d' d.
G7 r~
N N
N N
120
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-r ~ ~n~ ,-; o
N i i ~ M
.-ir-i~ ~ ~ '-r ~ ri ~ ~ ~ d1M lflM ri 01
d.
00~ ~ O O ~ M O d'O Wiv-;d1~ O ~n oo~ \O O O
N
-,,--~~ h fx N O ~ O , ~ , ~'' ~
~
'
o O d ~ p ~ ~ ' ,., \O~
o ~ p ~ T~
O O o ''~' ~
ff,a ,xx x a a a a a N a ' a
, N ~ ,T~' O
M t ,--~ cd
-i~--i~--ir-.; riri ri,~;ri ~--i~--~ri ~--i ~O~jri
00
O w-O ~ ~ '~ VN1d'v0 en~j~O V'i~'_'O oo'"',~ opp~,~ '-'
i
O M M ~ N ~ O N O O M ~ p V1~ ~ ~ O O
~ p ~ o
0 0 0 0 0 a o ~ o o O O O O x ~ ~ o
a
N N
~ ~
ap~ ~~'~ ~ 'U~ _ _
C7U
O O
M V1'"~O ~ ~ O V1 O
~ M ~p,-i,-,'"iN
v~ ' ' v W ~
-. .
x v w ~ a H a H a~ x
0
O
N
i
' ~ M
M O
M M M
V7 M M
00 N
d1 O~ M
N M
V7 N O
a\
U
d
x x x
N
N N
121
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i~ N ~ O
N ,-;r-i~ ~-i ,-iM N N N ,-;r-i,-;~ ,-i,~~-iH '"'H N d- M
cn
M M O p O O p O~~ ~ O l0~ d' ~ .-i(sja1 ~ d ~
' O
O
O _ ~ ~ G~ (xO ~ ~ v'1N o0,-~W O V~d' M
O O "'t7~ ~ ~ O O p O O p O p O O O O O "'~~ a O
O O
= ,~x ~7 ~ "~C/~x ~l~l~l '~',
1 ,~ N d ~ n N N '~,.i i i i ~ i ~ i =
i n
- r, ~ c ,-,-,- ,--,-.- ,- ,-.-r d
c
p M O N ~ ~ O M M Ovd'Ov O W"'r 01 ~ ~ M
O
O O d ~O~Od' ~ r ~ ooN r d1 O r d'
~ o ' o ~ ~ V1
o M r o vo r M --~~ r r ~ r r ~n o r
a o 0 0 ~ x ~ a o 0 0 0 0 0 0 0 0 0 0 0 0 0 ~ r
o
0
,.. a x a x ~ a ,~,~a ~ x a .~ ,~
,
a
0 0 0 0 0 0
0
-~-i~ N ~--~~ N
i , , ,
,
_~_~ _~_~ ,
F~ ~UC7 L7~U ~
H
N M d-
r r r
r ~ M
M 00 In
M ,
, ~ i
N in
01 O
M d-
H ~ H
O~ ~ O
M M H
H M lD
_ a1 r
o~
r ~ N
H U
x
a\ o H
N M M
e~ r-1 H
122
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N (~jN ,---;'-ir-iriri ri~ ri,-i,-i~ .-i,-ir-i~-i,-i,~'"'''-;.-i~ ~--i
N ~ ~j~ ~ l~\O l~ OvO \OM M p M M ~Od'Q N ~ O
~ ~pv0 V'1000o N M O N O ~ ~ M l~N ~D~ ~ ~ V1
O p ~pN d'~ d' d' O M O '-'l~ \Ol~V1 lp~ ~ l~a
O x x O O O O O O O O O O O O p O O O O O O O "'C7
~ x x x x x x x ~ x x ~ x a a a ~ a a x ,~~
M C~jN N N ri r;ri,~ ~-i~;,-;,~ ,-i~-;,-i,~,-a~-ir;,-i~-~,-;'-i,~
--iood' ~p~j01 N ~Dd' M p p l~ ~"~d'~ pp~p,-iVicnl~ 01
M M d\ N d-~ O~00[~ ~ ,..~,-i~ V1O ~' M ~'V1 O ~O~ O M M
[wf'~ V1I~~O M v7V1 O O ,-,,-,O l~~ \O~O~O 00~O~ d'd'd-O
O O O O O O O O O O O O p O O O O O O O O O O O O
~ x x a a x x x ~ ~ x a a x ~ ~ ~
0
N
N
N
d'
N
N
N
D\
x
x.
x
N
M
123
CA 02395816 2002-06-26
N N N N '_'~ ri ~ ,-i ,-i ,_; ,-; ,-i ,-i ~ ,~ ~-i ~-.i ~--i '"~ '"'i r-i
O O ~ ~ O ~ O ~ O ~ ~ ~ ~ O ~ ~ ~ O O O ~ ~ ~ l~ ~ r~
'~xaaxx~xxxxxxx°a°axx°°aa°~
M N N N N .---i ~-i '-i ' ~ ,-i ,-..i ,-i ~---i ,~ r-i ,-i r--i ,-i ~-.i ,-i ,-
i r-i ,...,; ,-; ,_;
M ~~ .. .. ..
000~oN~ N~ ~000~Np~~ti ~ ~aO~~
O O d' M ~ N O O ~ d' M ~O 00 V'7 V1 V1 ~O [~ l~ d' O
00~~0,~0.,~0.,0000~~OOOOOO~~~~0000
O
.,d'
~,G~
O
O O
O M
t
124
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ,~ N
~--iM N ,...i'-''-''-',-ir-io ~ ~ M M N N N N ~w''-"ir''r''
O ~ op~p \OO ~ d-v~p O ~ ~ ~O~OM M 01~''~N O '_''
O O lfl~ ~ C/~ ~-'p M V>O O 000l~O O ,~ O
p O O O O O O "C ~ ,..~O O O O O O O O O p
a ~ x a x a a ~ N ~ a x x ~ ,~x x ~ O
N ,.,.~,-;,-i,-ir;,-i,-~ ~ d' M (wj~'1N N ,-i,-i'-iO
O
O
xx
,~
,-i
O oo ~OooOv ~ ~ oo a1~Op ~ d'a1O ~ p
p M l~u'~O ~ M d'\OV1 p M in l~l~N I~ V1O ~ ~ o0
O l~M ~ V~O ~pl~~ O l~ l~M ~ I~ \O~ ~ V'1d-
O O O O x ~lO O ~' ~ a1 O O ~ ~l ~-.7O x O M
O
O
O
x
O
N
0 p O p ~0~0 ~0+~
tn ,~ [~00 ~'
d-~ O~.-
~
_~, s~ N p N _~ _.f~,
-',
N
M l!1
M M Q1
l0M In M
N , , tn
41 M M
M
N d N
"
N M
M
w W
x x
M
M M
125
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
H '"~r-W--IH y -1y --1~ N ~ ~ r-1H H e-1r-iy"'~r--IH O O1~ M M
~O V1 " .. tn ~O01
ooii'iN p ~ p O d'tn I~N ~p'"'O ,-~~ ~ O 01O O M 01 (V
C/~R~ ~p O O
,.~,~ ~p o0
O ~ O O
O O O O O O 'O O O O O O O O O O
~~
x ,~ ,~w ~ ~ a ~ ~ ~ x x x x x w a a x x a ~ ~
v-Iv--1.r-1r-Ir-I,y--Ir-1 M r-1r-1',.,y-i H .,~r-1r-1,..~H '-1 'd'M
~"''~t~OO ~ l~N ~ ~ oo COv'ip O cn M M d:N ~j ~'~ op ,--i
~ 01 O l~d\~ M V7 ~ ~ lp~ ~ ~ O ~O~ N v~ p l~V7 l~
~OV1 l~l~I~ d'l~V1 O l~ N M '-'~ l000 \OM ~ d' O l~ l
~ ~
0 0 0 0 0 0 0 0 (/~0 0 0 0 0 0 0 0 0 0 0 0 ,~0 0
x w a ~ ~ w w ~ x x .~w w ~ x ~ ~ w
~ N O N M V
0
e c ~
n O
I~ lDV1 '~~ CVM M M ,~, i
-,
~N r rn ["~
~ ~ C7~ ~C7h
~J
1 ~ , r ~
~
t- r O O O O O p O O
O O O ~ ~ N N ~ ~ ~ N ~ 00
~ 0 ~ ~ M 00
.--~N 0 N M M ~ ~
0
s ~...~ ~ ~, ~ ~, O O t~ ~
; O O
_ ~ _ _
~ ~
G7 H ~ ~ ~ ~rG7
Q\
N N
O
O ~D
O
O
i
N . l~
ue ~
d d
' -
M O
w
w
U
x x
M M
126
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M M N N N N N ,-i,~ ,~,..1r.;~;,-i,-i,-i~ ,-;,-i,-i,-i~ 01
urncn ~ ~ d'l~ l~l~N ~ O_~l~ y r101N O ooOv ~ v0O O
O O O O O O O O O O O O p O O O O p O O O
a a x a a a a x x x a a a a a a x a a a ~ ~ M
M M N N N N N ,-i~--~.-;.--i'-i,-~,-;,-i,-ir-i,-i,-i~ ,-i
-i a1\O~ O O ~p'-'~ O 01 p M l~\O M d' V1N ~ \O
~Od' ~ ~ O d' V~V1~ 'CI'N M O O V1M ~ ~ V1 V7O\~ O
l~ ~ N oot~ l~M ~ v1~OO o00ov0~O \OO l~ l~~n
O O O O O O O O O O O O O O O O O O O O O O
a a x x a a a v~ x x a a a v~a x
~pooN
cVM ~n Qi
c~a ~
O O O ''~
.,r''''a'~O
M
i
M
O
M
i
N
ue
N d
"
N
d1
N
x
a
w
x
127
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N O
N
i'N '-''"' Ovoo(~ W d'd= M M cn N N N N c~jc~jN N
~
i ~pO oo O ~ d' O N 01 O M O 01N t~M ~ ~pcrip
V1
N ~pV1 00
~
O N O O d ~1W O lpo0 tnO ~nV7~ l~
r~ : ~ ~ t~'x ~ x x r~ x x '~a r~r-aa r~
d
-i,-i oo ~ V'id' d'M cn ~j~j~'1N N N N N
vjcV M M ~ ~ c~nO O W ~i'i~ d\ \ON ~ M N O~
'i
N d-V1 ~ N O l~O V1'd'O l0W n v1N N '"''~ ooM
O O O d- 'd"N
O O oo l~l~oo ~O~ ~D M N ~Ot~~ t~
" O O O ~ O O O O
~
,,.O ,~O O O O O O O O O O O
.,
T
~ G7
v0 0od=~ ~ ~ ~ O ~ ~ I~ N
~ ~ ~ N N ~ '
vDo ~rid'~ o "''~ ~ o N ~ M ~ d
o o o
i i N ~ . i ~ i ~ i ,~O O ~ ~, v y''Q.~ ,_,~ ~ s.,
'
r.,,~O ~ ,-,~ 0 ~ O ,-,O cd~ ~ ~ (~ d [~d ~ U ,~~, H
~ ~
9, U V''~1,~ ~1,7 p..,~ O O O
C
''~ d ~ O O O .,~.,rO O .,~O O O
O ~ O O O O O O 01O d'
p
ooO ,-.~N
O ~' ~ ~O O ~ M o0 M \ l~
O ~p ~p M O 0o N N t<1O ~
tnl O> M Ln00 ~ M ~O [~~ ~ ~ e-~,-..~~ ~ N M
~
i ~
~,~..cd O ~,~..cc W ' j, O N O O o""O ~ R''O O f3.~"'~,_,v~
n ~'
_ _ _ _ x ~ _ d d d
~ d L7 d ~
cn w v~ w a,a~ a,N a., w w H v~ a
M
_
i
M
00
N d'
N O
O
N
d\
O
d
w
x
M
128
CA 02395816 2002-06-26
'-; ,-.-i ri ,--i ,--i ri ,--i ,~ ~-i ,-; ~-i ,~ ,--i ~-i ~-; ri ri ~-; r; ,--
i ,-; ,cad
d' oo H ~ ~ O '~d' ~ ~' oho N ~ ~ p ~O ~ d' O in oo vD ~ t~ oo dv
V1 ,~-i M V') O p ~O ~f' l0 ~ ~--~ ~ ~ ~ ~D ~ M ~ O ~ ~ O~
p ~ O O O O O O O O O O O O O O O O O O O O O O O
x~xxxxxx~xxx~x,~,~,~a,~a~~,a,~~
r-1 ry r1 r1 r-i v--i e-1 e-1 H r-I H r..j r-1 r1 r1 v--1 ~r-1 H v--I r1 v-I v-
i H
N v'i O '-' O °° l~ O ~ ~n N cn d' ~O p ~ ~ d' d' t~ cn p O
cV a1 N
0o O ~p ~ oo ~' N ~ V1 l~ a> ~n N ~ ,-y0 O oo ~ \O M d' VW n
N O M N ~ M O O M N ~n ~--~ ~ N ~ ~p op ~ M l0 M l~ l~ l~ M
O O O O O O O O O O O O O O O O O O O O O O O O O O
rn . 1 rn !'T! rn !T! !T! !'T'! !T! !T! !T! h'! !T! !T! rn . 1 . 1 . 1 . 1 . 1
. 1 rn . 1 . 1 . 1 !T!
129
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
.-iM
O ~ '~~'~'- m-ir-i~ ~ ~ ~ V~ Vl~ d' d'd"~f'
o ~ ~ o a ~ ,~~o M
x o 0 0 0 0 0 ~ ~ 0 0 0 0 0 0
~?~ H x x ~ ~ ~:o x x a a a a 0
7 ~--i,...i~--a,-i,-i,-;~ N ~p triV'jd= d'd'0
a
a
d'
M
~ N ooN _DO (V~ ~ d Yi ~ SriO vD
M 0 ~ 00~ V1 O O I~ ~ I~~ ~ l~l~
C/7,~.,O ,~,O OOO O ~ ,.~OO ~ O O O O O
O
N
O1 ~ ~ ~ ~ p O
O ~ ~ O ~ O
+~ ,-W ~.~--~N ''
O
N M ~O~ O~ ,-iN
_~O O O _~
H ~ C7G~;0.~!~C7
M
N M
O
i
i N
N
N d~-
V7 .-~ ~ ,
N
O
N
a
O
d'
130
CA 02395816 2002-06-26
M M (V N N N N N N N N N N N '-' .--i r' '_'i --i r'' ~ '_"," '-i ,-~ '-' ,-i
N N v~'~ ~ v~ dM' ~ ~ a> ~ ~-~ °o ~ ~ ~ due' ~n ~ ~ N
O O O O O O O O O O O O O O O p O O O O O O O O O p
~a~x~~x~a,~xaaax~ax~xxxxxxx
MMMNNNNN~j~jNNNN'1~'"~~'~~,-i~'-~~~-i~r.i
0o Vj \D O cYi N N cn ~j M ~ p l~ ,~ W Q1 Qv N t~ O O N M 01 O p
~O Wr1 ~ N ~ N oo ~p ~ 01 d' oo ~ d- '"'' p~ t~ d- ,-, v7 N
l~ ~O l~ V1 ~ O ~O M ~p \p ~ M l~ V'7 N O ~ ~ d' O O O O O ~ N
O O O O O O O O O O O O O O O O O O O O O O O O O
1 . 1 . 1 !'1'! !T! !T! !'N !'T'! . 1 . 1 !T! rn . 1 . 1 !T! ~, ~'1"! !'T'! t
~, rn ~"r~ !T! ~ !-N
131
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r' r'~;,-i,-;,-1,-~r',-i,-i,~ ~ ~ ~ ~ r;cd
v ~ vM'1~ x N
N d'N ~ ~ ~ ~ ~ ~ p c t O
n
~ a ~ ~ ~ x x o ~ ~ M C/~l
0
r- r.r G7 ~ ~
ri~ ~i riri ~ ~ ri~..~ri~i~ ~-ir-i
t~rld0'N ~ ~ ~ ~ ~ d~"~ ~ ~ N ,--i
~ N O ~D
N inM N ~
O M
d-O ~ O I~~ M l~ ~ ~O~OO l~l~O O O O
O O O O O ~
O O O O O O O O O O C/~O O
C/W .-ar.~~ ~ ~ ~rC/~ ,~C/~ G7C~
M
N N O N ~
_
- Oy,-,O s
d ' ~n
~ _ .,
O O
O
O O O O O O O ~m n
u~
0~1
~
W, a~ j, ~ .~~,~: W
.
0..~ ~ ~ C7 w C7~ H 0.~U
a\ d.
M
'~ l~
d.. M
i
i
00
N v1
M
00
O
dl
O
N
~.
132
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
M
~ d= d'd'M M M M ~j N N N N N ~j ~y"
(V
O W ,_-ioo~ cri~--~O M Vp ~ cn~D \O01
M <f'[~~'[~ p
p
O O O O O O p O O O O O O Q ~
x a x x ~ x x ~ ~ x x x x x ,~x
~
d= 'dd=wjM ~.rjM N ~jN N N N N N
N
p ~ oo ~ ooO p 01~ ~Od
p ..
Q ' ~ _ ~ '
O M d ,~M ~O'-~~ \O'CfV1O O V"7
Q ~ p V1
x a ~ ~ ~ O ,QO O
~ ~ ~ ~ ~,
~ ' O ~ O ~
dl M l~N .. ., M ~"~M d V7~ ~ ~ O O
N p ~!
N N M ~ V1'-''"~ N O '-',-~'-''-~,-,,--aN N ~'1N M
M
'~~' ~~ ~ ~ ~ ~ 'nf"'~ ~ bD R.'
o
_ C ~ ',p,, ~ ~, ~, j,~ ~ ~ ~ ~ ~ ~ U H
~ 7 ~ ~ ~ a 7 C '-'7 ~ ~ C7
0 C 7 ~ C 0 0
0 0 ~ o 0 0 0 0 0 o o 0 0 0 0 0 0 0
0
~,.,.~.~ .~-.o .,.~~ ~ ~ N O~,--~~ O~O OWn I~ N
-,N l~,-~O tryooM d',~ M ~ O N ~ d'l~ 00OlM d'~ l~ 01
N
N ~r1,-rN d' ooO~,~~, ,~,-~,--,,~,~N N N N N
M
J, p y~byD~ ~ Q.'~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
x ~ 7 ~ 7 , ~ , , c
7 d
v~a1 a w a,c ~ ~ v~ c ~ ~ C ~ ~ x w d ~ C7~ ~ ~
a
dp'
d'
dl M
M
N
l~ N
N N
N
N
O N
O O
N
x
z
w
x
x
N
d'
133
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N N N ~.j,-i,-i~'',-i,-;r-ir-i,-i~;,-i~;,-i,-i~;,-i'--ir;ri~
~-i
o0o~ d~'~ ~ opo~ ~ O ~ON d~'M ~ N ~ O O ~ ~ ~ p~pN NO
O M O l~tnp ~ lDd' N d'N N M O d' O O O O O tn lDO N
O O O O O O O O O O O O O p O O O O O O O O O O
x ~ ~ ~ ,~~, ~ x x ~ ~ ~ x x H x a x x x x x x x ~
O
~H
N N N N ~.jN ~-i,.;~-i.-;,-i~-i,-ir;r-i,-i,-ir-i,-i,_;,-i,-i~;,--i,-;
,-i
0ocV ~ ~OvjN d'~jVj oov'i~' ~'1cnoo,-iM ~ cn ,.-iM m ~pO p
~nl~ N t~op~p N r,O r.,d-W Ovd'~ oo ~Od'N ~ N oo ~.,~01~r7
~O V1V1d-M ~pN M d'O M M ~O~ l/'1N v7~ d-O O M N ~
O O O O O O O O O O O O O O O O O O O O O O O O N
x ~ ~ x ~ ~ x x x x ~O
O
O
O N
oMO~ dO
'
~ '
~
x _ _
c~ ~
O O O
d-N M
r~ r~
134
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r;,--i'-.i~"''""~,--ir--~'"~~-.i~-;.--irir; ,--ir;.--i~-i~--~~ ,-ir;r; ,~ri,--
i
00~ O N Wit'd'~ ~O proW riOv a>~ ~ ~ ~ d' ~ ~OO~ ~h ~-i
x O M O ~'V1 d'~ O IND~ ~O0001~M 1~ d'VlO O N
x x x x a x x x a ~aa ~a a x x x o 0 0 ~ ~ a
O d'~O ~ O 01 N ~ N O d W l~ a1dWi'i~ ~ oo ~Ooo~ O OWa
M ~O~O ~ ~'~O d'~ N N ~DO ~n ~--W ~O M ~ l~ d'N d' d'd'E
O M M ~ O O O M V1l~O ~ V'7O V1 d'~ M ~--iO l~ l~l~00
O O O O O O O O ~ O O 00O O l0O O O O O O O O O t~
O O 07 ~ ~r1
l~
l~
O
O
135
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ~ O M
cd O ~ ,~~ M
"' i "'i
riri' r ~ -, p ~ p~ N .--i ,-i
O O O O
O O ~ ~ N N ~Y O ~
1 , fx C/~ fx fx
p
O O O _ O O ~ M ~ x ''~ ~ x '~ ~ ~ x
O
a a x ~ x ~ ~"
~ ~ ..N a.;
i i ~ -i--i-i -i V7 ~ N
- ,- , ~ ~ , ,--i
O
d' O ~ O r-i~ d1 O a1
d i ~ x
~ V 'd n o ~ O ~ ~ O 1fl ~ p ~ O
O t ,.
x ~ x '~ ~ ~ x
~ x x x x x ~ ~ ~ ~ x
O_
M 01O M ~ N O M Vl l~,-iM
M ~O~-~~--~i i ~ ..-iV1 ~ ~ ~ ~L
~A a ~ ~ ~D N ~ N ~ W n
. , ~ N
teW
~ r~~
O O O ~ ~ ~ O ~ p p p p ~ O
O ~ M
N ~ ~ ~ O
N 1
~ ~ ~ ~ f N ~ ~ N
.~.~ N N N N . ,L
" " i ",
H H ~U v~v~v~ C7v~E-~~ E-
d- d dM'
M N d- 1~ ~ v1 O
N
ue N
' d d'
'
i i i i i
due' ~ ~ M N N
N ~ N O ~
~ M V
'1
~0
t~ ~ 0 " N
d
n 0
c o
r ~ N
~ d' oo N
N O ,--~ ~,
M d-
00
M
W
W
,
x x x
d. d- d.
136
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M N N N N N ,-i,_,r-i,-i,--i,---i,-i,-i,-ir.;~-;r-i,-i,-i,-ir-i,-i~;~
,.1
.-i~ p~oo pp~pv'i~ opN Ov N ~ cn a1" " d1 ~D
N M inN ~ N ~nN ,-~,--mnO ~ 00l~ M Y7l~0l~0d1~ M M M N
V7~[-V1d-\p O V1'-'~D ~OO O O ~ l0 r-~O l~l~ l~V1~ d'O ~
x x x x a x x x x x x x x x x x a a ~ x x x \p
x
M ~rjN N nj N N ~ ,-i,-i'--i,-i,-ir.i~-i,-;,-;,-ir; ,--a,~~ ,-i,~r;
,--,"
d'cril~O ~ t~p WVop ,--ioo~ N ~Dl~ ~ l~01~j crioofV d'l~~p
Ov~ ooN \p d'M ~ ,-~N ~--~d' l~~p,--~\Do N ~p O M ~ M l~,=i
d'in ~WO ~ v~d-~ ~. O M V~ ~--~N ~ M O ~n~p ood'~ '.~ O
O O O O p O O O O O O O O O O p O O O O O O ' O O
x a x ~ x ~ x ~ ~ x x ~ x ~ ~ O x N
~O
p
O
~~
0 0
N
M 00
by
_~
137
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d-
~ O O
i --.i-,-i; i ~ ~ "
N N ,-, , , r-,- r-;,-ir-i,--i,-i,--i 01 l~
d.
~O O O d1 d'l~~-'r-io_o~ p~ d:,.'...il~ t%iM O O O
~ ~
O "~ ppd" dl~ M M M N ~ ~ ~ ~ M ~DV1 0.!O l~ V1
~
o a o 0 0 ~ 0 0 0 0 0 0 0 0 0 0 ~ ''a~ a o
0
,~ o a a '~,x x x r~a a a a a a a , a
.--i'-' N N N .--i,-ar-i,-ir;N r.;,-i,-i,-i,-;,-ia N O O oo
~-i ,.-i,--rVi
00
N ~ ~ ~ ~ ~ ~ o p ~ O ~ O ~ h ~ ~ ~ ~ ~Ol~ l~
O
~ ~ o
o
0 0 ~ ~TO O O O O O p O 0 0 0 0 0 0 0 ~ ~ 0 0 00
'
, a a ~ x x a a a a x C a
,
,
N
= ~ d'
d SriN N C'M ~1l
t~7I ~1 c'i
~
~, _j, n
~ ~ O
O O O O p O
O ~ ~ N ~ o ~ .-.-M.i
O N _cd _cw3~. _~
a a ~
O
M
o
N v0
O
M
N
M V1
O
O
~nd'
N M
as z
x
x
138
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d'd'd- M M M M M cn ~.,jcncnN N N N N N N N N N N cV~j
ch~O ~ ~ ~ d'O ~pO N o O ~OO N ~ O N 01~ ~ N (V
O O O ~ O ~ ~ O O p O O O O ~ O O ~ O O O O O OMop
~ a a x x x a a ~ ~ a ~ ~ ~ ~ H x ~ x ~ ,~,~ x ~ trj
d=d'd' d~M m M cri~''~M M cnN ~jN (V N N N (V~j~j N N p0
d'd'01 00~ criN crio d-d'~ ~ ooI~d' cri0100 ~ 'd'M r''~,a
v1OvO d'~ O M O ~ ,~v'1M ~ tn,--W~ ~ O N Ovp ~p ~ N ~j
M l~00 l~O O O o0~ O I~l~~ M l~V~ O O d' V N
O O O O O O O O O M O O O O O O O O O O O O O O cV
~ x ~ x ~ x ~ x x x x ~ x
O
~~
139
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N ,-i'--i~ ,-i,-i~ ~ ,-;,-i,-i,~,-i,-;,-i.-ir,.;,~,-i,~,-ir;,-;
~Ocn ~'~'~ O ~Dcnoo ~ ~~cYiii'icV~ ~n y 0 in ~jcnN ~pc~ r-i
v1~n N l_~d' ~n~ O d'r",tn V1cnN l~ p d'tn ~ in~ ~.,~N 01
O O O O O O O O O O p O O p O p O O p O O p O p cn
~ a x x ~ x x x x x x x x x x x x x x x x ~ x x d1
N N N N ~1 ,-;,-i,-i~ ~'r; ,-i,-;r;,-i,-;r-i-i r;,-i~-i,-i,-i,-iO
I~O ~ cV~ OvN oo ~ ~~~.jiVt~~ ~D ~:~Om ~j,--io0 0000~ xa
d'oo ~O,_,oo d-,-,O ,~v~N d100,-,v1 ~ 010o N M N ~O\O ,~
t~l~ ~ d-~ O N d- ~ M N cmn ,-,~ d-inO O O ~D O N O ,-i
O O O O O O O O ~ O O O O O O O O O O O O O O O p
~ x ~ x ~ ~ x ~ x x ~ ~ x x x x O
cn
N
O
O
140
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
'-i~-i~---ir-i~--i~-ir-i'"'i-i.--y-- y--m-i~--y-i~--iN ~ M ~ ~--~
M
d'0 O ~ ..O
0 '-'
O
M d-M a\d'~D l~d-~ oo~ N ue'~ r-~~ N ~ x
' - ~ ~
vpt~ d t~M d ~ ~ d v o
1
I~l~ \Ol~~ lflM ~ M l~l~
O ~
O O O O O O O O O O O O O O O O 'C3" .t", '~''O
"C~
a ~ ~ a ~ ~ a ~ x ~ x ~ a a a x x ~ ~ ~
~ ~ ~ N
~ ,-irir-.i~ ~-ir-i,-ir; ~--~--i,-i ri ~i.--.~ r"'
'.-i
01'--i,-i~.joot~ M O oo ~po_o~O ii~jvi,-iN N ~ d' ~ N ~
--~
N ' ~ ~ ~ O O 0 ,
V7l0lW D M l0 t~l~d' ,-~ d O N O O 0
-i
O O O O O O O O O O O O O O O O O O ~ ,~ ~ VjO
O
x ~ ~ ~ ~ a ~ x x a .
0 0
N ,~
~_
U x
d'
N O~ ~D
i ~D N
~ i
~O ' O
M N l~
01 N O
V7 M \O
M N
O
M
N
x
a\ O
141
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
,~-i ~ ,-,
cd ~ N
r-i ; -ii ~
O ~ ~ M M ~ ~ r;
~ -, p o ~ O O O
N ~ ~; x x x x x i
N N ,-i~-i~ ,-i
N ~ O ~ N ~ o ~ o~oo~o
O p p O O O
~ ,~ Q~ ~ rnrn~ ~ ~ '
N ~ ~ l~
N ~ due'~ ~' N ~ M ~ y i ~ M N
d n ~ a
N ~ b4 N j, .'~~,~ ,~ ~ , ;' t~'pa~rig'~ p
4?
~''~ -~,~ ~ ~ ~ C7 ~ ~ a~ ~ ~,~ aA ~.
~ ~ G~ U '~ f~
p~ 0 0 0 0 0 0 0 .~ ~ ,~ .,
.N.~ .~ p~
p O O O O
~ ~ ~ ~ ~ ,~N ~ O
ueM ~ N
M d ~ ~ M ~ ~n d' N d'~ d- N
'
~,~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ' ' ~ '
7
H a c ~ H ~-'~ a w ~ d ~ ~,~ ~ a..~
M
,d., I~ '~' M
i M
' ' ~ O ' '
M N d' ~ M
M ~ d' N V1 M
M \O M ~O M l~
O ~D
~
01 ~ l~ O
, ~ O
O
N ~ ~--~ ~ N
w w
a
x x x
M
142
CA 02395816 2002-06-26
trj d' d' M M M M N ~j N CV CV N N N N N N N N N '_'' ,"' ,-i ,-i
.. ..
l~ ~ oo ~ Vj oo N ~p N ,-, oo l~ cV l~ ,-; 01 ~j vj ~n N ~' ~ oo O
pppp ~QppONp0000~~~~ V~d'Nd'
O O O O O O O O O O O O O
_~aa~~xaax~~~xxxx,~~~axxxx~x
h ~' d' d' M M M (V N N N N N N N ~j N (V N CV N N ~"~ r'' ,-i
t~ 01 N oo d= ~ ~O (V l~ N ~''~ d' cn d' O ~.j d' tV d1 t~ d' M~ d" ~ O
l~ ~D ~ M O ~ ~ l~ r-t Q M V1 Ol .-y~ O O I~ V1 M V7 O~ ~f V1 N
l~ O d' ~ N M l~ N O ,--~ N v> N ~6 ~ O t~ ,-i d' l~ ~n ~ c'1 ,-'
O O O O O O O O O O O O O O O O O O O O O O O O O p
1 . 1 !T! . 1 . 1 !T! rn . 1 rn rn rn !T! !T~ !T! !T! !T! 1 n 1 1 1 !'T~ ~ h'~
~ \O 00
00~ O \O 00 M 00
-
N M M M M d.d. d
t '~r" ~ 7-.~L, i..
_ ~" %
~ ~ ~ ~ C/]
,,
O p p O
~ O p p ~ O
'
''-'~''''J,~l~ 1OV1~ N l0M O d-
O l N ~
~. ~ .~ s~. j, tiAp ~ Q.,
,
_ _
H ~ ~ v~~ H U C7H ~ P~C~
143
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
ON M N N ~ ~ 00 ~ O O N ~ 0o N N ~ d' cri M O \O ~ M M M
O~OOOOOOOOOMOO~OOOOOOOOOOOOO
xxaxxxx~xx~H~xxxxxx~~aaaax
~; ~ ~ ~ ~ ~ ~ ~; ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~;
l~ O '~ d' ~ N vp dv °° N O M O O ~ ''' vW O d' cn oo v'i oo ~O
O a
--w O l~ ~_-r 01 pp ~' l~ l~ '~ ~ ~O '~ ~ '~ M ~ M O~ ~O ~O l~ I~ O 01 \D
O O O O O O O O ~ ~ O O O O O O O O O O O O O O O O
1 h'! ~T! L., !T~ L. rn rn ~T'! ~T'! rn . 1 ~ rn ~ ~ . 1 rn !T! 1 1 . 1 . 1 1
1 1
144
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d-
-i'-i'-'..-;,~ r-.i,-i,-i~',-~ O\ (sj~''1N (V N N ~ ,-i'-i~;r-i,-i,-i
~OO ~ I~N d'O N ~ cri O ~ N p ~O d101~1 W1'~O,~N ~pp
~ O l~O~
N_M N M tnV~tn N p~,.,O ~'~.--~l~ d'01O tnM l0p
~ O O
O O O O O O O O O O '~ ''O o O O O O p O O p
~ ~ x ~,~ a a a x x ~; M x ~ a ,~~ H x x x x ~ ~
-i,~ .-i,_;,.._;,-i,-ir-i-~,-i,-i ~ d'M N N N ~ '-;'-ir;,-i~
N ~O O d1Ov ~ ~ivd' ~ due-000od' 0101O r-'N o0
' '
N O d d t~ OvN l~M N ~ ~ l~
M N l~I~l~ -~d- O O d'M l~ ~Ol~'"'~M O p ~ O d-
O O O O . ~ a O O O O O O O O
x ~ ~ ~-1i-1v-1 C/~o a ~l~ a
O ~p
O1
~
--~i ~ ~ ,,~ _~s..O
07 ~
O O
~ O
tI~ Q~ 00
~ ~ i ~ i
i i S~~'~ i _~i i byGp
~ _cCt
i
i N
M
~O d'
M \O
!n
N
M
00
O
x
145
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N r-i O
i ~ ~ ~ N ; i
-;r , , ~--~ '- N 01 '-'ri
r
vo00~t ~n o0 d'
-i61 O pp O p O
~ ,~ N
~ ~
~ x a ~ x r~-i~ O ~rO
r . N ., cd ~ C/~
~ N i
ri,-i ~-i,-i ,~ ,~ ,-.i,~
,-
M ,--i M N o ~ O N l'_'~Dtn N ri
N
0 0 0 0 0 P~" O O ~ ~ O p0
''
~
~ a x a ~ ~ ~
x
~ ~ ~
~ M ~ 0
0 N
V'7Irj~ l ~ ~ ~ ~ O '' ~ O
i O
cClcd ~ ~ N ~ s t- ~ tnp i GD d'~,"
~ "' cn
_ '-', r-~CJ~/7~ ~ _N.-,~ ~ _N,
~
O O O O O '"'''~d', H O
O
O O O O O O O ~
p ''' ~'~'~ ~ O "i ''''''''~ ~O
N
M W ~
d o ~ ~ ~ ~ ~ ~nN
-
~, p ~ ~'a ~ c~~ tillti-0 cCci~j ~, ~:ciW;
~,
H ~ _ ~ ~ _ _ ~ _ x ~ _ H x
L7 ~ ~ ~ 7 H
F C ~ ~ C
0
00
40 M l~ O
N
l~ ~ ~ N
M 00
0o Ov N ~O
N d'
Dm
M ~ M \O
O
~
l~ O
O
146
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r;
N i
--i~ '-i ,-r;
O r-i ~O l~ Mp O
M ~.,O lpN C/~
O
N x x x cd
N
rir;r; ~ r;
d\ppp ~ d'~O~ O 01
~
o_oN 'p M tn~ d'~n
O Ra x O O O fx
Cpp x
M ~ ~ ~ ~ tn O
N
~ o0 1fl, ~ ~ N N ~'?M N l~Vj 01 O O M
-~
_ N ~ ' ~ N ~ ~
~, '-' ~ ~'j, ~ ,'~~'~ ' ~, ~--~~ N v~-
~ ~ H ' ~ 7 ~ ~ ~ ~,
'
U ~ x ~ ~..~C C ti~, ~ ' ~ j ' ~ > ~'1
7 ~
a ~ " , r-
H p H
~ O O ~ ~ ~ N ~ ~ ~ ~ p O O O O O
''.' ~ ~ 01 ~ t d'
''' '" r-'
M O ,-,l0l N c O N 01 ~ N n ,-i
, d
,~N ~ ,-i~.,, N N V M M ~ ~y~Ot N d-i l~ N
i i
~" ~
c7 d C7 ~ 7 ~ c , W 7 ~ ~
n
d
H a w t w a w H a...
N
N
d- d'
M
N N
0
d ~ d'
'
N
x x
-,
147
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M ~ N r; O
.-i cCi ~j ., ., c~
--iI\'--i,~ 01 cV,-i,-,.-~,-i,-i,-i,-i~ ,--i
O
p ~ ~ p p ~ ~ p \O N p ~:rj,=ippo p
d x ~ x o
a x x x a a x a ~
.o M a x
--. ,~ . ~ ~ ....
-i '-i N N ~ --~,--~r.;,-i,-;,--i
-~
~M 00 due"~ ~ ~O~ ~ ~ VN1~ ~ ~ 01 d~~ 00
~
O ~ O l~ t~ O O O l~O O O ~ l~ l~~n O
x x o ~ ~ o o 0 0 0 O
o
~ a o~a ~ ~
~ ~_
wivpN ~Od' O p"N ~y~ ~ ~j~jM cn~;
' ~O l0 00
'
~ M l~ tn V1
N ~ i Q C7
U"E-~a d ~ ~l ~ E-~C/~. p J, e~d d ,~cn
O O p
O ~ O O O p ~ ~ o p O ~ O O
00o N V~1
cd ~, ~ ~ ~ ~,
~ a d ~ d d ~ c~ x x ~ ~ ~ ~ d H ~
M ~ 0~0 M
M O1 d"
i ~ i _~
d' O N
ij~ ~ O ~
t ,-
t
O ,-, O ,.-~ d-
O1 d\ a\
~ ~
U
d
x
a, o
~n
148
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ~ O
N
ri~ ri
~ O t~r1~ ~ ~ ~ ~ O
x x x x x ~ N ~ x~
-i,-i,-i,-i; O ~ ~ O
d-d-~ ~ M O ~ o ~ ~ r~
Y, ~ O O O O M f
l~ M ~ ~ ~ M ~ in~OO o0
-; V'iOv~ ~ ~'~' ~ j N ~nQ1O ,~,~,~ vp
V1N
N ~ ~ ~ N ~ ~ ~ ~
ap~ N ~ ~ ~,~ ~ ~~ ~ N .~,"~bA ,ti
l ~' G E-~ ~ s '~ I ~' l . ' '~ ~ E-
~ ~
~l~ ~ v~ ~ , ~ ~ a ~ ~ ~ '~~ a
~ '"~~ '~-'
O O O O O 4 O O O O O
O O ~ O O ~'''-'''-'''-' O O O O ''J
O M a N ~ o a N _
00~ N ,-~~ , c ~ o O ~ N Wit'~ c ~ o ,-~ooO o0
-~n o n o
M ~ M tni w --r~--~~ (~lN ~ M ~ y --~w --m--i ~ ~ d' V>
OO~'',~,~~ ~ j~~ O ~,O ~''~ ~~"~~".~~"" ce3at
c7w a a.,~ ~ ~7c7 c7~..a~ a..a w ~ ~ t7L7 c7 ~ d a H
~
M 'Cf' In
Q1 ~O d' U1
i i i i
N N M M
d-~ d'
y -- y l'~ ~ .-i
N M
d
d'
149
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
~ ri riri
M '~.
'
0oN u N Ov
O ~ ~ p 1 '
N O ~ v1~Od
v~c H H ~ x ~ x x v~ a
,~
ri~;,~ ~-ir-;,-i,--ir;,~.-ir.~,-ir-i
r-i
_. _.
. ~ O N 0 ~ . ~
O d'~ ~ " ~ d' ~
d '
O M d-lflO O O O d O SD ~D
O O O O O O
O ~ ~ ~ ~ ~ O
N ~
o
N ~ N ~ _ ,~
~,N N d. v s~
~ '
1
_ ~ ~ ~ ~ ~
7
. E-'E~ d
c d ~ a H
~ , ~ O O
O
O ~ ~ O O
~ ~ ~ ~ ~
M
er M \O~ ~ ~ M
r, N ,-~d' ~ l ,-i,
0 -,
~ N ~ N ~ ~ ~'':
c7N d ~ ...d C7
v , x
C7
~ ~, ,~,...a
~ o
M ~p
M O
O
tp CO M
d'
O
N
O N O
r~
C5
x
150
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r-;
0~0 l0N N r''~ '~ ,-i~ ,~ '"',-i,~,-i~-i~-i~; ,-i~ ,.~-;
O ~p .. .. " ..
p ~ ~ N ~ ~ ~ d~-c~n~ ~ 0 0 d'N ~ N
,~ ~ O ~ N O d' ~ M M O O d'\p V1O O O
O O O O O O O O O O O O O O O O
a a x ~ x ~ ~ x x x x H H ~ a a x ~ a
0oN N '"',-',-i~i,-i~ ,-;~-i,-i,-i,-i,-;,-ir;~ ,-;
r' 0~1d'01 ,-i,-'O o0O (~l~ O_~ l_0cnO ~j enOv~ ,--i
O
O ~ 000~ '"''~p N v~N v7O ~ d' O ~ p ~ ~ vM'7o
o a O o O o o O ~ O p O o 0 o O p ~ p O
f~rt- 1 . , !T!!T!rn!'hrn !T!rn!T!!T!!T!!T!rn . . ~~T'!!T!
1 1 1 1
N .--aO N ipjN ~ N a1 M irj~1N
O, o
o
~ N N N ~ ~ ~ ~ '~iN N N O M M M
C7~ ~ ~ ~ ~ H x ~' U 7 C ~ ~ C
C 7 . 7 ~
~
0 0 0 0 ~ o 0 0 0 0 0 0 0 0 0
0 0 ~' 0
~ o O
N ,-,~ ~ ,~N N ooN M
~ ~ ~"~ ~ ~ ~ ~ ~ ~ ~.~, N ~ ~ ~,b~
A
r ~ ~ , , w , x ~ ~ ~ ~ ~
n ~7~ ~
d
a ~ a H
dl
N
M
O
O
d'
O
x
151
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
N
O
N
a"
O N ~ V1
~
cd ,~..~ M c~c .,..
-, ,_i p~ ''."'~ 01 N '~ N '-''"
O
~ L~ O L~ ~ O
O
V7 O l0 O ~ O M M
a
= Q\
'"'N v1 M .... , ~ d . ,-~ .,..
~
r; ~ ~ ~ M
oo ~ ~ oo~t ~ ~ ~Or1
~j
N ~ O ~ O tNN
0 O 0
p f~''~~ x O O p fy,',,0 0 ~ a O Op
' ~'
0o d'~ ~' O o0
O
0o N M O~ ~ W oo,~l
~ ~ ' ~ ' ~
r E'-'d d ~ F~ ,~~,,
~ o O O ~ O ~ ~
O O ~ O
~
M Oy + t~N
~
~'j, cCv~~
_ _ _ _
U er
C~0.,~ x C7 ci ~ ~ .,~
p
0
~ ~ 0
N '~ ~ d ,
' ~ ~ i '
i
M
O
ue 0
d ~ ~ ~n o
' 0
y D ~ N v1
d'
M
r~ 0
l~ 00 al O
152
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0 0 0 o O ~ o o ~o~o~o
V1V1 O l~I~\O~O M M M
00 lp~O d1~ N M M
v0 ~ ~O d1M d-M M N N N N
N N N M V1l~I~ O O O O
N
N
C
a
"
' 'C N ~ ,-i N ,--i
ri~ ~ ~i
_.. ,--~,-- 01 a1 --i~ Ov o0
00
p ~p~ O V1O ~p O O M tn O O l~
l~ l~~ Ix ~ ~pM ~ ~ '-'~' r~ L~!d1
0 ~ ~ x a ~ ~ O
.-n~ V'i~ N ~ cd M .CI
00
r.~
,~
ri~ ri ~ ri~ ri ~ Q1
O o tIj ~ _0v~ p ,_;\O
due'~' ~ O O N ~ p ~ p . ~
O ~D~ N O O O O O l~ ~ a
O O
cri
00~ ~ N
~ a. a U
N O p ~ O
_
N O r-, d'
a y , ci~
d- tn ~ W
a1 D1 ~ a\
M
M 00 M M
N N ~O M
M i M
i i ~ i
N
N M d'
M d- I~ N
O o0 01
00 In M
l~ l~ N
M V1 M
O
o w
x x
N M d'
153
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d'M M M N N (~jN fV N r"'.--i'~,-i~-i'-',-.;,-i,-i,-i,-i~ ~ ,-i
O 01~ ~ I~d- ~ Q110d' v7'-'N ~ O l~ ~ O oo ~ ,-i oo~p.--i
v7V~ ~Od-~ d-O ,-,ooI~O ~p,-, ~ ,-,,--~I~~ opd'M
l~O l~I~V7 ~ O 000O d'0~ O M M l~ O O M ~ d'M '_'~~pO~
a x a a x x ,~a ~ a x ~ x a x x x x lp
V1d~~''~M M N N N N N N N ~-i'-'ri,-a~'~ '-i~'~-'r''~~~ V~
0ot~"''l~O M ~ O M N l~01~ l~op~j N 01~p ,--i~ d' M o0a
d'l~~ \Ol~o ~ tnO O~ V7d1N ~ I~M M d1d' V~ ,"~00N ~'
N ool~ t~v7O ~ M ,-~~ ~ M N ~ O O d-r-i
O O O O O O O O O O O O ~p O O O O O O O O O O O 00
a a x ~ ~ ~ a ~ x ~ ~ x x ~ x x x M
\p
~n
O
O
154
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
a,
.-i,-i,-i,-i,--i,-i,~~;; ,-i; ,-i~ p~ N d' M N N N N ~jcVN
~ ~
N \O 01cnV1O O ~jp M ,-i~O l~ O N l~ \Ooo~ M O ypd'O
p
~ M ~ M ~ ~ ~" ~ ~ N ~ ~ ~ ~ O
c ~ p O ,-.p N
n ~ O O ~ O O
O
O O O O O O O O p O O O O x O O O p p
a ,~ ~ a a x ~ ~ ~ x ~ ~ a ~ x ~ ~ x x x ~ x x~
~
-i,-..i,-i,-i,-ir; ~ ,-i,.~,-i,-i~i ~ ,~ d= M N (VN (VN N N
N
i ~
-
a\oo ~i~OQ100 ~ N ~p iV~ ~i'iM ~j, ~ VjM 010o O ~ Vit~
- M
~
\Ol~ ~ N 00~j-'"~O M V1lp~ N \O O d' ~ O~Q1~ V1l~M 00
M
O O O ~ O O O O O
O O O O O O O O O O O ,.~,O O O O O
~ ~ ~ a ~ x ~ ~ ~ x ~ x x x x
O ~ ~ (V
;~N
~ ~
G
O O
O O r-'~ O
N d'M ~
N d;
N
er
p U C7 C7
.,
0
N
O
N
N
a\
M
M
x
lss
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N N N .-i,-i,-i,-i~ ,_;~ ,-i,~,-;,-i,-i,-i,...;,~.-i,-i,-ir;,-i
-;N CV M I~~O p O \O\p~ N wj ~OM ~ M ~ ~-i
O O O N ~ ~ OM N ~ ~ ~ V~1due'~ ~ ~ p N ~ ~--i
O O O O O O ~ p O O O O O O O O O O O O O a1
x a a a x x x x x x x x x x x x x x x x x x
N (VN N N H r1r1H ~ H H H H H r-Ir-Ir1~ H H r1 r1~ O
op Vj~ ~O d'O d' ood'l~ ~ ~'1M N l~Ov,~-i~ O oo ~DppO
O M 01~ v~ DlIn00 ,~~ o r"i01M N OvO ~ l~X31N V1M xx
O d'~ tn~ ~ N ~ d" d"M O ~ M M -~ V1O d- O N ~O O H
O O O O O O O O O O O O O O O O O O O O O O O p v--I
a x x x x ~ ~ ~ x x x x ~ irn
~O
N
o0
l~
M
O
O
xx
156
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
p O a
.-irir;~ ,-i~ ,~;.-i,..._,.-i~-i,-iN ~ ~ ~ ~ M y
O
d\l~~ O l~~.jt~ O ~ M ~ O p pp(,~ O ~ d'ri...i
O N d'M M N M d- ~ ~ ~ ~ x W n M ~ fx M N N O
O V~V1d'M O O l~ N V~V~ ~ ~, ~ M O ~ \O~
O O O O O O O O ~~ ~ O O a
x ~ x x x v~ ~ a a a x ~ o ~ o ~ ~ ~; ~ x a l~
,~~-i~ ~ ,~~ e--i~ ~i r-i ~ '~ 0 M M O
--;~O ~pVj~ ~ ~ ooOv 01~~-Wit'~ N ~ ~ ~ Q O ~ ~ ~l'N a
,M-~l~O~ i~~ ~ ~ p dM'~ ~ ~ M N O O ~ ~ O O ~ ~
O O p p O O O x ~"'~
x x ~ a x x o Q p x a ~ rx x ~ ~ ~ ~ ~ O O
~M
o
0
0
~. ~ ~
H a
o 0 0
O p N V1 ~O
i i
i
a ~ ~ c~ c~
01 O
O~ O O
00 M
l~ O 00
N V1 M
i
M M
M ~ 00
M
.--i ~ O
N M ~1
~O l~ N
d1 a\
O O
N '"'
O
x x
157
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0 0 ~ ~ ~t
d1 a\O ~ 00
w o ~ o m
O~ 01M O O
O O N o0 O
M
C
.-;M ~ .. N
-1 .. N
'~
_ ,--i~ ~-,~ ~ ,-i (~j.. N
00 ~ ohotV~ O o~OM_ ~ dN'~ O ~ ~ N N N_~',-i
~,dM'O O O p~ a O d' ~ r~i~''x ~ N 1~0~ ~ ~ M1
,r~,0, ~ ~ ~ ~ ~ d~"~~ ~ 'Orb,'~ ,r~0,,0~,,O O
r.'~j ~ '-'~-ii ~ N '_'~,-;,~~ ~ ~ N ~ ~ t~i
~ .. ~ ~ ~.rjN N ,-.,,-,
O O O N ~ ~ O ~ ~ O N ~ can 0
N ~ N O O M p ~ N
O ~ x ~ ''~o r~
O 0o O O O N ,-~,-,,~ O
M ~ ,-~ ~ V)
~ N ~ ~ ~
O ~ ~ a; ~ O ' i O
O A" ~ O o O
M -~ O O ~,.,.~.,.~ +~~ op N .N
M ~ l~ N .-~iV1 ~ ~ ~ ~ ~ ~ ~ D1
_~~ 4,~ i C%~~ C%~ ~ ~ _~'1
~r O
O O O O O ~ O
M M ~ [~ N M
i i i i i
M M ~ M N N
Ov O ~ N M N d'
a1 dl a\ ~ d\
M ~ ~O M ~ O
M O ~ ~ M
O\ Q1 01 '~ 0~O00
r~ H ~L,
x w w w w x
x x x x
158
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
.--io ~ ,-i N ,-i
~
-.,-. ~ ,,~.. en.. ~--~
-i ,-id~,-~ ~ t~, 0101~ ~ d'd~ cri
in~O ~'' ~ O ooM cri
00~ 00_ ~ 0~0~ ~ ' O O d ~ O ,.~ O d'V~ ~ ~O~ Q_1
~O ~ x (Y ~ ~ o O\
d'~n,~ N tn~ ~ ~ ~ ~ ' p ~ f ..~ ~ ~ ~ ~ ~O
O O O O O O o '~~ x ~ ~ ~ ''~ O
o o O O O O O
x x H x x ,~ x x ~ ~ ~ : x O
, , ~ ~ (V
O oo~ d ~ ~ ~ O d ~ ~ oho~ _ ~ oo~ vp~ ~ N oo~ ,-i
N ~D
O O O O O p O p ~ p p ~ ~ O p R~ ~ ~ O O O O
O
x x x x , x O
~ ~ ~ ~ a
0
N d'Q~ N M l!7
a
O O O ~ O O O
O ,'_'
+~O ~pN
N N N d'
_c~N _~ ~ ~. ~ ~_
~ x
00 01 O
O O
M
i
i i
N M 1D
d> d>
d' O ~O
N N ~O
O d' a\
-i M lp
U
x x x
159
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M N N N N N '"',-i,...i,-i,-i,-;r-i,-~,-i,-i,-i~;,-i,-i.-i,-i,--.i.--.i''-'
0000 ~ M ,--ip M oo ~ oo~ip '-.ioo~ trj~ ~ ,--i'd'oo~--~l~a\r.;
00.--~~ l~01 ~ ~ ~ ~ ~ N ~ O O ~ ~ ,-,N ~O ~D~ ~ ~ r''~
a a ~ a ~ a x x x x x ~ x x ~ a ~ a ~ a a a x .-i
M N N N N N ~',-i~~,-i.-i~; ,-i.-i,-i,-i,-i,._;,-i~-i,-i,-a.--i,-i~
I~oo p Ovd' l~~ ~O ~ ~ ~ O ~ ~ ~ d' ~ON M N N ~ 01cnin
In~ ~ \OI~ d'~ V1 ~ ~ tn 00 M d1 O1O lO 'CI"\OO Vl~Ox
l~d- ~ ~ l~ l~N M M ~ ~ O N W --W' M O I~ ~O\O00 \O~Oa
O O p O O O ~ O p O O p O O O O O p O O O O O O ~
G7 ~ ~ ~ x x x x ~ ~ ~ ~ ~ ,-i
M
~
O
p
M
~
G7
160
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
'~ M ~
~ h0 -i'~ ~''-~ ~1 Ov~ ~ d'd' M criM ~.j(VN N N '~,-i~
,-i
p , ~ M
O ~np N ~p O d-t;jv'i~p,=i01O~0000 ~ m ,~O M oo~
00
o x ~ o ~ ~ O ~ O ~ ~ ~ M ,-,~ oo,--.~n~ own 'flO o
,.-.
O ~ ~ d' '-~O O O
O
x O O O O O O O O O O O O O O O
a ~ o x a ~ M ~ a a a a a a a a a a a a x x xx
M
-i~ ..C~jr.;,-ir; [W ~ d=d' d=M cri~j C'1N N N r"'i.-;,-~
,--i
O~~ ~ N vD O N ~ '-'W O ~-'oo~ ~--~~ ~ o O a;d't~ W O O
o v'i
~ ~ O ~ ~ ~ ~ ~ ~ _ ~ ~ ~ v
O ~ N ~ ~ ~ d' ~ N M M
O O O O O
O
O x O O O ,~O O O O O O O O O O O
a x ~ x a ~ a ~ ~ ~ x ~ ~ x ~
,~ ~ ~ N N N
,.N.~M ~ ~ ~. ~ ~ v~ ~ ~ R,
~~
r
O ~ O O ~ O O
-~ ~ N ~ d'd'
~'
,_.~-i ~ ,-~-~~ ~ O N
~ N .., CVN
j
+ R. + ~ N a~w y w
~ te
a, a x a w
...
N
M
O
i
O r,
N
a1
a\ a\
dl
N
O O
a>
d\
N
O
d\
x x
d\
161
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
'-' N d'
rir;ri ~ r;ri ~ ~ ~ ~ ~ ~ ri ~ ~ ri ri~ ~ ~ dl
\O,-1d'0o,-i~ O~~ ,-;crjQ O p O
O p O O ~ O ~ N ~ lpW O \O '""~ ~ O
d-l~ I~l~~OM
x x x x a a ~ p O O O O O Q x O O ,
~ a a a a a x a a ~
Q oho~ M 0~10~1N cn N N ~OOv M M ~ 01~
O p O O O O O p O O O O O O O o O 0 ~ Cp/~
x ~ x x x x x ~ a s x ~
0
a;
0 a E-~o ~ C7U
0 0 ~ ~ 0 0
p
,~ o 00
0 0 ~ ~ ~ o
a; w x x a a~c7
M
00 d'
M l~ d1
l~
i i
N M N
M O
V1 O O
V1 N N
~O N o0
O l~
N a\
M O
00 Q\ dl
O
H
x x
O
162
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-iN .--r ,-iO
l~ " oo N
O\p 01 ..-, Ov ~ ,--i~ d1~ ~ M ~ ,-i,-i~ ~ ':-i..~jN '"a,-i
,-i
00 oo O oo ~p ~ ooO ~ ~j ~ ~p ,~
O V7O x' d'N O a O d-~OI~~p O O ~ ~ ~ ~
, r O Q 1
Gi ~., L~ O !~ ,~Ix ix N ~ ,-r~ I~C/7p-!I~~ 01 1 0
~ ~ ~ ~ ~ O p O O ~ ~ ~ O O O
O
~ C ~ ~
j " ~ '~ o ,...1~ ' ~ ~ a ''~x ~ O a ~l
r .-', N o N ., d ~--~ ,- l!7 .,.. ~ ~y
,-i,-i
-, ,-, N ,-,,-~,.-~,-, N cV ,-i
'-r~ ''..,~ ''.i~ ,-;~ '-'due. O~ ~ V p ,-id'cri~ N \Od' ~Ol~
'i d\
~ _ ~ O
O O o o d ~ O O O o lp~ l ~ ~ O ~ ~ ~ ~
0
~ '~ '~x ~ '~ ~ x x x
a a ~ ~ a a
(V p
N
~ ~ +~
a W-",~
~
1 ~%O ~ ~ P~-~C
7
~ ~ O ~ O
d w n
~ i i '~
0.,v~U U ~
m o ~ oo a1 0
N
ue h
d o V~ ~ O
" o
i i M '~' l~ M
N i i i
~O ~ M N
M
N M d- tn lfl
N O O O O
N N N
d- M t~ N o0 01
O M ~
d ~ ~ d
- ..
O
z
x ~ x x
x x
163
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
a\
--iN
.;,-i,-iN ,-i~ ~ ,~ ~ ~ v'i~id'd'M M M M M N fV N N N .N
N
r ....
p1v'iO O O O M d'p~ op l~~ oo~j~t WVo00o M ~ M O
"
"
\p~ ~ r Px ~ x lx ~ ~ ~ ~ ~ ~ ~ ~ ~ V7N M "~~N
1
.i
~ " ' ~ O O ~ O c M O ~ O
"' O O O
O O O ~ , O x O O O O O O O O O
~
~ ~ M ~ a ~ a x x a ,~~ x ~ ~ x x x xx
--i,-i~ ,--W ~ trjtrj~l=d~M crjc,jcrjcrjN N N (VN N
N
iVd'l~ O i ~ d'~ due'N 01 W ri~--i~ ~ ~ON v'i~ cn O 01~nO
01
p M ~ N ~ O
p
0 ~ ~ ~ O O ~ O O ~ d ~ ~ ~ N ~ ~ ~ V N ~
' '7
O O O O ~ C/~O ~'',~O O O O O O O O O O O O O O O O
O
a ~ x ~ a ~ ~ ~ x x x x
x
~ N
a
_'~c j, ~,v~
n
''~
O O O p O O
a-'.~,'~
01 l~O ~ O d'
V1 00,--,,~ N
N
p
C7 ~ 0..v~ G.,a
N
N N
O
N
O
a\
N M
00 01
O O
N N
01 M
O 00
01 N
0o a>
N
C U
.7
C7 x
W W
x x
x x
a,
a, a,
164
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N ~jN N N N N N ~"''-i,-,''',~,-i'-i,-;r; ~ r.-i,-i,--i~ ~-i
in~ M ~.j~Od' ~n~ Vj inN ~ O ~ (Vd' ~_~ p \O~r7ON10~oN ,-i
-,O ~O 0~1
p lp[w V'7O ~ ~ O ~ ~ ~ N d' ~'M to ~ M M d'a
x x x ~ a a a ~ ~ x ~ x ~ x ~ x ~ x ~ x x x
N N N N N N N N N N ~ r-i,--i,-i~-i~; ,-i,-i,-i,-i~-i,-;,-i,~x
~Dd' O O 0100 ~ ~ l~ M ~ fV d'M t~c~j~ O O t~O~Ov ~ p ,-i
M O ,~~Ov0 ~ d- O~~ N O~oo~nop O N v0 O ~'d- oo~p,-i
O ~p '"''N t~l~ '"'~ l~ t<7N N N ~nt0N M d-M O ~D~n v7O N
p O O O O O O O O O O O O O O O O O O O O O O O t~
~ x x ~ x x a ~ x ~ x ~ ~ ~ N
Ov
~
tn
O
O
x
165
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i,-;,--ir;ri~--i~-i'-i,-i~ ,-i~--i~ ,-;~"~,-;,-;,-i,-;,-i~ '"'~r;~~r;
N M ~ ~jM (V ~ M_M d:,-ia1 O ~ c~i~ ~.j~O M l~~ O ~ oo
N vDN ir10~0~ d'~ ~ ~ v10~ ~ N ~O M ~OI~ ood'~ M dM.,O
O p O p O O O O O p O O O p ~ O p O O O O O p O N
x x x ~ x x x x x x x x x ~ a ,~,~,~ a x x ~ x V1
~ ~ ~ ~ ~ ~ ~;~ ~ ~;~;~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ O
01,-i~ O O oo l~~ l~ opa ~O ri\~ d1 p cVv'i01O ~ O ~"'~
t~01M N ~ ~ntn M N oo M d'~ N ~ l~I~ V101M l~N
O d- O N O ~D ~ V~O O l~M ~ \OM V> ~ M ~ ~p[~d- ~OV7O
O p O O O O O O O O O O O O O O O O O O O O O O c~1
x ~ x x x x ~ x x x ~ a ~ ~ a x p~
M
M
O
O
O
166
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N
cd
~
.-i,-i'"',-i,-i~--i ,_-i ,-i M cnwjN N N N ~j .-i,-ir-~,-;
,-i
Sri
N O O in~ d\~O~ a\ N 01 N
v ~ ~ ~ d N 'd.' ~ p o N M
' p
O O O O O p ~ ' "' ~ a O p ~ 0 0 0 0 p 0 0 0 00
'
Z ' 0
,
,
a C/~x a ~ x M ~ c V '~'a a r~x a r~a ~ rxx ~
j ~''
~ C ~
.-~i,-i~ ri'-iri ~-.-i ~ cric'ric~jN (~jC~jN C~j'~'-.i~ ri
,-i
cn01 ~ l~~ M (V~ 0~1p ~ pipl~ ~O Vj,--ioop~~rj\Oppo001
' ~' ' ~ (V
~
v1in ~ d1~ N in~ v - ~ ~ v1 d O o0 M ~ d- V~~ ~ ~O
W , N
l~l~ v7~Dd' M O ..~ p ~p O ~ O tn O ~p[w V7M \OV7
1O
O O O O O O O w x ~ ~ ~ O O p O O O ~ p O p O O
O
a x x ~ , x x a a a ~ x
x
~ ~ ~ c~
E~ 0 0 0 0
N O M M
v~ a E-~F-~C7
M d'
N N
d- dM'
i '
O
M
O
N N
p
d
'
O .--i
d\
d\ a\
~
_
O
O O
N N
167
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i,-i~ ,-i,-i,-i,~,-i,-i,-i,..._;,-i,~ r;~ ,-;~ cn cnN Cj'~ r.i,~,-i
,-i
~DM ~ (Vd'~ t~~ O N oo~tO N O o ~ ~D a\N 01~ N oo~
d'
~ -' ~ ~ ~ ~
O O r' M ~O lD' O O M ~ "'d~ O ~ ~ O p ~OO
O O O O O O O O O
O O O ,~O O O
x x ~ a a a a x x x ~ ~ a ~,~ a a a a x ~ x xx
,~ ~
-i,-i,-i,-i~-;,-i,-i,-i~ .-i,-i'-i,.~,-~,~ cYicnN N ~--'~a,-i,--~
,-i
~r7cn,=ia1N tn t~~ l~ oo~ ~i'i~ ~pN ~ ~ ,=;o0~ d'O M p M
d' tnM ~n d'~ ~ ~ ' in 00 '_"' l0
tn
,-i
d'V7 ~ ~ h N l0V1 ~ V1V~~ d1~ O l D d V~V1~ O ~ V1
~ ~ ~ ~ w O ~ ~ ~ \O
O O M l l V1O O O O [ n O fx a l l l O O O O
O O O O O O O
a a ~ ~ ~ ~ a x
~ M M
pp5..~
'
O O O a O
O
V1 ~ ~ M
i
_~,~:v~ ~ _cd
N
N
N
N
d\
O
x
N
O
N
168
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
o\
-i-i-i -i~''"' ,--iN ,-i~ ~ r-i,-i,-i,-;~ ~ 0~., ~ riN N
N
, , , ,--~ \O c
00 M O ~ 00
O l~ " O~~ 01d1~O 01 ~ M d'lI1
1 ~O
0 _ ~ O N
~ ~ ~ ~ ~ ~ M O ~ V1~ ' N ~
-
~
0 ~ l~ O O ~ ,.O O OOO
0 1
~
~ r~ r~x x C/~ ,.~,x o x x r~ ~ ~ ~O 0
~
-i,-i,-i,-i-~~ ,-i,--; C~j'"',-;,-i,-i~-;r-i,-i O ~ d'N N
N
\pM M l~O '~ ~ ~ ~ M 0o~ N ~ ~ '~ O ~ V ~-'O ~ Qvo0N
l~
01l~O v~N N M ~D~ d'N ~'N N 01 N d-O ~ ~"'t~ l~in
O O O
O O O O O O O O ~ a O O O O p fx ~ ~ a O O O
x x x ~ ,~ ,~~ ~
x
M
N d ~
by '~'~ ~ >,
~U o
O O O O
M d
.
'd~
_ _
(~ ~ C7H E-
N N
O
'~ N
M d.
i
M
M
N N
d- M
M
01
M
d>
x
H
x
x
M ~f'
N
N
169
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N ~"'r-i'-~,-i,-i,-;,-i,-ir;,-i~.;,-i~-i~ ~ ~--;,-i,-i,-i,-ir-i-i,-i
O O N ~ ~ ~ ~ ~ ~ due.,O~ ~nOvW O tri,-i
O I~N N ~ ~O V'7,-iM ~ d-M M O d'~ ~ ~p~O 00l0l~ ~OV'1oo
M O O O O O O O O O O O O O O O O O O O O O O O N
~ x ~ x x x a x x a x x x x ~ ,~a ~ ~ a ~ .~x p
N N N '"',-i,-;.-;,-i,-i,-i,-i,-i,_..;,-i~-;,_;,..1r-i,-i,-i,-i.-i'-i,-iO
0ot~oo ~ c''~O ~ oo,--i~ O ~ty:,~cnN_,=i~jO~~.-i~to00o cV O
N N d' ~ ~ ~ d~'~DN v~O O ~ tind'~ p ~ ~ O ~ N O~~ O
M O I~ O O O M 00V1V~ (~M
O O O O O O O O O O O O O O O O O O O O O O O O ,-i
~ x x x x x x ~ ~ x ~ ~ ~ a ,-;
~
p
O
N
M
O
170
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d=,--iood~Ov OWo
M 01M O 001D 1D
M ~ N ooN l~ ~
~ O O O ~ ~ ~ N
N O O O O O O O
M
N
N
r-i~ ~ N
-i ,-ip ~ N ,-i,-i~ ~ ,-i,-i,-~ O\ M C~jN N N ,-i,-i~i~ ,-i
-i
~ N ~ ,
O N E a.;~ ~ o ~ ~ N ~ ~ ~ ~i~ d ~ ~ - ~ ~ ~ ~oMo
o ' d
p O O ~ ~ a O O O O O p O ~ ' O ~ O O O O O O O
' O
0
C ' ~
~ ,.
r-1~i x,~ N x x' "~'yC ~l ,~''~' ,rj ,y -1r-~r~ ~ ,."L~,~ x ra
-
,
M . ~ ~
-i,-i,-i,~ N ,-i~ ,--,,-i,-;,~,-~ Cj N N N '"'~
01,-i~j~j~ O oo~ Ov,-icn a>p ~n~ ~ ~p Q~ ~ N 'pO d' O
~D
O ~
d'O ~ O O ~ !~ ~ ~ '~ ~DM ~ O O \O ~ l~l~ ~ M O ~ !~
~ 0 0 o o rx v7
0 0 0 0 a O o O O ,~0 0 O 0 0 0 0 0 0
0
a ~ ~ ~ ~ a x x x ~ ~ a a ~ x ~ x a
~
~ N
00 ~ O ,-,,,_,
~ i
O
r-~E-~~ O
O
O O O .~'
M ~ M '"~M
M O1~
O ~ ~ _~ O
N N
co O
N N
\O O
N
M O1
O
M M
U
z
x x
N
N
I7I
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i N r' O ~ ~ ~ O
..~ .. ....N ..,-i.. .,.,~O .. ..,-;.,O y; O .--i
~ M ,--i ,--~ ,.-1M (~, 01 ..
p p O O N M ooO _ O p N ~ p O ~ p opo
O v'i
~ ~ ~ ''~~''O O O N x Ix IxN M r-)~''M ~.,~
V1
V7O t~ O O "'~~' O O t "'~~ d'~ 0 ~ ~ N d- ~' O
O O O MO
x ~ r-~r-~~ N ~ x x x'a ~ i l ~ ~ ~ x~
x
N i r c ,--~ r.c M O ..
d U
r ,-,,-~~ ,_..j~ o ~ ,-i
h d ~ ~ oo ~ ~ N O O ue~ ~ ~ ~ ~ O
N
o N ~ ' O ~ d d N d f vp
o . '
O O O O O O
x O O O O ~ x ~'' O O ~ ~~~ ~''~
, V7 ~ 01 ' (O
~, '
N
M
N o0
" 01 ~ ,-i N ,--a
N
gyp~ p~ '~ ~ ~ ~ >,
N
C~ ~ ~ ~ ,?''~ ~ H
v~
0 O ~ O o O
O
v M ~
M
~ N N o0 o ,-
~ O ~
b ~ c_i~~ ~, ~
~-0 N
w x w ~ ~ c~ x ~ H a
a
O ~ N M d'
M M M M M
v1 00
i
N ~ i i
0o N N ~ N
l~ oo a1 O
N N
N N N N N
M
N o~ ~ ,~-, 00
o
due' _
N
d' o0
a x
o
z z z 0
x x x x x
00 a\ O .--
O O O ~ ,--
N N N N N
I72
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O N
M ~.jN N N N N '"',-i,-i,.;,-ir-;,-i,-i~--~r-.i,-i,-i
v000 ~ ~ ,_;01OvN ~ ~ M ~ W ~ l~ ~ v'i Ov
O fx ~,~ V~'7~ ~O~ inO~~ ~ ~ ~ ~ l~O O d'v~~ a
~ ~ ,.0~p O O O O Q O O O O O p p O O O O ~
a o M ~ ~ a a a a ~ x a H a a a a a x x a V~
-ii nj N (VN cVN ~-',-,~ ,.;,- y;,--ir-i,-i,.._;,-ip
O
a
~
,-i
,-i
O N pip pipO N t~oo l~oo'"'<''~oo~ M N ~ ~
~_ O O 00~--~M ~pd' d'00'_"iM '~I~M lfll~O O~ON l~O
O O ~ ~ ,.~O O O O O O O O O ~pO p O O O O O d'
~ x x x ~ ,~ ~ x V1
O
O
~i N N
C/~ CL
O E, ~ 'U
.'-' O
O O
~ ~, ~ ~
_ _ _
C7 C7 E-~ 'U
y vo
dN'
N
d' N M
N N
N N
M
~n oo O
C~' 00
d- M
U
U
x
N M
N N
173
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
vo '--~ ,-~Wit'
h N N N ~ ,-i'"'r-i,~ ,~~ ,--i.-i'"'~~-i,-i
O O o N ~~ ~ cV oo M O
o ~ ~ 0
O
O N ~ ~py n ~ ~ ~ ~n0 p ~ d 0 O
1 o
~C ~ _ O O O O O O p _ O O O O O O
O O
'
.. ~,x W -xrn x x [~ ~ x ~1,-1x ,-1~l ~ c~i
N
i , n N N N .. .,i i .,.." " . " i ,~-a,~
_, r"''-' ,_,-, --a
- N c 01 ooue h ,-,- , ,-~,-~, ~ ,- ,-;~ 0~1
,--i p -i y 1'~ oo,~p
~ d o , l\ 0 ~O
O ' o 0 0
O O O ~ ~ ~ ~ ~ ~ O O N ~ ~ 0 v~~ ~ ~ O O O
o ~
C/~O O ~ a ~ o O O O ~ o ~ ~ '~' fx
~l~l ~l ~
~ d'
..
,
v'i ~
~, , C,'7
N r~
'-'
O r O
-,
.~-~O~ O .~'~ O O
01 O M
,~ N ~ d-
tn R. ~ ~ '~T,~ s
~
H
l~ oo Ov O
d- d'
, ~ , ,
N M
N d\
N N
N N
N
1~ N N
- d d N
.~ '
a> al
ue'
d U
x x x
N N N N
174
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
N
p p ~ M wjM ~.,jN N N N N N ~ r-ir' '_''r,1,-i,-i,...;,-i,-i
O o (Vp~l~ opM l~ O~cn~O ~n~ 01N 'd"~D(V O O ooM
O O ~''0 ~ ~ ~ ~ ~ N-~~ ~ 000~ ~ N ~ ~ ~ ~ ~ p ~ndN'~O
C/~~~ ~ ,~ O O p O O O O O O O O O O O O O O O p O O
a ~ a x a x x ~ a ~ ,~x x a x x ~ H x x O
p '"''..~ d'M wjM M N N N N N N N ,-i~ '~,-i~ r-i,-i,-ix~
l~op '"'~ N d'Vjoo O ~ d' ~ s0~p ,-i,~ppI~ ~ oo~t M M \fl'.-i
M N ~ d" ~ M O M V1O '~ M l0I~ ~ M O ~ ~ M N ~p00\O,-i
O d. O O O ~ 0pd- l~N O '"''l~l~ l~l~,d'd wnl~O ,--~O N N
x O ~ ,~ Q Q O O O O O O ~ O O O O Q p O Q ~ O O o0
~ ,~ a x ~ ~ ~ .~x x N
01
~O
V1
O
O
x
01 M ~ ~Dp.,i
O y!,by~
O
p O O O
0 ~ Q1O O i
0o N
M V> \O--i
i ~ ~ ~ ~ O
a O ~ ~ a ~ a,
w
M
DD
N
N
d'
dl
N
a\
d-
M
H
G7
G7
x
DD
N
175
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M ~ O
-i,-ari~ '-iririri r"'~-i'~~i riri~ p1N ~--i~ ,~,N '"'i
~ O ~ O ~ ~N ~ ~ ~ N t~O ~ O t~no0O O dd' M
O ~ O O ~ O O O ~ O ~ O O O "~ ~ ,'2',O "~ ~ ,-O1
M raW W r~r~x x x x ~ r~W ~ pp~ x cad ~-iN p
-i~ ~-i,-i,-iriri,-i~-'~~-i''~~ ~-iri.-~ r-i,-~ '-~~",~
O t~~ d' l~oo ,-i ,~~ .. ~ ~ p d'
0 l~ ~ ~ p oo r;OyV v1 ,-~O M ~
l~d' ~Od'~D ~noo~ l~M N l~ d'd'V1 p l~ O ~ ~ ~ x ~D
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 ~ a o 0 lfl
a a a a ,~~ ~ x ~ x a ~ x ~
l~
V'7M
cC~ ~, N
/~
O
O O O
-aN d'
OvooN
O O O
U ~h ~ P~-~I~f~
N M
d d
- '
M 00
i i
M O
O
N
d1 O
N M M
N N N
M M 00
Q1 00 O
In V1 M
N M
N M tr1
d> ~ a1
O M
O
M W W
O~ O
N N
N N N
176
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N ~"'r..i~'~-''-''-',~ ,-i,-i,-i,~ ,-i,-i,.._;r;,....;,-1'~ O\
O ~ N O~IOMOOMO~ ~ ~ M tnd'oo ~ ~ ~ ~ 0101 ~ O
O O O O O O O O O O O O p O O p p ~ ~ O
~ a x x x a x x ~ a a a ,~ x x x a a a x
M N N ,~.--i,~ ,--i,-i,--i~-;r-i,-i,~ ,-irir,;r-i~-;,.;.-
~ vv~1~ t~N ~ ~ O ~ ~ ~ ~ N M N O O
l~l~l~ ,-id"d' O d'V'7l~l~l~M V'7d',-~-~~f'~ ~ ~ ue'
O O O O O O O O O O O O O O O O O O O O O ~ ,'2',
a ~ w x x a a ~ ~ x x ~ a
N
O M '-1
i
l~ M V7Q,
si,
~' N canN
Ur O ~ ~
O Cl~
p
O
O N
-
_c~~ ' _~
O
~, r.~
d'
M
dl
d'
N
M
N
d,
O1
W
H
x
N
N
N
177
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
--y
M ~ M i i
i
'"'' N ,~,-i,-i'-' 01 ~ 01 M ~j N N cVN ~ '"',-i,- ,-~
,-
v~pp O pp O1 .. ..
O ~ ~ oo,:~vp t~O O ~ N oop ,-;~ ,--;~1 d'~ d W''M
,.
O O
O
, O O O O '~~ ~ ~ r~iO p O O O O O O
-1
, a a a x ~ ~ ~ a a a ~ a a x x ~ x xx
~ M
N ~ r-i,-i~--i~--~ criN N N (VN N ~ ~-i,-i,-i
,-i
~ y 0 ~ ~ N ~ ~ _ Ovoo cri~ ~ O~ ~ a1~ncn N
~ in
~O M \OO I~ ~ v1\p~ l~ d'V~ O d'0100 ~
M
O ~ O l~oo ~ ~OO O O t~d. l~t~l~t~ ~O,-~N V~ v1
O ~ w x ~ ~
~ ~ o a ~ ~ ~- ~
, l
~ o
o
inO O m O N
~ 1~~ ~ N d'l~
' ~ i o ~''~ ' ~
~ ~ C7C7
.
~ p ~ ~ ~ ~ O
, p 0 O
O O O O O
'_' r-'-' .,,.,
.,~+~ ~,,~ O ~ .~,O O O ~ ~ O d1N
0o N vDN
N ~ ~ ~ ~ ~ ~ ~
1 01 ~ M ~ N v0 N
0
G~.~ ~ M ~'N ~r v~ p cdGp N ,'i~~ 5~,
_ ~ _ _ ~
~
r~ -~ ~ ~ G7 x ~ ~ ~ ~ ~ H
r
h
i M
i
i ~ i N
M d' V1 lt>
M M V1 M
N N ~n N
M ~ . 00
O
00 ~ O
O
d\
O
.
M ~' tn
N N
N
17g
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~r
M
_
O"
O t
M f1
.-i,-iriririri
ue ~ O
d ~ ~ ~ M N ~ ~
'
O O O O O O O O ~ ~ ~ x O O
O p O
x ~ a a a a x x ~ a x M M o ~ a x
..
p N M d'~Oc~n~ N ~ O ~ M '-'~~ '-'~ ooN
_ _ N O p p O
1
M d ~ ~ M
"
~ ~ o ~ ~ x ~ x ~
~ a a a x ~ a x x
O
'
O M O ~ ,~,~O d '-'~ O tnpv
~"' b~ M 00Q\
U
byR, ~ ~p~ ~ ~ ~ ~ ~ ~ ~ ~d~
i
_ _ _ _ _,
,
O O O
O ~
O O ~ ~ ~ ~ O O p
O 01 ,-, ~
N ~p N ~ O N N v0'--~~ ~ o0
r,N ~p~ ,-~,~in oo~ ,~M N ~O
a\
c b a~~ ~'.~ap~ ~ O
'~A
x w ~ ~ w c7H w a x a~~ c7x
~ ~
a>
O
N
i
~ N
V7 M M
v7 N N
O
M M
O M
N
N
W
a a
x
N N
N N
179
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
r-i~ ,-i 01~ d'M ~rjcri~rjN N N (~j. Cy
N ,-i
M O O ~ O ~ o0(Vpy~ ooM ~ ~ cri~O
GY~ ai ~ ~ ~ ~ ~ 0 N
" , , ~ ~ ~ ~ O \O 0 ~ ~
~ ~ O 0
O r7 x a O O O O p O O O O
O
i ~ j r-.~a ,~r~ ~ x r~ r~a ~ r~
- , (~~ ' i V N
N
-i,-, d c~~rjwj wjc N (pN N
N
-i\O 01~ O '-~~ cald W oo O ~ d' ~ \O\p.-i
ij ,-i
l0O ~ l~ x ~ d' VlM p M ~ O '"~M ~pt~V1
O O M
0o O .b O O ~Do0d' l~N O ,~~ ~ t~
0 0 ~ 0 l~
a 0 0 x 0 0 ~
0
O oo ~ ~'lnj ~N~ O1
v1N t
M ~ M n
( M
]
i N M M
O O ~ O O O O O E-~
O
M N ~ ~ ~ ~ .~ O
O
~ ~ N N N M o0
i i i ~ M i M \p M
cdcd h~0~ b.40 bn0 t; O
_ _ G7
N
v~ ~n
00
N
M ~
M
i i
M
d\
~ M M
N N
O N
v0 O o0
0o N
N ~O
d' ~o
d1 a\ d\
d' in
C7
x
a1
N N
.N N
18O
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i,~ ~ ,-i,-;,-i~ -i~--i,-;,-ir,;r;,~'-i.-iri~--i'--i.-ir..;~i ,_;--i,-i
d'N ~ d'~ ~ ~ N ~ ~ "~d' M ~ O due'O ~ N ~ ~ ~ N due-00o
O O O O O p Qp~ O ~ ~ oo~O oo~Dv'~O ~ O p O O
O O O O
x a x x ~ ~ ~ d'~O ~ x O O O O O O O O x x x ~ ~
x x x H ,~,~a a a ~ x ~
opI~ ~ opd'M cnlflcV oocnp ~ ~ ~pdv ~ oo~ O p ,--ioo,=ip~
O 01 0oM N ~p oo~ N 01~O~ d'~Od'~D v'100~ ~ M N l~ cV
d.d' ~ [wO .-1O N l~ V~~ M ~O~O~Ol~ ~ l~M ~ M ~ ~'I~
O O O O O O O O O O O p O O O O O O O O O O O O l~
x x a x x x x ,~ ~ ,~~ x ~ ~ l~
O
O
.~
101
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O ~ O ~ N
N ~-;,~~i~ ,-;~ ,,~~ M ~.,.jN N N N'N r-;~ '--irir; ,~~-i
N ooo~o ~ ~l~ ~ in~ p 0_IOMOOjdM.~ o olOoM N ~ N
",'01,0 0 0 0 . ~ ~ ~ a 0 0 0 0 0 0 0 0 o 0 0 p p 0
..i xiV]r~,~ ~ ~ N r~r-~~lx x r-~~ t~iCPSx x x x x
M ~ ~ ~ ,~ ~ ~ ~ ~ n
N ,-~,~,-~--~ ' m cn cri(VeV N N N ,-;
~ lW0 O Vj \p ~ ~ ~ oho~ oo O~~ ~ O ~-'d1~.j010ocj ~OM
O p ~ ~~r1O ~ ~ O p O p ~ dM.~ ~ O o0oV~~ N ~plp~ O
P~,,~o 0 0 0 0 ~ ~ P4 ,~o 0 0 0 0 0 0 0 0 0 0 0 0 o
x x x ~ ~ ~ x ~ ~ x ~ x a ~ x ~ x
N
U ~ N t~,N
~ ~ H
0 0
O ~ ~ O
N N
_~~ _~ ~ _~
C7x 'U ~ U E
N c~ o
' ~ i
M M
O oo~ N
N N N
~
N
d~~'~ N
'-'~ N
d- ,--~ 00
N
C7
x
O .-r N
M M M
N N N
182
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
cd ,-
~ i
,.._;,-;..-i,-i,-i,-i,-~-~,~ ,,-~,-i,--i O\ '"~\p ~ M crjN N
N
O N d' ~ l~~ ~ ~ ~ I~~O(V O ~ O ~ i~~ Vj ~
~ 00
~ ~ ''~ ~
O ~ O O ~ ~
O O O O O O O O ~ -p O
~ a a ~ ~,~ ~l O O
r-~r-1~i x x
~ ~ ~
-i,-i,-i,-i,-i,-i ,-i,-i,--i,-i ,-i,-~ crinjcrjN
~--~ N
d1N ~nl~~O O N oo d'O (V '~ oo,-icri ~ ohol~op
M
V1\Ol~ l~N ~D ~ ~ ~ M l~ ~
d'
M I~~ l~~ \O ~ ~ M l~l~~ O O V1V1 O O ~ d'l~ V~
d' O
0 0 0 0 0 00 ~ x ~ a 0
~ ~ ~ ~ x, ~ ~',x ~ ~ ~ ~i
O N ue'
wi ~ d
~ ~ ~ ~ ~ ~.
O p O O O
p O p~~ O M
_ d'~O
N N N
~ ~
_
C~ v~U L7C7
r
d.
, ,-,
M
V1d'
~nN ~nN
N
N
dl
O
d'
~p O
w
d
x x
M d-
M M
N N
183
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~,"
M
~ rir; ,_;.-;~~ ri~-iri,-iri~--i,-iri,_;~ ri,~ r.-i N N
M ~ o ohoM N ~ N o cVwt~ l~~ ~ ~ v'il~ soN O
M V1N ~ \O~ ~ M ~ ~ ~ lp V1~ ~ ~ ~ ~ O O
0 0 0 ~ O o O o ~ ~D l O O O o O ~ x o
D
0 O O O O o O O O
a a x v,x x x x x ~ a a a a x x x x a a x : x a
~ ~
N N N ,-i''1'-a,-i,-i~ ,-i,-;,-i~-i,-ir.i~ ~ ,....;,-i,-i,-i~ N N
p ~--~cj~~jaio N ~pc ,=ip~cV1n l~~D~ N oodv O cV~''~~ _ ~ I
o n
0 ~ ~ N \O_ ~ _ ~ ~ ~ ~ d'O O V
l~ d'
0 O M \Ol~ ~1l~ M I~ l~ 1
0 O O O O ~ O O O O O O O O O O O O O O ~ x O O
O
~ x x ~ x a a a a x x O O x a
~ ~
ri
~ i i
"~a H
a
~ O O
O O al d'
i ~ ri.,
w
a ~ e7
00
a,
N
d'
M
DD
d'
Q\
w
x
M
N
184
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N r-i
-i,-i,-ir''~"~~--i,-i,-i,-i,~ ,_;N N N ,.;,-i<-i'-''"'~,-i~; ,-i,~r;
O O ~O~ ~''~,-;01d'uj Vi O N O ~ O O ~O ~ ~ cri~ ~ p ~
V1~O 00~ ~ ~p 00l~V~ ~ (x ~ ~ in V~~O00 ~ M ~O~D r-iO
M 'C1" x ~
x x x x ~ a ~ x x N ~ x ~ x ~ x x x a a M C/~
o
a
r-ir''~.-i,-~~ ,-i,-i~ ,-i.-i,-i N N ,-;~-i,.~r-i,--i,-i,-;,-.;~;r-;
,--.
d:~r1opo001rj ~ ~ p op~p~ o v'i~ ~ ~i'iop ool~M .-;d\d'~
'"~M ~O ~D ~ ~ [~o V~l~[~ ~ V7[~ ~ InIn~p pp[~V7
r,N N M O l~ l~r''M t~N O v~t~ ,~N N M d'v7(~ t~M v~
O O O O O O O O O O p ~ x O O O O O O O O O O O O
~ x ~ x ,~ ~ x ~ a ~ x ~ x ~ x ~ O
x
M
CV ,-i~DO
tw N d-,-~
d'
O r~
O O O O
N
d'O~
R, cat
C7
d>
d\
M
M
~f'
N
N
N
O
M
G7
M
N
185
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
o ,--~,-. ~ ,--. y o ..-.
-. ~ ~ ~t .. ~
,:-.i-'~ 0v.. ; --~~--i--~--;'--i-;,--y "' ,-i
o ~ dvo M cnOs ,=-~ O '-'
o O dlM V7~j ~ ~
i ~ o ~ a ~ ~ a a N - o0
i ~nx ,-. ~
'~ N ~ ~ N
~
o
~
N
~ ,- ,-~~ d' ,~,-i'~ ,-i,-iO W ,-i,~~ O
O 0 O O crid'O O d'oo~''~d'ovl0 'ipptrj~ O ~
~ ~ '""~~ a ~ M O ~ l~O ~f1~ ~j~ x O
C G O O Q' O O ~ O O '",.L'O O O Q' ~
~'~,'''"~L' rnrn~ ,~,~ ~ ,~,~ (/~
Q'
0o cn N Ov .-iop~-iop
-i\O p
.n~
.
~ ~.p~ ~ ~ ~ C7 E-~C7 H
~
'
H ~ ~ ,~ O , ,
~ O O
O O O E"''p ~ .~.~ O O O O O
''''~ '"'Q ''"'~ ,J~ M Ov b- N b- N
O
d" M ~ d- M
i a1,--,i ~ Q\~ i i ~ i i i
i
~ ~ O .~ .~ N ~ .~~,~ ,~ ..c,'r.~rt,"
, ,
ue ~ ~ N
M d N ~ ~O ~ V~
'
M i d' , ~ i n i
O N ~ M M d-
N N O ~ N
N V
1
'D
O 'D O ~ l\ M
O ~ O
d>
N
O 00
O
w x
x x W
x x x
N IN IN IN IN
186
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M r-1
O N N ,~'"~'~'-',-i,-i,-i O_N N ri~ ~
0oN O p ,-ioo ~ ood_'~ cn01O O O ,-ioop oo ,-'
p ~ ~ fx O ~ ~ ~ M N ~ ~ ~ ~ '~' O ~ ~ ~ ~ d_v
x ~ ~ ~ ~ a a ~, a a a a y ~ a a H N
a
-;,-i,~ cnN ,-i~ ,-i,-ir.;,-i,,~r, c-;N ,-i~-'i,-i
'"'' ~ ~ ~ vD01 ~j~ oo(V ooO ,-il~ 0~1vp 01~j~ oo
~ O O O M dM'N O ~ N dM'~ O ~ x O M N O (V
~ ~ '~v~a x x o o ~ a o ~ 0 0 ~N
dM 0
M
~O O trjO ,-~,~ \O ,-iO ,-iO .--i,~,--aN
~ d'l ;' ~ ~ M t ;'(Vi' fV
~ c~~ a ~ ~ c~ i a ~ ~ ~ ~ c~
O ~ O ~ O ~ ~ O ~ O p O ~ ~ ~ c~
O O ~ ~ ~ ~ O d Wp~ N dN'~ a
l~,~ M 01O~ ,-,~ N v1O~,-~l ,-i~ ,-i~
l0 ~ i O
O
N
N
>,~,~ ~;bD J, ~,~ cCdp cC~ ~, J,
~ ~ ~ ~ a ~ ~ ~ ~ a ~ ~ ~ a ~ ~
a
M
ohoM N N
O
M
M N d' M
N ~ N
d1~ N
00 ~ M
dl~
N
x
N N
187
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N o
-i,-i,~~ ,-i~ l~ ~p~ V'iv'i~ d'd' d~d'M N N N N N N N N
M Ov p O O ~ ~'''~\O~ ~O~ ''~'-'0 O ~D~ O ~'oo l~O
M '-, ~ M '~ all~I~ ~O
O O O x ~ a pp M ~ ~O'd'O inl0 ~ ~ ~ O M M M ~--~l~l~ ~O
'C ~ O p O p Q O O O ~ p O O p ~ O O O O O
d' M a ~ ~ ~ r~ x a x r~t-~x ~ C/~x x x a r~
-i--i-i,~ l~ ~ ~ ~ptrjd'd'd' d'd'M ~''~N N N N N N N
0oO ,=il~ ~ ~ M ,--i~-'ooO~ ~Oc''~~t ood W"'M ~lv~ O ,-.;oo~j ,.-i
d'l~ O V> ~ O ~ l~ l~~ ~ ~ ~ M l~'~"~ M ~ O d'd'l0 lD
O O O O ~ ,~~ O ~ O O O ~ O O O ~ ~ O ~ O O ~ O O
x a x a ~ x x ~ ~ a ~ x .~x
M d'M
E~ Q
O~ O ~ YpO
t~bA b4b-0p _~
H
d-O
N
M M
i
O1M
it'sd-
v'7N
M l~
O1~
V7M
d\
O
r~
x
Igg
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
--;,-;~ ririr;,-i~--irir.;~-iri~-iri riri,..-i.-i~-i~;
~ O ,=i~ ~ d'~p N 01\O ~ oo,-iM l~O~~O d_'O_01 ~:01~
N O ~ O ~ M tin~ p ~ N O ~ N ~ O N O inO ~ t~
x a x ~ x x H x x H ~ x x x x x x x ~
N N N N N ~ ~ ,-i,-;r-i,-;,.;,,--i,_;,-i,-ir-i,-i,-i,-i~.-.i,-ir;x
M ~ t~a1'-i(V V'iop l~~ cVp '-io0d: ,-;~p~--~iOv ~ v'i01 d' a
V101~ ~ V1 M '~M 00 N ~ [~ ~ O1M dl tnV1l~ O1~ ,-;
0 0 0 ~ O p O 0 0 N d' N VAN r-~O M M d' ,-i
~ ~ x ~ x x x ~ ~ o o
M
x
189
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M r-.t
~ M N N
i ~ --i-i-~ "'"' -i-i-i-i -i-i~ O -i
O ~ oNo~ ~ ~ N ooN N O ~ d'O p ~ _ ,~oo O ono
00l~ M lfl'"'~o ~ ~ O l~~ M ~"'~ \O00a O O 01V1 \O
O O O O p o o O O O O ~ O O O -~ ~ O o o~ ~ oM
.-ax H x ~ v~,~~ ~ ~ x x ~ ~ ~ 'r'~ ~ H v~
c~j~-'
-i,~ ,-;,-i,-i~ ,-i,-ir-i,-ir-i,-i,-i ri'-i~--i cnN .--i
v-i~ a1~n~ O oo ~ O~~h v0~ ~ oocnO~ ~ ~ ~OO~ c~j,--i
l~O V1O ~O~ N N ~ ~ O ~ p l~ ~ ~ t~ p l~d-M N
0 0 0 0 0 0 0 0 0 0 0 0 0 ~ ,~ 0 0 0 ~ .~0 0 0 x
a x x a a ~ ~ ~ ~ ~
. .
. o . o
~
0 0 0 0
M M
i i
M M
N
N in N
O
O
1
N
U
x
x
N N
190
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
i N ~ ~ oo ~ a
- ,~ , ~-i c o0
d
cd
~ l~ ~ '_', '"'~ .d' _; ,-itrj ~ ,--r '-i
--i..-i-i ,-i,-..,v0 , ~ ,-, 01 ,~01 , O ,
~ ~
O O -- cn ~ ~ ~ O O
d'~ cn 01p , O ~ O ~ ~
~
O
O O p O O " ~ x O ~ O '~ ~ ~ ~ ,0
,
O x ,2,
'
C/~~ ,~ ,~a ~. l0 x ~ ~ a ~ O ~ M ~
M N ~ '.-~ ,-~~j~ ,-~,-,. ~ N
r-1e-i~ ,~~ H H e-1 y -1 H H
oo O ~ ~ ~ d'~ B O ~ ~ ~ ~ ~ ~ oHo
00tnM tn~ t p l0 O M O O d'O\ ~ 00 M
Ol p H
M M
O O O O O ~ x O O R~ a p O R~,a O fx ~ O P~x
O
x x ~ ~ x ~ ~ a x
N N N N j
~ ~ w
~,~ =~ ~ ~.i s~
~~ ~ C7U ~ ~
~, a
o ~ O O O x
O O O O
~ ~
0 N y o ~ d' ~ 00
1
d' ~ d' l~ d' N ~ M
~ , , ~ ~
N N
N .~,
"
d'~ 'Ud'rav~ ~lr3,'U C"Jd''U
O ~ N
O
l~ ~ ~ ~
r-, ,~ ,-i
H
O ~ N M h h
o o
~ o o
N M ~ N ,
' ~ ' i O
O
d ~ M ~
00 ~ Ov ooO 01 H
N N inN tr1N ~n N
00 ~p~ oo~ O
~ h
o 00 ~ o o ~n N
0 o o
O _
M
N N N N ~ N
a1 ~ ~ ~
~ ~ H H
p
N N
N N N
191
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d- N ~ ,-,
~
h '-'r"''-',-,.-i,-i~ ~ d' d'M
N
o ~O v0l~
o
O ~ O 01~ ~ ,-,~ d'~O\~ 01 O ~ ~ O
" O ~p
X
O ~ ~ ~' O O O O O ~ 0 O O O
' O
O ,-a~ ~ O O O ,..
~
x x = = x a ~ a a ~ a ~ : x a ax
~ ~ ~ ~ M .,.,., .,. ~ l0
' '
N ...,~ ,-,,-~,-~,~.-i d d M
,--~,-~ cri
cn oo ~ ~-,O ~ ~ 01 O ~ ~ oo~ Qv cnl~ ~ d~O ~'O
~O
a _ M _ N
O ~ ~ O O O O d M O ~ ~ ~ ~ ~ ~ O O ~ V ~
' o
O O O ~ ,"2~ ~ ~ O O 10O O O O O O ~ ~ O O O
' O
, cd , C/~C/7x r-.a ,
ue'
N d
N N ~ ~ M M '"'' ~ ~
N
d ~ ~
'
ai~ '~
~ _'~U
~ ~
U ~ ~ ; ~ ~
''.1
~ 0 ~ 00
0 0 0 0 0 0 0 0 0
0
0
O ~ ~ ~
~n~ N oo ~ ~ M M ~ ~ ~ N
~ ~ ~
r i i i t t t , i i
it p W ,~" Q''v~ i
~ H ~ a H w a c7 ~ a a~a ~ ~
~
o ~ ~ ~ o
~
M i M
i ~ N
M i
oo O~
N ~ N
N ~ ~ N o0
o N N ~
~ v N
'1
O
N N O ~ N
Q\ N N
~
N
M
N N N
192
CA 02395816 2002-06-26
N N N N N N N ,-~ '""' ,~ ~' ,~ ,--i ,-i ,-i ,~ ,--i ~--i ~ ,-i ,~ ~ ,--i ,-i
,-i
~Oo~o~~N~~~~ ~OMOoMO~ON~0l~~N1~01,-;
~O h ~ d' l~ M
O O O O ~ O O O O O O O O O O O O O ~ O O O O O O O
xx~a~ax~x°xxxxxxxx,~aax~aa~
N N N N N N N r'' ,--i r.i ,-i ,-i ,-; ,-i ,~ ,-; '--i ,-i r; ,-i ,-i ,-~ r-i
,-i ,-i ,-i
O ~ O M d1 l~ ~-i l~ ~ pp O ~ p '-i M ~ d' d' ~ d' ~D N ~ 'd' O o0
N ~O O 00 l~ M ~ O ifs ~ 00 pp 00 l~ M_ M O1 N O O M ~ V1 V1 V1
O O ~ ~ ~ ~ O O M O O N O O O d O ~ ~ ~ ~ O
O ~ ~ O O O OO ,T, 'T' O ,~-, ,-r O rr rr.i ,-r., ,..r, ~,r, O OO O OO ~ O O O
N ood.~ d=p d:~-i d=~ ~ cn
N ~ M l~~ O M ~ M
N M M I ~n W ~ ~ ~ oho~ ~ 0~1
p r.~r~~ ,~'U~ ~ C'>Q,'V' E-i
O O O p O O v0 p p p ~ O p
M (~ ~U
N M M M O~ M U ~ N ~ d' 00~
N ~ ~ , d"d' ~ p ~ ~ ~ O ~ ;
,~_~ ~ .~,~ ~ O p r..~y.,O ~ r.
0..C7 G..~E-~~U C7 G~E-~v~ C7v~
p~p~ 1~0~0
~ ~
~ ~
s-.~ w~
v~ ~
~ C7
193
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0
,_;V~it~d-M M M cri~jN N N N ~jN N N ~jN e"''
O p N ,-;cn~D ~ d'u"i~ O t~cn d'~j~ V'i~p_;cn ~OO ~O
v7
x ~ M ~ i , ~ O
'''"~'V1d'd' V7~ V~ M N O \O~ p l~I~V'1V1 M
p ~O
O O O O O O O O O O O O O O O O O O O
O
x x x x x x ~ x x x x ~ O ~ ~ ~ x x x xx
o ~ ,~ , , ,
l~d'cn c~icncri(VN N N N N ~j N N N N N ,-i,-i
,-i
~ O ~ ~ ~ ~ ~
0 o d' ~ ~ ~ l~~O ~f'O 0 l~ M 00 l~O 00
p D ~nN N N N N M O 0 O O d- ~ O O
m1v1
O O O O O O O O O O O O p O O O d O O
O
a x x x x x x ~ ~ ~ x
M 00M t~ M ~ tfj~ (~N ~ M
~ ~ N M M ~ ' _
a\ N ~ d ~
~
\O ppO M ~ ~ ~ ~ i i , i i i i
~ ~ ~ '' ~ ~ ~
N ,-,~ _ .~ ~ ~ O c ~
n
~ C7 'U~ ~U E-~~ _ ~ ~ p,~ _
(~ ~U
,
~ ~ O O ~ O O O O O O O ~ O
O O O O
~ ~ ~ ~ N ~ h M ~ ~ ~ ~ ~ '-iN vD
N ~"'~ o ~ V
o M '1
M
M 00O~N V1 ~ N M M
i ~ i
i i i i t i ~ i i
j
, ~
M
N '-'
~h
M
~n N
O ~
d'
N
N
O
w
x
N
194
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
ri
r,;,~ r;-i,-i,--ir;,-i,-i,-i,-i~--~~-.i,-ip ,-i.~M.M N N N
N o~Od' ~ ~ 0 ~ ~ ~ ~ N O ~ ~ ~ ~ 0M10
p O p O O O ~ p O O O O O O -~ ~ a ~ O O O
~ x ~ x x x ,~,~,~ ,~a x x x ~ N M x x x a
-iri ,-i,-i,-i~-i,~,-i,-i,-i,-iri ,-;,-i,-, M cncV N
N ~ N ~ '-'d' d'h M ~ l0N pip~ v'1O 01
l~ l0Q1 O o0\D tnV7 ~ ~ d'v7 N
O O O O O O O O ~ a O O O
,~,~ ,~,,~,,~,O O O O O
N
O M
~ N ; N
N r
v~C7x
~r O O
O
N l~ N
~;~, ~ ..~,~,
H U ~ C7~n
~ al
~n
O
a\
d., M
O
~n N
N
O
d> N
O
x
I95
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ri ~ ri,-iri ~--~~-i~"'.-i,-i~ ~ ri,--i~"~r-iri~--i,--~ ~ .---i
p100 ~ O 1~d- '"~Ov'd"O ooOv ~iN N ~ O O N d- ~ O
V1'-~O \O~'I~ ~ M N l~~Od' 00M o0~ d'00O1 0 N
O O M O O O O p O 0 ~ \O l~v~~O~ V7l~v7 l~ M
a ~ x ~ ~ ~ x x x a a a a x x x a O
~j ,-iriri,-i~-i,~~--i~-ir;~--ir;~ ,.--i'"i~--i,-iri ' 0 0
o dN ~ d~~ d~-O M ~ d'~ ~ ~ ~ N ~ N I~I~ V~
O O O O O O o O O O O O O O O o 0 0 o O ~ x
~ x x x ~ x ~ ~ ~ x ~ .~x
0
0
0
0
H
O
M
~ M
i
N ~ M N
~n ~ ~ 00
~n N ~n N
N O ~ N
N
O
N
r~i W
x
N N
196
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d- M
lp OvM M M N N N N N ~j~jN '-i~--i
ri
O ~ O ~ ~O Ov~ ~ ~ N cV ~.j~pc~ O ~
x M
M (fi L~O d- l~d-~n M O I~ O V~N V100
'~ O O p ~
O O O O O p 0 0 0
0
o ~ ,~~ x x ~ a a a x x a
x
.--ioo ~ N M
~ =
N d criCVN N N N N CVCV ~-i'"~
' .-i
'
'-iO ~ ~ ~ v ~D N Vj,.'_.;~ M O~ O~d=~n d~~
p cV
N O ~ o ~
O ~ o p ~ p ~ ~ ~ N ~ d ~ , ~N
~ ~ O O O . -,
r.~i~ ' a ,.~ O -,O a O ~ O
O
x .-~ ~ ~ C
/~
O~ O d\d= N O ~' gyp"~ ~ N ~ ~ d1M
d=
~ 00 ~ N N ~ ~ ~ ~ M N
M 1 ~
N ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~o I ~
"'"~t ~ ' d '~'"'~ ~ ,.~N ' ' C'7 .-. ' ' ' v
, '-' '
a m..~,~ _ ,., v~~.,v~ e(,~ ~ C>~, a U ~, d a
. ,. , 7
O ~ ~ rxt~iO
~ ~
O O ~ O ''-, O O O ~'-'~ ~ ~ ~ ~ O O O O O O
"-' O
a''~ ~ O O .,..,.,~-,r01d-M \pO~~ V1d O M p~O ,~~
01
O ~O.-W-'0000O N ~Dl~ ppM ~ O M ~ l~(yw-tM 00
''1N 00.-l d \O00 '~''~~ ~ N N M M M M ~j-V7 ~ ~
lfl
~ ~ 1 ~ ~ ~ ~ ~ ~ '~~ ~
~
c y , . ~ . ~1~c . ~ .s',
C . r ~ n ~ ~ ~ ~
~ ~ ~
H ~ C~ hii a a ~ CI~~ ~ A-I ~1
N ~ M
d
'''~ ' N
d y n
N O 01
l~ a1 00 O
V7 N v1 N
O ~ N
M
G7
a\ O
N N
197
CA 02395816 2002-06-26
.--.i ~ ~--i .--i ,--i ,-; .-i r; ri .-i ,--i ,--i ,-i r-.; ,..._; r-i ~--i ,--
i r-i ,--i ,-i ,-i r; v-i ,-; .-;
a; O_ l~ 01 c_n a v'i oo ~ ,--.i tW _ri ,.~ ~ d' ~-1 O~ N m t~ 'd' ~h I
pM ~ ~ l0 ~ N O ~ ti M O O N ~D p ~ due" ~ ~ ~ ~ ~ ~ ~ l00
O O O O O O O O O O O O O O p O O O O O p O O O O O
x ~, x x x x x x x x x x x x x x x x a ,~ a ,~ ,~ ,~ ,~ ,~
(V op l~ Ov N M l0 01 ~ O N (~ M d- ~ oo N ~n ~rj ,=i ,--i op op \p ~rj pp
~ M O O M 00 l0 V1 01 V7 V7 00 00 p~ M l~ N ~p \O l~ ~' ~O \O l~ 00
~O M d' ~D ~O M d' O ,-, v7 O d- O N ,-~ O N ~O ~ l~ l~ ~O l~ I~ M l~
O O O O O O O O O O O O O O O O O O O O O O O O O O
rn "'~ ~ ~ "~'~ ~'h ~ ~ !T! ~'I~ !T! !T! ~T! . 1 ~T! !T! !'I"! . 1 . 1 , 1 . 1
, 1 . 1 . 1 . t
r-i
O o00
i
N
O O
M
D\O1
O O
s~,
198
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~ r-.i,--i'~ ,-i~ Vj d'M cnN N N N ~-i~-i,-i.-i
,_;
M oo~ d',-ioo ~ O ~ p oo~Op~d' ~OO oo~O o000...;
00
O ~ ,
O l~~ O M l~~ l~~ lDl~\OV1 M d'O
O O O M O O O
,~O O O O O O O O O O O lfl
p
x x x ~ ,~a x N ~ a ~ a ~ a a a x ~ x ~
H
' ' ' ~ ~
~"'--ir' ~",...;, ,"~"' W O d'M M N N N (VN '"''~ '-'
~-i
~pO tny n N N ~ O ~ Vid'vDcO ooa101(V ~ vD~
~ ~ ~'~ l~ ' O ~O
O~
N l~~ 00\O O Ifs[~ ~ M d d' l~M
O
,.-.~~O V1[ W n M O I~ 00~ l~l~ V1d'l~N M M ~
~ O ~ O
~ ~ a ~ ~ x
O
x x x x ~ x ~ a a ~ x o
a
N
~ %
C/~[-C ~"
i
O O
O O
~
N ~ r M N
li M V1
i ~ ~
_
N d.
D1
I~ N
i
i
N
a\
v1 N
M
d\
M
x
199
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i N ,..1 O
rir-ir; ,-i,-i,--,i,-i~-iri -~,-i~ ~ N '-'~r-i,-i,- W -i M
O 0o N N ~ ~ ~O O1
cVoo M .--iti~jooO ~O M ~ p~ O ~ d' N N oo p O N
O M ~ l~~ ~O d'M ~ l~~ ~ '~ ~ O ~ d' ~ M d- r~ M
a a ~ a .-a~ a x a a a ~ ~ ~ ~ x ~ a a a
.-i,-iri r-ir-i,-a~--~,~~--i~"'~~-ir-i~--i N ~--~~-ir;~--i.-1
'n
N Ovd' cnv>d' ~ ~ M ~ ~ ~ v0 ~ ~ a1~''~'d'cn~ a\ pipd
O ~D1D O d'l0 ~ ~ ~ M Q1 O h M ~ lDO ~O d' O l~
O O O O O O O O o O O O O ~ ,~O O O O O O ~ ~7
,.~
O
O dM'cn
~:
O
O O O
O
dM y o W
M o
~p
G~
D_\~ O1
M
O
N N
, ,
I ~ ~ ono
N
O N ~ M
~nN ~r1N
a>
O
a\
r~
r~
N M
N N
200
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r-i M
N ,-i~-i~ ~-',-i,~.-ir-i,-i,-iN ,-iN ~.j,-i,-i~--i,-i.-;,-i,-i~ dN
ofd: ,-iM d-c~iOWiia; I~sir~ O ~ Wit'due-~0.,oMO~ ~ M ~
N N O ~ O O \Dd' l~O p~.,, O~ _ d- O I
O ~ O O O O O O O O O "~ ~ x O O O O O p p O x
a ~ ~ ~ ~ a a a a a a ~ ~ ~ H ~ x .~a a a
N ,--i~--i,--~,~,-;,-i,~,-ir-i,-i,-, M ~jN ,-i,-i~--~~ ,-i,-i,-i~
v'i(V l0O d_"~t cWD o0 0100~p ~ M ~h~ O ,-i~ ,=-i,--i~ Q_vo0
l~M M '~O ~ I~~Dd' l~l~O O O ~ V1 l0p N ~ l~00V1tn
O O O O O O O O O O O O ~ ,~O O O O O O O O O O
x x ~ ~ ~ ~ ~ ~ x ~ x
N ~ ~ ~ ~ M
0 o H o . o ~-al
,.~o .~ ~ o
N a\
oo~ N O ~ O
c~'n ~ ~ ~ O
N r
' ,
d
ue
d N
'
N
N d' M
~ N
N ~
M ~
N
PA
W
x
x
d-
N
201
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O O O ~ ~ N N ~O~O
~O
a1 O1O co 0oO O d-~t
d-
N N O O
Q1 a1d'O O ~ ,~ ,-i,-i
M M N O O O O O O
O
H
N
a'
N
H
C
O
d\
-, ,-~ .--a N
r-1 H
H r1 H H
H H
~ N M ~"~~ ~ ~-i~
. .
0v~ 01N O 01 ~ O d1
0 o x o x o
0 o o
~ x ~ x ~ ~
a
' ~ ; o ~
~ ,-~ o
~ ~ ' ~' a~ '
~ U U p~e~E
,
0 0 0 0 0 0 0 0 0 0 0
ue ~ N
M ~ M
d ~ ~ ~ N ~ , .-r
' a; -a
~ . i
~ ~ N , i i
, ~ O t-' ~ ~ ~
C7a C7~UU P~E-~~ _ _ _
~U ~U~U
d\
~
N ~ ~ N
M
i i i ~ ~ i
~O ~ ~ ~ N
~n d' ~O ~nl~ ~ 00
N ~n N ~nN ~r1N
~
O
H
d1
M '" ~ d'
~
H O o0
w
w
a
,
x x
x x
N N N N
202
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d-
~ M M ~j N (~j N N N .-i ~--~ ,-i ~ ri .--i ~ ,-i ~---i ,-i ,-i ,-a r-.i ~-i r-
i r-i
O\ V'1 V7 '-~ t~ O ~ ~p p l~ O M ,-; O 00 ~ ~ r-i V1 M ~ O
O ~ ~. ~ ~ ~ pip M V~ ,~ U'1 ~p O dl V1 tn M M N \O l~ l~ \O M
a o o p o o O o O O o p o O o p O O p O O D o 0 0
xa,~xxxaa~~~~xx~xxxa,~ai~~x
M wj N N N N C~j N "' ,~ ,-i ,-i .-i ,-i ,-i ~-i ,~ ri ,-i ~--i .-i ~ ,-i
00 ..
pyn ~ ~ cn M oo cn ~p v~i ~ oo ui N v~i ~p en ~t M oo O
O ~ try .--i O 01 ~ ~ l~ d- V7 ~ ~ ~ ~ ~ d' N M N ~O \O l~ o0
O l~ ~O 00 N M ~ ~ l~ l~ ~O M ~O d' ~O V1 ~O ~'-~ d- l~ l~ l~ I
L~r ,~ O O O O O O O O O O O O O O O O O O O O O O O O
1 !T! . 1 !T! rn !T! !T! . 1 . 1 !T! rn !T! !T! !T! !T! !T! !T! rn . 1 . 1 , 1
. 1 !'N !T!
N
~
'
O
O '~ tV
''
~
O
% ~ ~
C
O O
''''d' V1
O p1
p. ~0
~ ~U
N
d\
M
Y
N
M
N
N
M
O
d-
W
G?
x
x
d>
N
203
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
,~ cad d-
-i,-i,-i~p ,-i r-iO ~ ~ t~jd' M cn~.,.jN N
N
00l~Ov O O 0 ~ ooO l~cV '"''~pO1
O O O '~ ~ O ~ O O O O O O O O O O
O
~i~l ~ ,....;[ ~ N C/7x r~r~'x ~"~a x x
-i xr
,.-,r-i,-~ ~ ,~ ~ W r1vi d'M criN N
N
N \Ol~ Ov M N tn (j~O.--i.--i
d' V~ ~ d'V~ ~ l~ ' ~'~nO d'~ ~ d'
'-'
O O O ~ a O ~ a V O O O O ~ ~ 0
O 7 O O
~ O ~ ,
,
~ ~
O
00 ~ i ~ b-0~ ~ M l~
i ~
p y ! ~ CJ~'
p O O O O M p p O p O
N
.---mn ,-idue'~ ~ ,-~ N
' M D
~ s~.,~ ~,_cd
<C C7U ~l~ C7L7 v~C7 v~
N N N
~
0o N O
N
v~ '"
d' ~ N
N M ~ O
M
l~ O 00 01
~n N ~n ~r1N
O ~ O O
d'
z
U
W
0
N N
204
CA 02395816 2002-06-26
N N N N N N N N N CJ N N N N H '~ H ,-i ,~ '~ '-~ '-' r' '_'' '-'
O M '--i o0
N~NI~~I~~N_~NOurlo~oOoNo~oooN~001~_~~Ot~rl~_
O O O O O O O O O O O O O O O O O p O O O O p O O O
xxxa~.~~~x~~a~a~xx~xxxxxxxx
N N ~j N N N N N N ~j N N N N ~ ~ H e--I e-1
~ iV M N d' iV 01 M ~j oo ~p oo '-' ~ od'o ~p p ii'i ~ N oho ~ due' ~
d' ~D l~ l~ \O O M d' V1 ~ O~ V7 d' O
O l~ [~ M ~D 00 ~' M l~ l~ l~ in ~O ~' M .-~ O N d- O r, V'~ O N
O O O O O O O O O O O O O O O O O O O O O O O O O O
!T! ~ G..~ '1 . 1 ~ 1 . 1 . 1 !T! rn . 1 . 1 . 1 , 1 fit'! !T! rn rn rn !T!
!T! !T! fr ~f'! !T! !T!
205
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
r--; .--i ,-i ~--i ,-i ,~--i ,-; .-i ,--.i r; ~"~ ,~ .-; ,--i r-; ,--i r-; ,~
~--; .-i ~--i ri ~--i ~ ,--i ,--i
O o0 c~ M d' ~ ~ (V d' N O 01 M ~ (V N l~ VO d' ~ ~ ~ 01
01 N ~-i ~ I~ M_ ~ ~ Q1 d- ~ ~p l~ \O 'CI" 00 \U ~D l~ d' ~D M
O O O O O O O O O O O O O O O O O O O O O O O p O O
x x x x x x x x x ~ ~ ,~ a a ,~ ,~ a ,~ ,~ x x x x ,~ x ~
0o N d' ~ N ~-~ oo 'd' ~ ~ cV l~ ~ cn O O M ~i'i O M ~O ~ h t~
00 V1 N M M \O M \O tr1 lfl ~ O ~ l0 l~ 00 M 01 lfl lp N d\ d1 d- tn O
Nd'OOMONOW MO~I~~I~VII~
O O O O O O O O O O p p O O O O O O O O O O O
5'! !T~ ~S! !2! 5"! !'T1 ~~T'! !T! ~~T'! !T! rn rn ~l . 1 '1 . 1 ~ 1 . 1 .1 ,
T !T! !T! !T! ,O1 .O1 !T!
206
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i N ~ ~ ~ ~O
N N
,_i'~''~~ t7~ ~ ~-i C~jri,-iri '"',-i~ ,,~ ~1 cri
N N O O ~ ~ o ~ N n ~ ~ N ue' O ~
O~
o ~ x ~ o d M
o
O ~ p l~ O V1~OM M
,-
cat N M M d= ~ ~ ~ ~ ~ ~
-i N ~ (V,-i~ ,~-1~ ~ ,-,~ ,~ cri
cn~ M vD '-' in~-i ~ ~ tj~pV>,~ d'O ooa1 00 '~ ~
cn
~ N 0
t ~ d ~ O O o ~ O O ~ O ~ O N ~ ~ ~ ~ O 0
W ' 0
~ x ~ ~ O O ~ a
O
,.-7xi~, ~ ,-a~-7 r-a~ ,-~~ ~l~-.1'x
O O
1 ~ ~ ~ ~ ~ N N O M M N ~
0 ~ l N
M V1V100 d- s~v~ ~ 5..,"~
ctiQ.~ bA ~-~.s:9, ~ r~~ y n ~ ~.'
:...
~-~v~~,s.r ~
r~ H
~ O O O O ~ O O ~
~ ~
.N ~ ~ 00 ~ [~l~M ~ ,-~ .,~'~
+~
--aN O ~ .v-~V1lfl0oM ~ o0 p l~ ~O N
V1
~ ~n~ p~ ~ ~ ~ N N N M M ,~ ~'?
tn
v y;v~a.. ~; b ~ ~ atR.~: '~~ ~ b
A p
s.:
~ v a H v ~ te H w w h
H
, ~ ~ d d C7P ~ ~ ~
.,
N i Q
p N p N
p p
d' ~p O
M
~ M
V1 O ~ V~
N , N , N
, r, , ~ ~ ,
M M M ~ O
N
O N ~ M N d'
O1 ~ d\ ~ a\
V1 N ~n N t~N
~ N ~ ~ N
l
0
D1 y t' ~ ~O~O
M
_
~
U
_
x
N M d'
N
N N
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
b~., M
i i i i M
M N N N r-i'"',-;,-,- ,-,-,,.._;,-ir-i,-i,-i,-i'-'~ d1 N N ,-i
,-;
v0 d'l0 O\~ ~ r"',-i,--iO ~l'p N 01ViO\ ooN t~ O p ,-iI~l~
~ 0ol~a1 d'01 ~ ' lp
N ~OO M ,---i N ~p ~ l~O M d ~, 0O~D~ ~
O1
O O O O O O O O O p p O O O O ~ O O O O
O
O p O O ~
.]
~, a ,~ a ~,x x x x x x ,~a a a ,~ ,~x a : ,~x xa
~ ~
M N N N N '~ r"'r'''"'''"''"~~ '--i.-~~ ,--i~ '"'''',~ N N .-i
~--i
N V'ia 01O O ~ n ooM opr-i~ cWri 'd'~ , ~O~ ~ O N o0
~ ~ 00
N ~ ~ N _ O O ~ ~ ~ ~ 0 ~ ~ O O _ ~
.'0 ~ ~ ~ d ~ 0 ~Od" O N
d l ' 0 ~ O
O O O O ~ x 0 ~ 0 0 O O a ~ ~ ~ O ' ,~0 0 0
0
~ a ,~ ~ = ~
,
I~M
M
~ 00M
M ,--i
00
O i , N
c y
O ~
O
~ O O
N
O ~ 00
~ N
,- M oo
N ~p N
N
s~.~.'.~~ s:~
O
C% C~~ V7
'd'
N
~n
N
a\
O
U
x
N
208
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0
-i,~ ~ ~'--~ 0~0 ~ ~' N ~-i,-i,-i"'',-ir-;,_;
,-i
~ ~
N ~ N M ~ O N ~ ~ N N
1 d
v '
O a a ~ O O p
r-~a r~ir.~ t~ O ~ ~ ,
,I,,
. ~--~ .. .." ...,
M ~ ..
-i,-i'-ic-i,~ ,~ N ~.j,--~,-;.-i,.~
M ' ~ ue N ~ N
O
d M " cs
d
O O O O O ~ ~ O ~ ~ O O o O ~ O O O
O
a ~ a e~ x ,~x v~ r m o
r~
O p ~ ~O I~ oo~ ~ N O ~ O ~
O
~ ~ N
00~ N N ~ ~ o ~ ,-~ N M M M ~ M
O -i d'
O ~ ~ ~ ~ > ~ ~ M Gn ~ i J~ >,~.,~ ~ ~
LD ~ C',
_ ~ ~ ~ ~ , tn_ _ t ~ ' ~ = _ _ _ "~_
_ ~ [~" ~ C~ C~ C~ a
CJ
y. .- CJ ~] "' ~ , , (~ ,
. " a
_ ~ ~ O ~ O O O O O O p O p O
O
O O O ~ O
O +~+~ .~-~~ d. \Q~ ~..~a-'.~N ,-iO Ol M \O M N
M
O ,--i ~
''-'M V'1d' ~ V~O~~''~01O N d'~ ~ v~ ~ O~
O
-.,N ~I'~ N N c~IM M M M ,.~~ ~ N M M M M Md'
i i i ~ ~ i i i ~ i i i i i i i i i i
~ N ~ ~ ~ ~ i
~
N
N N ~ ~-.'~ ~ ~ ,~" o ~ ~ ~ r'~
w H a w ~ w H a a...a, ~ c~~ a ~ ~ H ~
a
O
N o N ~
M
N ~ M
. o
o
d' ' N ~--
i ~ i
N N N
N
~n N ~n N
O
O O
~ N
N
00
,~
L1 W
x
N N
209
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
--i M ~ M '~ M
''"~ . pp r''_..;cV ..
h ~ h V-i, ~ _ ~ ~ O
o ~ o ~ ~D O o
o o o
~ d1 N ~ O O ~ O O O
M O O
~ ' 'd
'
O O ,, O O
T,
r-~ j ~ r-a~ j x ~j 0
~ N V N ~d e, ~ l N
~ ~ ~ ~
o N
~ ~ _
p ~ ~ a p fx ~ O O ~ ~ ~ 'x
..i
~.i
00t~~1 t~ d= M 00ri In d"t~d'
M Qvd-oo a; N v> ~ oo N ~';~O~';~ N
0o bA~ ~ ~ l , v W V t~
i
~ ' a ~ x , ~ ~ U ~ ~ -~~ , -~,
x
- C ~ C7 ' C E ~
7
O 4 ~ ~ o O O
p p O O O O
'''O M r,'-'~ ~ ue M d- N ~ N
d', , d ,--~~ ~ ,--i,
'.
N ~ ~ y~,~ ~ ~ ~ ~ ~,~ ~ Q,
G7~
N M d-
O
N
N ~ ~ N ~ N ~ N
O ~ ~ ~ ~ O
~ t N
r~
~O l~ N , N ~ ~ N M
d' , , , , ,
, r, ~
N
M ~ N
~n oo ~O 01 l~ O oo ~ O~
a\ ~ a> ~ a1 D\ ~ a1
V7 N try N tW N v~ N . V7
M ~ O O
I~ 00 d1 M
O
~ ~ O
N N
o
o
~
~ _
C
/7
0o O~ O
N N N N
Z1O
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
cri~-iO
r,.-~,~ ..
_ D v0trjWi~nM criM cn N N ~j~j N ~
O y ~ 'dd~ due-ood' 01N N ,-~~ oo M ~ O W1 ~ ~ M W
f?; O M 0 o0
~
"' a O O O d ~ ~ ~ O ~ ~ ~ O O ~ 0 ~ N ~ ~
,~,~ ,~' O O O O O O O O O O 0 O O O d-
N ..O r~ ~ ~ x t~r-ar.~x,~ r~O a ~ x O
' ~ -icnN ~ r-a ~ .. O
r~
07
..
..
~ 00~O v'i~nd' M M cri~jN N N N N ~' r''
~'
N d' Q\Vj,--i\O01,-iy -iM O ~ oocriO .-il~ l~
O '--ip l~C~'~ M O M O I~l~ Old'V1 ~p~ \D00 l~Q~00 N
O ~ O l~l~ d'00I~ 00l~l~ l~h l~ M O I~i~ V1
Q" rr y, ,~0 0 0 0 0 0 0 0 o O o o ,T,0 0 0 0 ~,
O
.
o
00
0
0 0 0
a H ~
M
Q\ ~ d\
.~N
N
'
i a>
N h
o M
o
N O M .
O1 O d\
N ~ON
O
N
O
a
x x
M
DD
N
211
CA 02395816 2002-06-26
~ ~ ,-~ ,--i ,-.a ~"'~ ,-. ~ ,-. ,~ ,-~ ,--i ,-a ,-a ,~ r-i r..; r; ,--.," .-i
,--; ,-i r-; '-' '"~ r-i
N~o~p~~N_~Np~oN_oN_o°~oV~'I~MOO~~Oo~o~°~~000
N O O O O O O O O O O O O O p O ~ O O O O O O O O O
°xxxxx~xxxxxxxxx~,~aa,~a,~xx~
N '~ N 01 p ~ d' v'i ~p d' ~ L~ oo M nj vj O p M d' ~ l~ O~ M 01 Vo
cn ~ N cn ,-1 d' N ~ ~ N O ~ M N .-., l~ ~ l~ l~ l~ ~ N o0 01 v7 l0
~O O O in O ~ O d' d' ~O O l0 ,-., d- V~ l~ l~ l~ ~O V> l~ ~ ~O ~D
O O O O O O O O O O O O O O p O O O O O O O O O O O
rn ~ 1 f~ rn !'L ~"! !'Ti L. !'T~ ~S! ~f! 5'! !T! rn , 1 !T! , 1 '1 . 1 '1 , 1
,1 !T! !T! !T!
212
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r"' ,-. ~ ~
N -i~ ,-1
r--W--W--~~ M v--1 O W --I O
~
N r~ P~ ~ R~,~
o o o ~ S a o x
~ ~
a a a ~ ~ N ~ a
N ~
.-i'-i~ ri~ '--ia a
~o ~~ co
N
~ ~
r ~ O ~ ~ o ~ M ~ o ~ o
x x ~ rx
a ~ a x a a ~
Sri oo N cncri~O
~
_ M l~00
~
M v~ ~ N M M
b ~ ci~ ~ ~ ~ ~ N ~ ~ ~
4
~ v~~, U a v~~n Is,_
~ ~
C7 ~ o a C7o 0 0 0 o ~ C7 C7
0 0 0 '
O O M ~ O O O
O
~ ~, ~ O
~ ue ~ ~ ~
d ~ N ~ ~ N
-
~: ~ ,.:~'~".,' p'ca ~.~ cn ~ O ~'.~s..~
_
H C7H 0.~v~ p,~ ~ a a ~ P-,Cn H ~
~
O '-'O O r,
D\ ~ a, ~ d1 ~ d1
01 N
N N M' N a h
d c o
n o
i ' i i i 01 N N
~
vd N N ue
1
N ,-,l\ ,- d
'
~ O ~ O ~
O 1 ~ O 1
0 0
\O N ~DN \O N ~ON
O ~ ~
~
' a x
U
x x
d' en ~ t~
00 00 00 00
N N N N
213
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O ~ O
l~d'd'd- M M ~rjM M N ~jCVN N
= h ~ CV
v0 d o ~f . .
O ~O o " l~~ '"''. CV(V~p N cnO ui. ~ N
O l~ M ~' 0
N 0.!O d'~OV1~p N l~N ~ 01~ r,l~o d
o
~C O ~ ~ O ~ o O '~ l~V7M ~ ~ pNO
O
O O a
~ o a x x x ~ ~ x xx
-i l~Vjd'd' d'M M criM N N N N N
N
~rj ~ ~ O [~m ~O \p~ \p ,-i,-.i(~ (~lOvdvOWn
Vl
O O O N O ~ ~ O ~ O
p p ~ l ~ ~ ~ ~ ~ p N
0
C/~O x ~ O O O O O O O O O O O O O
O
F,- ,] ~,
W -1 ~ x
'--i,-i~ ,-i oo r;V'iO
01 ~~ M
~ ~ ~
-i ' ~ Cj trj~ N , N (V
, ;' N -i
ci~N cii~ a~~ ~ ~~~~~ ~ ~
a P~_ ~ '" _ _
~
r ..~ r4
O O O ~ p ~ ~'O O O p O O
O
~ ue n r h
p d ~ o ~ + ~ ~,d.~ o N
- o o
~1 N
~ ~ N ~
N N . a~~ ~,
~ ~ ' ~ ~
1~ ~ C~U ~ l~ ~ ~ ~ , ra
~ N
a\ ~ a\
~
N
y,
M t
M N M
M M
~ D\
(T O O~
N ~ N
O
N
O
w w
c7
x
x
a,
N N
214
CA 02395816 2002-06-26
N N N N N N N N ,-i ~ ,-i ,-i ,-i ,-i ~.--i ~ ,-i ,_; ,-i ,...; ,-i .-i ~ ~--i
,-i ~--i
~dN.'N~~hcVMO~oo~opo~o~ o~~o~o~~~,-N-~
0 O O O O ~ O O O O p p O O O ~ O p O p O O ~ O O O
a,~~~~xxx~x~~xxx~x~xxxx~,xxx
N N N N N N N N ~ '--i ,-i ,-i ,-i ~ ~ ,~-i ,-i r-i '-i "~ ri r-i ,~ ,-~i ,-i
,-i
M Ov d' d' oo l~ v'i M N o0 00 ~O oo O N O oo vj ~i'i ~j vD N Cj O oo cn
N ~D O M M ~ Ol N O r--~ V1 d' l~ ~ M d' ~-'' 00 d' ~p ~O Ol d. 01 M M
l~ ~ ~ d' l~ v1 d' O N M O N M ~ O M p ~ M N N M O O d-
O O O O O O O O O O O O O O ~ O O O O O O O O O O O
!T! . 1 . 1 . 1 . 1 . 1 . 1 !T! Lr rn rn rn rn !T! !T! Lr !T! ~I'! !T! rn !T!
!'I'! rn !T'! !T! !T!
215
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r-1y -Ir-1r-ir-1v-ir-1r-1r1r-1~ ~ r1r-I~ r..~r1v-~Iv-1r-1W -i
a\cVd'~--~~ wto0 0oviM ~ ~ ~ ~ ~ 01ri oo,~~ cn
~DI~I~l~ 00l~l~ V1~O~ N ,-,M d-M 00~O d'
x M M M l~ M [~M ~D\D~ ~ M O 0
a a a a a a x x ~ o o o o o 0
~ a a a a a x x
r1v--1v--1r-1r1r-1r-1v-~1e-Iv--Iv-1r-1~ e-Ir-i~ r.,1y -I r1r1'~ r-1r-i
0oN (V~~ d' M oo,-..i~ cn(V ~ O ~D~ \O~lvO a1N M l~dv
M ~ d'~D~ \D 1~00~ V700V~ ~ ~O41M O V~V) ~ l0~ O1N
O M ~--~l~~Ol~ l~M \O ~OM M ~ ~ ~ O N l~l~ l~M ~ ~--i
0 0 o a ~ o ~ o ~ ~ ~ a o ~ ~ o o O a a ~ o o <o
M
a
0
0
~.
d
a
a\
N
a,
0
0
N
N
d1
216
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ~ try N
01 ~-~ ~ M ~ l~~OV'7~' M M M M
y O ~ r N ~ oho M
N - x ~ '~ ~ O x x x ~.,'"x ,,.~_j
O N l~ ,- ~l
-i ..~ trid= d=cncrjen
N d: .. M M
O O O O O Q O p
x Q,~ fx ~
J G "~ G O
V ~ ~ O ~ ~ M 01
0o 1 ;'~ p"V'i;' ,-~~, ~ N cn M
O N
pMpr; ',~ ~ 'd'~ .~ra y; Wj ~,b0 fir'
~',.?'_ _ ~ N ~ _ ~ ~ ~ H
C7C7 C7 per
~ , ,.., .,
E'' ~
O O ~ O p O p O O O
O
~
O ~ ~
N N N c
~ o ~ ~ ,~ o o >, ,~
C7 ~,P~C7 d v~ C~ C7E
H
M ~ d' N ~n
d1 ~ d\
d'
N
O~ M ~O O
~p ~ M ,~N
O ~ ~ ooN
O O O O O
M ~D M ~OM
M
N ~ N
-, M r, N ,-,
M
~x x x
N
d,
N
217
CA 02395816 2002-06-26
N N ~i N N eV cV cV ~,j N N N cV N N '"' r' ,-; ,-i ,-~ '-'~ '-' '_'_,"
~i o~o~~~no°°o n~~d'~~O~~~d'~O~NOo~o~
d' M ~ N ~ O d' ~ ~ 00o dM' ~ ~ ~ ~ N dN' l~ N ~''~ ~n ~O O ~-~ M
x r~.~ x r~
N N N ~j N N N N ~j N N N N N N N r'' ,-' ~"' ~"' ,"' ,"' r, ,-i ~
--i ~ tvi p O ~ d' O ~.j wj \O ,=i ~-i ~ij .-i d\ ~ l~ ~ ~ N l~ t~ Vi N
d' Vl ~p V7 ~ N d" ~ lp 00 ~ V1 M O O ~ V~ M ~ ~ 01 01 V1 M
.--i M N M V1 O d' O M 'p l~ ~ [w [yp ~p ~ ~ ~ M V1 d' N ~O O
O O O O O O O O O p O O O O O O O O O O O O O O O O
!T! !'T'! !T! rn h'! !'T'! !T! !'T'! rn . 1 . 1 h'! . 1 . 1 . 1 . 1 !"I'! !T!
!T! h'! !T! !'I"! !'T~. ~T! !T! !T!
218
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
--i ~ ,--i ri r; ~-; ~ r-i ,-i r; ,--i r; ~ ,-; '-; ~ r-; r; ,-; ,--i ,~ ~-i
r; r-.; ~--~ ,-i
d' ~O oo M ,_; op ,-~ d' ,--~ oo M N ~; p oo ~j ,-; o0 ~i'i ~O ~O O O
O ~ O p p N ~ ~ O O d' ~ ~ ~ N l~ d' ~ ~O l~ O v1 Qv ~ N
O O O O O ~p O O O O O O ~ O O ~ p O O O O O O O O O
xxxx~~xxxxxx,~~x~,~,~,~aa,~aaxx
N ~ cn ~ oo l~ cri d' ~lyp O~ ~O ~j p (V m !WD oo N ~O d' d'
00 N O ~ O 00 ~ N ~ l0 M l0 M V1 d' O d- l~ d' ~O ~ l~ V1 M ~D
V7 M O O N O N d' d' ~ ~O N O M ~O O ~p M ~p [~ [~ M ~p ~p ~p M
O O O O O O O O O O O O O O O O O O O O O O O O O O
!'T! !T! !T! ~T'! !T! !T! !'1'! !T! !T! !T! !T! !T! rn !T! ~I"! rn . 1 . 1 . 1
. 1 . 1 . 1 . 1 . 1 . 1 rn
219
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~ ~ ~ M
~ N ~ c~ ~ cd
-i -i; .-i.--i--~--i"'i~ O ~ i -- O O ~
M ''1O1~jI~ p l~,=il~ ~''~O O ~ d' '-.-~~~ a1 ~O V~
V'7~O ~ M O l~I~O ~ ~ ~ ~CO ~ V1~ M l~
0 o a o 0 0 0 0 0 ~ ~ "' N
x x x ~ ~ ~ ~ ~ x x
~ u'7N . . . . j i
.--.i~ r;rir-.i~-i<-i~--i~-i-i '.-i~--m--~~---;", .i
ri
l~(V opO d' d'V'ioocn l_~N ~ ~ I~ cnM d' O M ~ ~ ~ O
~ N d O O I~ ~ oOo~ ~ ~ 0 0 tn
O O O p ~ O a O a O ~ ~ ,~a O O O O ~, ~ C/~O 0
O
O
Sri
~.
H
O
+~
i
~.
N ~ N
a, ~ O\
d' d'
N ~D
O ~ V1 M
O .-~ ,-~O
~n , , N
i
M ~O 00 M
M N
01 M O d'
O O ~ O
M ~ M
c~ N
N O l0
~_
al
in d
C7
H
M d"
d\
N N
220
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r; ,~ ,-; d.
,_; ~ ~ ~ ~ .. ,-a~ '-..~..
M N ,~,--r,-i,-,,~O ~ ,~,-i~ ~ ,~ ,-i
,-i
O Q
M ~ d'~ ~ lpM O lp~Olp O O ~ ~O ~
0 ~ ~ M
~ V~N o01 ~pd'~l 0.!M N N ,~ (yO n
o ~
a ~ ~ ~ x
M x ~ a a ~ ~ a x xx
'~' ~ '
N d' ~ ~ ~ ~ ~ ~ '~ M ~ ~ d ~.j~ ~
~
'--i,--~,--i,-, ,--~,--~,- y ., ,--~
,--i
~
O ~ ~ ~ o O ~ v1 o O
x O O O ~ '~',~ O O ~ a O ~
O
x ~
d'~i
~ ~
. O
M ~ -i M O d' N
d'xn
cV~ o o ~ ~ ~ ~ ~ o , ? s~
o O
a~ ~ ~ a ~ , ,
~ '
,~~l~ ~ U F-
% ~ ~ '~-' ~'~ '"'' J
C p p C/~ d L
~
O p O p p p p p O O
~ ~ N ~ ue
, , ~ N d
-' '
'i'~ ~ ~ p'~"p 0 0
~' .
~ x ~ ~ ~ ~ a x ~ ~ ~ ~ ~ ~ ~,
0o N 01 N O
d,
N
~ O
0 '-'
1
d' D1
M M N
M M
O . ~ O ~ O
M ~ M \O M
N
x x
N
N N
~~1
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
rj M ~ ~ M
i i N ~ M i i
- ,- ~ d1 o 01 ,-it"'r-i,-i Ov N r-r-
0
op 00
_ _ _
~ ~ O ~ N
M ~ ~ W -1 p~.,
o o ~ ~ ~ ~ o o o '~ ~ o o
~ , o , o o
~ ~
a a ~ ; ~ ~ a a a ~ ~ x ~ ~
x
~ N ~ ~ ~
-ir-i,--~ 00 ,-i~ ,-~r-i~ N ~ .--i
,-i
O
~ vp
o ~ a ~
O O ~ ~ O d O O Ria O O
~ a ~ a O ,~ O O
x
O~ a
~ ~ ~ ~ ~ 00
~ a ~ ~ ~ o ~.c~H a
O O O p
O ~ Ov
f O
M i lp
~, ~ ~p~, b ~ Q, ~,~!,~ ~,
A
~ ~ ~ ~
~
~ G7 ~ G7 G7
N ~ M
N N ~ N
1 ~ ~ 1
O r O
h N
o O
o N d'
r,i M ~O
N ' ' i i
N M N r'
M M
M 00 'd" O~ tn O
O ~ O
lCM l~ M \D M
_
N
M
0o a\ O
d1 dl O
N N M
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ~ ,-~ N ~ ,-i
''_''-' 01M N N ,~,-i,-i'--~ ,-i 01 N ~ -~ p\ N
.-i~j ~ ~ O M M O N .-ip O ~ O ~ , ~n O d~p
~p
~D~p fxO _ ~ ~ N f~, ~' N ~ l~ ~
~ d ~ ~ ~ . ~ O 1 ' O ''
- x ..
~ x x x a x x o ,~ ,~
~ M ~ a ~ a a ~ ~ o ~ ~ a
. ~ .
i ;
-i,-i~-;,-,-,.-i cncVN '"~,-~,-~~ ~ ,~ ~ ~ ..,-,
d W cn~ ~"'~n '-'~ a1~O~ ~ t~O~N ~ ~ ~' ~ oo M ~O~' ,M-r
h
d\\O V1~ N ' ~ I~ d'l~d'~ 00l~~ ~ \OC/7~ l~M 00 ~
d>
m o o ~ ~n'~ a o 0 0 0 0 0 0 ~ x w 0 0 0 ~ ~ o
'~
x x a ~ ,
~
~ ~ a ~ ~ x x
~ d1i
M Q.
ci W ,~"N ~ ~
O ~ ~ O
O O O O
N N
O v~ ~ >, ci~
~
f~ ~ -1 L5 U
N N
N N
d\ d> d1 a>
M
N
i i
N
,~ N M
M M M M
~ ~ O
O
N
d'
~7 Z
f~ (~ P
W ,
o0
x x x x
0 0 o a
M M M M
223
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0
O
M
O
M
CT
N
M ~ M ~ M
-;O '-iM N r'''~,-i,-ir"~,-i,-i~ ,~ ~ '-"',--i~ ,-a 01
O N N ~ oMOpOp~ O ~ oho~ ~_ ~ N ~ ~ ~ ~,
O O O p p O O O 0 O a ~ o O O O
= M x x x x x x x x a x x a ~ M
M M
M ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
cncrid'~j p O O o0~jl~~ ~ O -i -i
d' d'0000 V>M 00 O I~ 00 N l~M O
x' O O x ~ C/7 '~iO C/)x O ~ a O O O
x
d'
~ ,~-r ~OQ l~
i~ ~ O
~l7~' ~ , a~N ~'
0 0 o a a ~ ~ ~,
0 0 0 0 0 0
N ~ ~ N ~
~ a,
by_N'~ _' ' ~.p tip
~ Q,
d ~ H H r~
a
0o d1 O
N N M M
dl d\ d1 a>
p N M
due' o M N
i
N ~ N N
M M M M
V1 O 00
O O
01 D\ d1 01
N
'"'' x N f~
0 w H
C7
x x x
0 0 0
M M M M
224
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O O O ~--~O l~O O O O O O O O O O O O O O O N O M M
V1
!17M M 0000 N d''Cr'd'V1O O O O v'7~ ~f7U7 V'7V'700 ~ d'[~~-t
00
O O O d\M 00O O O l~00 00000000 000000 0000tf1O ~ N M
M d' d'00N 0oO O O ~ ~ ~ ~ ~ --~~ ~ ~ ~ \O~O ~ O O ~
O N N M o0 0oa\a\ a1d'd' d'd'd'd' d'd'd' d'~noo OvO O O
O
M
M
N
N N
D d1 ri.-i
o000
x
O O
,~ O
~
N
riri~;
~
c '-'~ (Vo0~p
~ x O O p
C7
O O
C~~l'
N
M
M
N
M
O
N
O1
a\
W
U
x
0
M
225
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~n
N ~ M ~~N M
..cri ~ ~ ~ ~ ~ ~ ~ ~ N .. '"'' .. N ~ ~
d' ,-i.. C~j.-.;,-a,--~,-i,.'~,-i,-~,~,.-a,-iN .-i ,-a N ~j r"'.
_ ,_
O x O N M ~jo M d'oo 1 O oocV ooO O N O ~ O ,
o O
" ~' ~ ~ _ ' ~ _ x ~
O O M O d Vl~ l~l~ Vl ~
~ ' p O 0 ~ ~ ~ ~ Q
''
~ p O 0 0 0 0 0 0 x ' ~IO O O
x ~
~ a ~ x x x x a a ~ ~ M ~ ~; M x a x ~
H ~ ~
N N ,-~H ,~-~,--r~ ,.._,,--~~ ,--~~ ~ ~ N N ~'
cnOv,~ M d'Cs1p vpN I~ a\N ~ M O i N Vi(V O d'
Q O ~ ~ ~ O ~ ~ O x p
p
O
O p M lptn \OI~ l~~ O O 00l~ H
x ~ O O O O O O ~ ~ ~ Q
. ~..a O O O O O O x x O O O
~ a ~ x x ~ a ~ ~ x ~ .~
d"~ N ~ oho,N-~
~
~_ M ~ ~ ~ _~_~
x
~, ,~ c7L7
O p O ~ O O O
M a-'O ~D
N O M ~ ~ .r-. M d1~i\O ooO
~
H H H
N y7~ ,~ ~ fV
~
E-~C7~ ~ ~n ~7 C7~ C7 C7E-
M '~' tn lD
dl ~ Q1
N O i~ h
o
i o
M i [~ i
M ~ N
N N N N
M M M M
d' M oo N
H oo N M
N N N
~--i ,-, N
a\ ~ D\
due'
w
x x x x
O H N M
H ~"~ r1 H
M M M M
226
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-.i~ ,-.i,~,-;r; ,-;r;.-.i~--i.-;~--i~--;,-ir-i,--i,-ir;~--ir-ir',-~~ ~-.i.~
N 0 O\ d:O ,=id',=i~ l~ O p p~ ,-it~'d't~M ~Ci,-io000 c-i
lp~p~-,l~~ ~ ,--''~ '-'~,~ ~p~ ~p l~M ~O \OO l~ 01~ ~ ~ d'..
O ~ O ~ O p O p O O O p O O O O O O O O O O p O V1
x ~ x x x ~ x x x x ~ ~ a a ~ a ~ a a a x x ~ a V1
.-id:p pp01~D d'cnO ~ ~ ~ ~j m ,--iO M 01d' 01~ N ~ t~O
d-~ oo ~ O~01 N ~ ~-1 ~OV1p ~OM O ~ d'l~ O N ,~d'O
M M V> N tnV1 O ,--iV1l0 O V>O l~~O00 M V1l~ 00'-'~~ O l~aa
O O O O O O O O O O O O p O O O O O O O O O M O cV
CJ7r~ C1~~, ~-x~ ~ x ~ L7 ~ ,.~ a ,~ ,~,G7~ V~
M
l~
l~
O
O
,~
227
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
-iO ~ ~ d' ~.rjN N ~j,-i,~~-i~-i,-i~-i,-i,-i.--i,~ ,~,-;,-i.--i~ r;
-iO O ~ Q~ ~ ~"'Ov ~ ~OVjM 01O ~ 0000\Op l~p~~p M N ~--i
p 'C~ x d 0 O O p O O O O O O O O O p O p ~ p O p
,=-i
a ~ N ~ a ~ x ,~ ~ x x x x x x x x x ~ x x a x x
d'
M
~
O
a
'--i,--i d' crjN N N N ,-ir"~,-i,-i,-i,-i.-i,-i,-i,-ir;,-i,-.i,-ir;
i ,-i
-
- . .
01~ ~ N d' ~jM_cn op,-ip Vi . N V'i~Dooc_n. M ~p01 ~0~_oo
O due',-~-rO ~ ~ ~ O ~ ,--i~ ~i N ~ d',--~~ ~ ~ oOpv1O
0 0 ~ ,"T',O O O O O O O O d'O O O O O ~ O p O 0 O p
O O 00
O
i
C5
O O
O
d'
M
d'
M
N
d'
N
M
N
M
N
d\
a
0
w
x
M
228
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
,_,,-~O r.;
a;
: , . .
i
, ~ ~ ., ...... .,....
- y1 l~N N (VN ,-,~ r-.i'-'.-i'~'"'r, ,-,,-~,-,,~,-~,-~,-i~ ,.-yn
--0o d- ~pO
p ~ - lp O ~ t~
_ d'ooI~ ~ M O vi O
C/~O ~ p d' OWE N d M ~ O ~ ~ L~
~ ~ ~ M ~ ~ _
"O~ O O d O N ~''~O N ~ O ~ ~ ~ ~ O O ~ ~ ~ '-
~ ' p O " O O O O O O O O O O O "'O
O ' ' ''te
'
N N ' a ~l~lC/~~ ~ ~ ~Cr W -1 ,-.y-)~-1Cl~rW-1
' , , ,
~''~N N N ,-i~'.''r-i,-a,~,-i,~,-i,-;.-i'-i,-i,-;.-i,-i,-,
Vj~ d'a;~p o00101 N Sri~ O ~ '-'t~l~a1 ~Oo001O oo~ 00
O O O ~ ~ ~ O ~ O ~ N ~O~ ~ ~ ~ l~0~ O ~ ~ ~ O O
tx "'O O O O 0 0 ~ '
'
O ,~ O O O O O p p p 0 0 0 0 0 0 x,
G7~
N M
a r~
O O
N
i i
~U E
00
O
d. d.
i
N
N N
M M
d' 00
M
d>
a
U
x
M M
229
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M N
O (W N ~ O
O N ,-~~ ~''~' 0000 ~ l~v0~p ~ ~pvD Vi~id'd' d'
d' oodv Ov(Vp
O l~ d'V~ M y l~ y 0 ~ p N 01v0 O oo (V01a\(V O~~ '"'
~ ,=..;
O l~l~ d'l~t~ ~ ~Od\ ~pN M ~p ~ V'1~O~ d'O ~~~ ~
t~
a O O O O p O (~tn M V1O ~p '-'t~t~ ~Ot~O ~ lDN ~O
p p
a a a a a a o o p O 0 0 o p o 0 0 o O O o
N a a ~ x x a x a a a a H x x x x
a
~ ~ N ,~~; o
N ,--r,~,--~,-r~ 0000 00l~~ lfl~D~O~ VjV'iirjd= d=d'd'
:
, .
.._;t~M ~ tnvp . ooa; ~jdvO N ~nsovi vpM a\cj d'O N
M ~ csj
op ~ ~tO M ~ N N y n 01v0,-aO ~ N ~n N ~ 010o v1N ~'~
O N
O l~O d'l~O ~ M ~ ~ l~O O ~ ~ l~ ~1'~OV1N M ~ O
O Wit'
O O O O O O O O O O O O O O O O O O O O O
O
~ a a ~ ~ a ~ ~ ~ a ~ ,.~~
N
i
H
O
O O .,..,
O d'
~
M
O
d- d'
d\ D\
01 M
N
i
i
N
N N
M M
M N
a\
a1
w
a
M M
230
CA 02395816 2002-06-26
d' '~' d' d' ~'''~ cn cri ~' M M M M M M cn rrj M cri cn cn N N ~j N ~j N
~O ~ O v'i O ~ ~j ~ p~ ~ ~ d' 01 0o Ov p ,-i cri cri ~ cfi fj O p
N ~ 01 01 N p N ~ M ~ ~ ~ d' ~ M ~ M 01 d' v~ lfl N l~ pp d'
V7~tn~nd'pONO~pO~~p~~O~OMpOOOppp~pOO
axa°°~~xHxxxa~a~a~axxx~x~~
d' d= d= dW''~ cn cn M cn ~''~ cri M M cri cri cn cYi cn cn cYi N cV N N N N
v0 ~t ~ oo O ~O in '-' ~_t rM",~ cn d' ~ cV ~ ~t dW~ ~n N p ~ O O~
l~ N ~ ,--~ ~n oo ~O l~ ~ o0 ~O N M
!~ ~D !~ ~O M M O ~ d' O d' '"~ ~ M tn M O l~ d' M 'WO ~ M d' O
O O O O O O O O O O O O O O O O M O O O O O O O O O
1 . 1 . 1 . 1 !T'! rn rn !T! rn !T! . 1 !T! !T! . 1 . 1 rn rn . 1 . 1 . 1 !T!
!T! !T! !T! !T! !T!
231
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N ~j N N N N ~j N N N N N N N N ~j N N N N N '~ ~ ,-i
N M p ~ N M Ov p d' O ~ o ~ ~ oo N ~ vj oo ,~ O ~ ~ ~j: O
O N ~ '"'' ~ ~ ~ ~ N ~ ~ N O O ~ ~ ~ ~ ~ 00 0o O ~ d' N V1
O O p o O O O p O O ~ p O O O O p O O O O O O O ~ O
xx~~xxxxxx,~,~,~,~xx~,~x,~,~,~x~~,x
N N N ~j CV N N ~j N N ~j N N N N N N N N N N N ~' ''' ri .--i
0_0 01 ~p ~j op ,-i cn ~ l~ M_ .~ p~ ~ ~ O_1 ~ p t~ O ~O N
M OM O p d' O ~ Mp O d' ,~ M l~ ~ ~ ~ M D N ~ ~ ~ N ~ M
O O O O O O O O O O O O O O O O O O O O O O O O O O
'Z' ',1,'' "'~'' rn ~,"' ''S' '',J~'' rn '~'' ',1.'' rn ,~ ,~ ,~ '',L'' '"~G'
rn rn rn ,~ ,~ ~.7 "Z' ',1,'' rn rn
232
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r-i ~-~ ,-i '--i ,--i ,--i ,-; ~-; ri r..; ~.; ~ ,--i ~-.; .--i r; ,-a ,-i ,~
,--i .-i ~-~i ,-; ,-i ~-;
,.; l~ op oo ~i'i O ~ ~ '"' N O p ~ O ~ Q1 O ~ p ~ O oo ,=i e1' c~
d' ~ ,~ O d' O ,-~ °~ M N d' ~p Q~ Ov oo d- ~ a> ,_, w' tn l~ (~
O O O O O O ~ O O O O p O O O p N O ~ O O O p O O
xx~xx~~xxa~~xxx~ax~xxxaxx~
m ~ oo m N v0 ~p ~ oo dv ~ ~O ~n Vj ~ v'i O~ cn cV v'i op
1p O ~ ~j- Q\ ~ M M M 00 pp ~ O N dl M ,~ Q\ d' O N ~ ~ pp
~O M M O M [w d' M l~ d' ~ N O O d' ~ N ,~ V~ tn O ~ O O M
O O O O O O O O O O O O O O O O O O O O O O O O O O
rn !T! !'T'! rn rn !T! . 1 !T! !T! !T! !T! . 1 !T! !T! !T! !T! !T! !T! L !T!
!T! ~T! !T! !T! ~T'! rn
233
CA 02395816 2002-06-26
v-i ~ e-i r-1 r1 ,~ .r..~ e-1 ,~ r-1 H r1 r-1 r-I r-1 r-1 ~j ~ ~ r-1 v-1 v-~1
r1 H r1 r-1
O op a\ 00 ~i'i ~ ~j t~ cYi O M oo ,-i N O H Oy~ p oo W O d' d' N v'i
N l~ N ~ O d""' 0o O lD M ~ ~-n 0 ~ 0 ~- ,~ M M d' Q\ O ~ V1
u~ O ,-~ O ~ O ,-~ ~ M d' H O ~n d' H ~n ~ ~p N ~O ~O ~O l~ oo ~O ~O
O ~p O O O O O O O O O O O O O O O O O O O O O O O O
x~xxxHaxxxxxxxxxxx~aaaaaaa
~~~~~~~;~~;~~~~~~~~~~;~~~~~~~
01 d' l~ oo N N O oo Vj d' iri ~ O o0 01 01 p p ~ M Ov N oo M oo M
M O~ ~O 00 tn 01 M N tn l~ M ~ d' 00 V~ N tn ~D M l~ ~D O l~ V7
N ~ N ~ N O O ~O O ~ H tn O d' O d' ~ r, M [~ ~p [~ [~ 00 M l0
O O O O O O O O O O O O O O O O O p O O O O O O O O
M M ~ M M M ~T'! ~'I'~ 1 ~ !T! ~T'! !T! h"! !"1'~ !T! rn rn rn . 1 1 . 1 . 1 .
1 . 1 . 1
234
WO 01/54733 PCT/USO1/01312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
.-i d-
r-i~ r;~ r; ~ ~-iri ~ ~ ~ ~,;ri~ ~ ,~;~ ~; ,--i~ ,
lfl~ d'd'M d' ~ ONOM ID~ ~ I~ d'M ~ O~O~ ~ ~ p~px ~/
O O O O O O O O O O ~ ~ p O ~ 0 O O O
.~.~ a a a x x x x x ,~~ x x ~ ~ x ~ x x ~ ~
~DM N d1fVo0 M Ovd' O p fV~D ~ N v0 l~~ ~-i~ d'N ~
O Ov ooN 01d- Ovo000 l~optnd- ~ ~ O t~~ ~ ~ 01d' p
\Dd' l~~ t~,~ V'1~ ~O ~OM ,~~ d'O N l~~ O ~ ~ V7 ~
O r-1.-W.-)r-1~ O ','1,''x O O O ~ O Cjt0/1i-7~.~'rC/~,.'
i
.
r,
x
O
,
U
a\o
N N ~
N N
N N
,
M
dl
N
~O~D M
N ~'
~O O
d\
x
M
235
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O O O O ~ O VjVj ~-iO ~r'iO O O ~n O O O I~V'i(V(V
l~ ~ O d'O 01 O O ~n~O ~ ~ ~ O O O 01O m n
O~
~ ~ 01O ~ ~ ~ O O t~o0 0oGoM 000oN o0
~ ~ N N _ O
O O ~ M d d ~ ~ ~ ~ ~ ~ o o O~ N M ~ 0 0 0 00
' ' o o
N
a'
,_, '"' i
O l0 '-
V
c l~
~
o 0 ~0 ~ 0
o
O
'~
c~ x ~ x
W
,-i h N cd
--i .--i
N ~
~ 0 0 00
p
C~ ~..fx x O
.,
C7
O
C7
M
d
-
d>
N
M ,
N
O
M M
M M
d'
O N
\O N
O N
D\
W
H
C1~ W
x x
O
N N
M M
236
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O O M
O M O~
d-~D ~--i
[~M O
M
N
C
O
'd" ~ M ,-rO ~-i~-i ~ '~O
'--i~ ~ ~ .. ~-I
d' N ''~
--i ~ ,--i ~j~"'~--~~ ,--i ~",',--i~N ,-~ ~"',-',--i ,-icT ..
O ~ O M N N ~ ~ O ~ ~ M O O O _
1 ~ l~ ~ O ~ l o 01
0 a x ~ x x
~ o ~ ~ o ~ ~ a o ~ ~ ~ r ~ o
~ ~ ~ ~ ~
a a x a ~ ~ x ~ x x x a x
O ~ ~ O n N O
~ ~ " l ~ " N " cd c ~ " ~ O
N .-;,-i,-~ ,--y;,~ ~ ~ ,-ia ,-;
O~~ M .d:~ ~ ,~~ N ~O~ ~ ~ ~OO ~ N ~ p N N ~ ~ p O
~ O ~ p ~ O O p
p p ~ ~ ~ ~ N ~ O p ~ p p ~ '-"p O
o , 0
O f~ O O Ix O o R~ O _, ~ P~~, O
p O
,~ p a ~ ~ a ~ ~ ~ ~ O ~
trj O
~'~ op"N ~ N
..-.iOi
~ H
~ ~ ~
O O O
p O O O
O 'gyd-O
N ~ ~ p
N
~, v~~ ,~~" v~ tip
~'
~ a c~~ a ~ ~ a
a, a, a, a, a\
M Op M ~O O
' ' 00
~ d
i ~ i i
M ~ N M d-
N M d' ut ~D
M M M M M
M M M M M
01 N d' M
d' l~ M l~
N
O ~ ~r
l~ O~ O M l~
p ~
M l~ h
N N N N
N
M M M M M
237
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d' '--i~ ~ N ~ M
N
--i~-','~,~ ,-ipMp,-i .-i,--i ~ M N ~jN ,...;~ ,~ ,~~ ,~ ~ r-i
O o0p O ~ O ~ p ~ O l~ ~j -i ~ CO
N ~j ( Vj.
~ N O ''~~''O ~ ~ ~'' N d" N O M
O O " ~ O ~ p M O ~ O ~
O O ~ a O ~ O O O O O O ~,,O
~ "
"
t~V~ C/~~ ~ '~'f-1 : C/~,~,'x CJ~~]r~ ,~,,a ~p ~
. d ~ . ~
N
-,,-~,-~,_, ,-;,-,,-~ cfi~.jcV ~ ,-~,.-~,-~,~~ ,-,
cnv'il~~ ~ ,-~N M c;~j'"''0 ~p~pt~ ~ vpO ~p~ M ~ oNoM
~ p ~
O p ~ O p p O N CI'~ o p ~ M M ~ p N ~ p O p O
p
GY.,a O O O O Ix 't,'~'O O O ~ ~ O O O O ~pN O O O ~ C/~O
x ~ x ~ x x ~ a ~ ~ x
M ~
N lp ~ O ~ ~ ~ ~ ~ N l~
cn ~ ,-~~ , ~ ~ ~ ~,, N
-,
C7 ~ ~ .~~U~U ~ ~UP~ ~
~ ~ ~' ,
O O O p O O O O
O O O ~ O
O
~ ~ ~ ~ ~ O N N
N N ~ ~ N
W o ~ ~,~..~, s.~.~ ~ ti~ v~
a~' a a c~c~~ ~ ~ a ~ ~ a
M O ~ N M
N ~ ~ ~
0 1 1
1 0 0
O
\O ~ M
i i
01N
N v~~1 '-' oho M
00 00 01
M
\DM M M M
~
_
M
01 o N 01
O
N ~ ~n O
v~oo ~n o0
al~ ~ ~ a\
~n
M
U ~ W O
x x
x
N
N N
M M M M
238
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
'"'' ~ '"' d\ ,-a ~ '~ O ~ V7
(V O
; c~ , ~ ~ . N W . d
-id' "' ~""~ -ip '~O . ''~ -i ; ~',--i
O l0O ~ ~ N N ~ ~ x O V \O
N ~ x ~ oo O ~n f~O fy ~ fx N o
x ~ ~ x o d ~ d , x ~.'~' d -~s d d O
.r~ ~ x x
N ~;x ~ ~ ~ ~ O ~; ~ ,~ ~ .~ ~ i ~: N
i -~ ,- i ,~ ,-~O ~ ,--y ,-i ,--~ ,-i
d1~ d1N d' O O ,--i O~~ 01 ~ D1 N
p ~ oo~~,~ N oo'~ tn~''P~ O oop M o0 O O
~ ~ '~'O Q P~~ ~ ~.~jM x N ~,'~'~ ~ ~ Ix ~
~p
O M ~ ~ ~ ~ l~
l oo, ,~ ~,N ~ , s..~ l0 , cd
y ~ ~ p t~.a~ ~ s~..~ ~ J,N ~ O ,-.
d C'7~ a.d ~ ~'~;rn ~ ~'''~ x p"'o
U O O O O p
O O O O +-'i-'O O O ~ M ~ t<7
p M
M d'~ ~ Ol~ ~ ~ ~ 00~
, , , ~ , i ,
d d a d c7w d c7d d c7 d H d
n
o, a, a, ~ a, a'
N ~n
O ~ ~ ~ N
' ~
, , , ,
~O N M ~ N
N M ~n
d' d d d
- - -
M M M M M M
N Q~ d' ~O O~ 00
N ~ due' due' due' o~o
Q\ Qt O1
O
d' ~ N O ~ H
x x x x
N M d- V'1 ~O
M M M M M M
M M M M M M
239
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
l~d=d' d'd cnM N N N N
O ~
--.,M ~ M
W 1 ~ O ~ ~ ~ ~ ~ O
- O O O
O r.~~ ~.-1~l~l,...)~l r~v7V7
l~~ d' d'd'c~icri(VN N N
N pipd OWO ~ t~~ N l~ OWO ~ O
d' l~ ~O l~ d'M V - d' ~
O N ~ 1 M d l
N O l~~ l~ l~l~~ l~ O M O I
~
O ,~ O O a a a O ~ O O O
N a O\~ N M ~ N O ~1M
n d o0
-,N c ';~~ d ' d'~ ~ ~ ~ ~ N O~
W .
m,p ~ Q, ~.A.~ ~.,~,~ ~ apN
, d
-.v~ a~~n~ ~ ~ ~ v~ ~,t~.r~ ~ , c
U ~ ~ ~ H r~ d
,.~ p~ ~ a ''
O p O o O ~ O p O O p p p o V O
~ N V Q O ~ ~ h0M V' ~ ~ O O O V'
1 1 M 7
' ~ M
N M M M d d"~ ~ ~ V1lp 1p ~ l~-i
R~~ b4 ~ b ~ by0 0 0 ~ O N ~A
A
~ . ~ L'7N ~ ~ O ~ O . ~ ~
~ C7 ~ ~ C7
v~ I~E-~G~ H
0
a1
0
d
d~
M
d.
d'
N
d>
U
x
M
M
240
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N N N N ~"'',~ ,~,-i,~~ '--i,-i,.;~-i,-i,-;,-i'-;,-i,-i,-i,-i,-i
~Ovi N O Ov N N iV ~p'd'~DO d'cV~ ~ d'p (Vy p v'iwtoo'-'
~mn ~DO ~ ~ M d'N ~'-'N r1 ~ M N [~O ~ M 00N ~t
O In [~l~l~ M O N M O V7~ O lfl~p O M ,~ M 00~ lp M V1vD
O O O O O O O O O O ~ O O O O O O O O O O O O ~O
a a a a a a a ~ ~ a x x x x x x x ~ a a a a a a O
N N N N N N '"a~' ,-i~-~.-i,-i,~-i,-i,-;,-i,-i,-iri~;.-i,-i,-i..-iO
~ N ~ N onoN ~~r1N ~ ~ ,N-aN oMOp ~ ~ ~O cMN d'~O cn01a
l0l~M 00O x
~ ~O O l~l~ ~ ~ ~ d'O l~O O O O O O V1 ~O~pl~\O I~00,-i
O O O O O O ~ O O O O O O O O O O O p O O O O ~O
a a ~ a a x x ~ x a x x x x x a a ~O
~p
O
O
x
241
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
.-iN
~ ~-i,-a,-i~ ~ N ,-i~ v'id' ~.rjcn~jN N N ,-i,~~-i,~ ~-.i,-i,-i
N O trjtij~ l~p O v1N ~ ~.jO ~ M M =i,--i~j~.j~O d'cVcn
O c/-t/~~ ~ x (y.,~ N M M O ~ 00 00O l~ 01M N VlV1
O V> ~ y 0 O ~pd- ,~,ooM d' ~ ~ ~ y n O O N V~
x O O O O O -~~ ,~O O O O p O O O O O O O O O O
~ x ~ a x x ~ ~; ~ x ~ ~ ~ ~ a a ~ x ~ x x x x O
~ x,~
-i,-i~.;,-i~-;.-i,-i,-a . trjV'id~M criN N N ~ r-i,-i~ ~-i,-i,-i
r;
O 01 ~ _ '~' O r-id' l~ O O d1
VO d'l~oo N ~ op M oo M d't~~f'~ O O
l~M O ~,l~V1 01p1O O ~ 01 d-d'I~' \D00~ tnlp~ ~ r-~M
O O p ~ O O O O ~ x O O O O O ', O O O O O O O O O
x ~ ~ a ~ ~ ~ ,~x O ~ ~ ~ ~ x x
o
a,
0
'~''dlM
M M lp~
i~ s~rYr
d'
d'
d'
M
d>
O
N
d\
M
H
x
M
M
242
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~ M '~d'
.-iri~-ir-i,--ir; -~r;~ p1 N ri,-i~--i~-iri rir;ri ~ VM'1~ N
d W0wt ~tcn , riO O ~ ,--icn~ (Vcn p ~:r~;dvO O ~ ~ o0
00V1~ ~ M \O d'O1~ V'100 p ~ p M x ~ p 00pp
~ ~ o o o o o o o ~ o o o
o ~ o o o o o ~ o o b ~
a ~ ; x x x x x x ~ x x ~ o x x x
~ N
v0c~nc~id'~Ovj o00100'-'~ 'd'njN ~O~ cnd'~y N ~ ~ ~ vi~ l~
~ ~
d't~O l~O v1 N d'v1 ,--~N ,--~~ M O o001O N M ~ ~DM d'
O O O O O O O O O ~ ~ ~ O O O O p O p O O C~ '"OO p O
~
~ ~ a .~~ a ~ ~ ~ x x z a ~ x ~ x
0
N
i
N ~ O
d' Q,
O O O
O
O
P~ H C7
N M
d1 a1
O o0
O1
~O N
O
M M
d\
~f' M
0o N
d
d\ O1
O
x
x
O~ O
M d'
M M
243
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N r..,,y--iri ~-ir-iM~'~ ~\O~n d=d'M M M M M N ~jN N
N
f
O ~ O O ~
O ~ O ~ O ~ i ''~ O d M O
o r1I ' O
'
~ , ~ a ~
,
p a O O O O O O '~ O O O O O O O O O Q O O
O
o x a a a a a ~ ~ o a a a x x x a a x ~ x x
x
~
-i,-; r-i,-i,_;,-i,~.-.i,-- y j d~d'M M c'~criM N N N N
N
cV~O~ oQo~ N M oo V'7M cVi ~ ~i'iiVooO M d\ r-iI~op~ ,-i
~O
N ~ ~ 0 ~ N p O O N ~ O ~ ~ ' ~
p
O
o d M ~ I~ ~ ~ '
0 ' N
d
O O ~ ,~O O O O O O O ~ ,~O O O O O O O O O O O O
O
x x a a a a a ~ x ~ x a x ~ a
~ M
~ ~ M
~' _
N 1 t~ v~
V >, O~~,
i
''i a _ i _
~ ~
~ ~
O O O
~ O O O
O .,..,~ M N
M ~n O d~ M
.--m
O o ~ ~ ~"
0 0
0.Ø._ U ~..a r~ 0.~C'7
C7
d- ~n
a, a1
N o0
d'
i
M
M N
N
~ m n
M M
O O1
a>
d\
d1 M
N
O1
a
x x
d' d'
M M
244
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N N N N N N N N '""'"~r''-',-i'-i'~'_,"r; '-i'-i'~ "'r'''-',-i
O ,-;V'iO W1~ O ~ O Cyd\r' ~p0op V7 N .-i~ ,-i,-i~O ,-io0
lp v1V~~ tn ~O~ 01 01d'~ V1O ,~V'7O\N ,-i00~ ~f'tnpp~ M
O l~ l0~O~ l~ N ~ V'1,--iO d' M N O d' ~'O O V1N O 00~p O
O O O O O O O O O O O O O O O O p p O O O x O
a a a a a a ~ a a ~ H a ~ x ,~x x a ~ x x x x x ~
N N N N N N N N N N '~'"'.-i,-;r-i""''","'-'''ir'''-''"',~,-~.-ir-i
01 ~Ot~cn~ Ov~ 01 00~i'iO o0opVj,- W v'i~n ooN l~ ~ ooM ~n
~O l0V'700lD ~f'7~ 00 O ~O~ M p d-"~ f'M l~ ~-iV~01 tI~~ 00
x t~ t~~ l~\O l~~ ~ ~ON ~ ~OO O \O I~lp~ M O tn ,-~O d- d'
a a a ~..aa a ~ a a x p x ~ x V1x x ~ x p a ~ ~ O
o
245
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
--i,--i,--i,~,_..;,-i,-ir; ,-i,-..i,~,--i~-i,--i~ ,-i~ ,--i,-i~ ,-i,-~ ~ N
~ ~ --i
~
0oO cV O ~ ' r-i~ oo N ~ O O
O ~ M ' ~ O ~ ~ N ~ due"~ ~ ~ 1
~ O~
O O d'p ~ ,- m l M o0~ ~ ~ ~ ~ V _ ~ O
O O - j ~ O O ~~
O O O
x x x a O x x x x ~ x ~ O O p O O ,~
~ a a a a x ~ ~,a a a x ~ x
ri,~ ri~-i,-i,-iri,-;.--irir;ri ~ ~ ri~ ,-ir-i~-i, ~-i~ N N
,-i ~
D1~ ~ N N O d'~ ~ ~ N ~ o ~ON N ~ dN"~ ~
V7M O l~O tn ~p~p l~l~V1~O ~ ~ M V~ M l~l~ M Vl~ O O
O O O O O O O O V'7 ~ \O
p O O O O O O O O O O O O O O x
O O
x x x x x a a a a a x x ~ x ~ a ~ x
M
O
N
~,C7
'U'O
O
i
C7H
f~
d\
O
M
M
M
O
O
N
M -
dl
N
M
d'
M
246
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d'
- y -i~ vjd''d=M crjM c~jN N N (J ~.jN N ~ ~-i'~ ,--~'-'i,--i
N o ~ ~ ~ ~ ~ ~ oMO~ ~ ~ d'0~1~ N N ii ON ~ ~ ,-i
O p Q,'O Q p O p ~ p ~ O O O O p p O O p O O O ono
x ~ ~;a ,~a a x a a ,~ x x x x a ~ ,~ ~ ~ x ~ x O
-i.-i-; h ~pd'd= d'M M M c'~(VcVcV ~.jN N ~'1.-i~ ,-i,-iO
xx
,-i
,-i
00~ ~ 01~ Ov OvM ~ ,-icnl~criN oocn~i'i~'10od1 ~O~noo
a1 ,-~I~~ d- ~nO N M N ~n~ ~ \pv0~n d'~ ~--~ool~d'
O O ~OO O l~~ l~ l~00~ l~ '~'~ O d' [~~OI~ ~ M ~ d'V7.-~
~ L~~ O O O O O O O O O O O p O O O O O O O M
x ~ x ~ ~ a x x x x ~ ~ x ~ x x M
d'
O
O
xx
a\
M
d'
M
O
N
M
O
M
x
M
247
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d'
ri'-ir-ir-ir-i,...~r-i~--i.-i~--i~-i,~ri ~ r-i~ r--iri'"~ 01 M
cVN N
N
I~M ~ drM p 01a1l~ OvO ~jl~ d'~ O o00oM O ~ Vioo~-i
O O O O O p p O O O O p O O O p O O O ~ o d O ,-i
x x x x x ~ x ,~a ,~a ~ x x x ,~ ,~,~x ~: ~ ,~,~O
i i i i i i O
aa
- ,-,- ,-,-i,-i,_;,-i,~ ,-i~-i,-i~ ,-,-'...;,-i,--i~ ,-i N N N
N
d_' O l~ooO ~.jO d' l~d'd'N Ovoo~j ~j~O~ ~ ~ ~ O a1a1
O ~ O due'N ~ O N t~ O oo~DO ,~,-'M ~h01~ ~ t~~ d'00
O O O O O O O ~ ~ ~ M ~D~ ~ ~ d' l~tn~ O ~ \OV1
x x x x x v~ O O O O ~ ~ ~ o~ a O ~ ~ tx ,~O ~ d'
~
[~
OO
a,
N
M
M
O1
d>
O
Q\
z
U
N
x
M
248
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i,-i,-i,-ir..i.-i'~,-i,-i~ O~~ d'cncricriN N N C~jN N N ~.j~--~
~nV1~ oo~tO O (V~ p O N ~D~ l~ M N O ~O ~ p Wi ~ op,-i
0 ~ ~ ~Ot~01 ~ M d- a R~~ ~ ~ ~ \O~ d'd' [~O ~O ~ O ~O
O O O p O O O O O 'T~~ x O O O O O O O p O O O O ~
x a ~l~-.l~l x ~ ~ c'a'dN x ~-.1r-~r~r-'"Gr'~a ~l~l~l a ~lN
-i~ ,-ir-i,-i~ ~ ,-i,~ ~ Vjd'cn cncn~j~'1N N N ~'1N O
O
x
x
."'
~nooM N M ~ ~ ~ O Ov'-'~ l~N N M N vp~ ~ V'iso ~ t~d'
M M ~ O O _ M d' l~~ V~ d'l~~ 00~ V1M l~O ~O ~''~I~N
O O O O O O O O O O ~ ,.~O O O O O O O O O O O O O~
a x .~ a ~ x ~ ~ ~ x ~ O
O
xx
a,
a,
N
M
i
M
M
O
M
D\
w
w
x
M
249
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i.-ir-i,-i,-i'-i,-i,-ir;'-i,W-i ,-i~--i,-i,-i'-'''',-ip O Ix ~ criN
0op (VO M d'lWI' ~ d ~jM yD,--ip d: ~Ooo~ O O ~C o0
v1~D ~ ,~-~O dN"\O~ p cM~ ~ 000~ ~ M ~ ~ ~ '~'~ N ~ O due'
O O ,-O~,r~x r~x ~ H r~,,.~.,~l ~l~ r-ao x r~,a ~ p .. ~ a ~
--i,-;,-i~--i,-i,-i,~,-i,-i,-.i,-i,-i,-i,--i~-~i,--i~ ~ir-i,~~ O ~ ~ ~ N
00~tj~jO O ~Dcna\ M oop Vj oo~py f' O~N pp ~p~ p~O ~ _..
[~ M dlN ~ ~ ~O ~O00~ <f'd-(~00l0 ~ ~ d' M ~ Q~,~ N M O
d'M ,-,V1l0 M N ~ O d'M ~O ~Ol~l~l0 ~ ~ l~ ~' Q,'O l~N
O O~ O ~ O x ~i x ~r~ ~ ~ O ~ O ~iO ~ ~ ~ ~ ~ ~ O O
x
00 0p"v'iop N
N d~~ o0
~
i ~ ~ ~ i
~U~ ~ ~ C5
O O O O O O
N d"tMn~
~D ~ ~ ~: v~
O
Q\
d'
M
00
M
M
M
N
x
W
M
250
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-; N N .-r
r;~ r; ri~ ~ r;r;~ ri ,..~ri .-i ~ ~ ,-iN
O O ~ O ohoN ~ ~ ~ N N ~_~ ~ ~ ~ ~'0~., p ~ ~ ,0,I,,~ ~
O p O O O O p O ~ O O O p p "L7~ ~ O O O ~G "'
,"..aCJ~C/~x x x x x x ~ x x x a ~ ~ ~ N ~ x a a ~ O o
N N ,-i,-ir-i,-i,-i~ ,-~.--i,-;,-i,-i,-i,-i,--~ ~ ,--~,-i p N
wt''d'~jO M M ~ p t~ d'p ~ oo \Dl~N ~ 'p ~ ~ ~ d' N oho~
~ M ''~01~,N d1tn M N_d'd' O O O '"~~ O tn
O O O O O O O p O O p p O O O O ~ ~ ~ CO/~O O O
x ~ x ~ ~ ~ ~ ~ ~ x
O ,-M-,,-l\~N N l~ O
~ ~.,_cC ~ di ~ _c~v~
p ~ O ~ ~,~ O ~ O
' '''' N
N ~ ~ O oo N O N
, ~ _.~~.~ ~ GA v~ R,_~
v~~ ~U~ "'~ ~ ~ ~U
r~
N
d1 a>
M
V1 d.
i
M
N
d\
M M
d1 N
d- O
d'
N N
r~ z
~
x x
a\
M M
251
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O
M
r--i cV N N C~j~',-i~-~~-i,-i'_'~~ .-r,--m-,,~,~,-;,-i,-i,-i,-i
iiv0 ~ ~ N ~ j-~ d'~_~ O v'~~~d'd'~ O ~ d'~ ~ ~ 0~1~
O ~ a 0 0 p p O 0 0 0 0 ~ 0 0 0 0 0 0 p 0 0 0 0
a , ~ x a ,~a x ~ x x x x ~ x x x x x a ,~,~,~ ,~
.. ~'d= .... ..~ ., .....,.. .,..., ...... ..
'"'r, M N N N N .-i,--i,-,~ ~ ,~,--~,-~,~ ,~,-i,-,,-.,,--~~ ,-i
dv~ ~ O ,-i0l~pp M Ol~O ~ ij~jO ~ oo~1'M 1~0 \O till~Ov \O
O ~OO ~ M op V'7~p~ N ~ ~n O d-~ M ~ N oo ~--io0 00~ d' O
N 00 O O tn O l~~ d''-I\D M O V~ O M O O ~ N ~ M l~~ 00
O O ~ x O O O O O O O O O O O O O O O O p O O O O
~ x ~ x x ~ x x
a;
0
x
M
M
N
N
M
O
M
O
O
M
d'
W
x
O
M
2S2
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
o cn
-i,-;'""',-i,-i'-i,-iN~,'-iopd"c~ncriM criM cnM M N N N N N N
0otn~j ~ O O ~ '-'~ oocV~p Sriv'i~ N N N
N ~ N intn 1 x fx ~ ~ ~ a O ~ 0 ~ M ' ' '
O
O O O _ ~ ~ O O c O O 0 O O d d d O O O O
O n 0 O O O
O O
x ~ ~ ~ ,~ N x x ~ ~ a a a ~ x ~ x x x x xa
-i,~~ ~ ,~,--.,-i~ ~nd= cnM c~jcnM M cn N N N N N N
~ ~j
O N ~ "
~ioMOO W o0odue'v~1dN'~ ~ 001~ ~ ~ 0~1O a\d'due"N ~ ~ t~N ~
O ~ d'N
~Dl~~ ~ M t~ t~~ O O t~ ~ O t~ ool~~ t~ O ~' d' N
~ '~ ~~ ~ ~ ~ ~
a x ~ ~ ~ x ~ x ~ ~ a ~ x x
M
i ~
O
O ''"'
O O
N '"~
i
N ~.'
d'
due'
N
M
d>
N
N
a
a~
x
M
253
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N CV ~jN '-'~''1'-'',-i,-i"_'~ ,-,'-;,-i~ r-i,-i~;~-i,-ir-i,~ ,-ir.;~
M c~j,_;. ,-i
000~ lpM ~ ~ ~OO 00 ~ ~ ~ O 00lp00 (~~ M ~ ~ ~ ~_pp
O O ~ O O O O O O O O O O O O O O ~ O O O p O ~
~ x ~ a x x x ~ ~ x H x x x x x x ~ x x x ~ x x
N N N N N ,-i''.'',-i,-i~~,-i,-W-i,-i.--ir-i,-;'-i,-i,~,-i,-i.--i,-;~a
(V d'l~N cV M oot~ p 01M a oo,-iO criOvoo M oocn v'i~ r;
M v~ ,~l~N O v0d'O p W '-'h ~ N v1 I~N N V~N l~ M ,-i
~ O l~d'O ~ M O ~ ~ O VlM d'O M ~DM V~lpl0 ~ p p
O O M O ~ O ~ O O O O O O O O O O O O O O O O O ,-i
GO G7~ x ~ G7~ ~ x ~ ~ ~ ~r
~
[w
O
O
254
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i N
O
r-i,-ir-i,--i,--i,-i" ,-i~~ ,-i~-;,-i,-i~--~,-iO V~ O\ ~ ,-i,-i~-ir-,
a
M \p ~Od1N O ~ ~ ~ d101CV ~1~ ~ O f~il~ O O O ~ ~ ,-i
V7d1N ~ M N M d'~ ~ ~ ~ ~ 00 ~..~d'N M ~ l~M
~ ~ ' ~
'
l~l~ \Dlpl~~ M d'l~l~ l~d r'' O ~ o
O O O
~ ~ ~ ~ ~ x x o x ~ ~ a O ~ ~ x
r r r r r r-a ~ c ..~~ d:M ,
C ,-
r-i~ ~--i~-~i~--i~-i~ ~ '--ir-jr-i~--ir-i~ r-i,~ '_'~O ..., ...,.,
,
O V~OIQv~ M OIN ~.jp Ol l~~ M N ~ ~' ~ ~ p ~ ~-iVld'
~ ~ v~N - '
t v1 ~ N O v0 d d ~ W
V'~ v' ~Oi O O O N ~ ~ ~ ~
a1
l~~O ~O~Ooo~O 1 1 ~ l~l~ l~ ~ n ~ ~ ~
O O O
O O O ~ O ~ a O ~ a ~ O x O O O O O
O
G?
N M ~
i
H
O O p
N
_, O
C'7d
D1
N
i
N
N
M
O
N
O
N
M
255
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
\O V1 M M M M M N N C~j N N N N '"~ ~ ~ ,_j '"~ ri r-i ri '-i
dM' ~ due" ~ due' ~ N due' ~ d°°' ~ N y oo ~ ~ .~ d1 00 ~ N_ N
a O O O O O O O O O p O O O O O O O p O O O O O p
~, ,~ ~l ~1 C~ a rte, ~-~' x v7 x x r~' '~, x
l~ ~ d' M M M M N N (vj N N N N N ,--i ,--i ,-i ~ .-a ~-~ ,-, ,--i ,-r
0o M oo d' d' ~ O M ~p a1 ~O l~ O Qi O N O '"' N ~ ~ N o0
~O v1 N ~ M ~D l~ ~ ~ ~' N ~ ~O ~n ~ d' d' ~ N ~ N ~ d' ~ 00
O O l~ v1 vp \O l~ l~ ~ '"'' d' d' l~ l~ ~O ~ l~ O N 'd' N O v~ ~n O
,~OOOOOOOOO~~~OOOOO~0000~0~
p
d\
O
N
N
M
M
M
N
x
M
M
256
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i N
cd ..,--i
~ N .-i.-iri ~-i'-i~-ir..jr-ir-iri r,.~r.1~ ~-iri~ ~ M
O cnO V~ Vj~-id= tijN o001 u'ic~jl~N cri ~ ~ O
O O O O O O O O p O O O p p p O O O
x x a ~ a a ,~a a a x x x ~ x a a ~ ~ O
M ~ d
~ .-a~ ~-i~-i~ ,~riri~--i~-i,-i,-i~--i~ '--.i~--i
M '''O cYicn~i'i'-i~p01 criO oo(V ~ o0cV M oo~ N
00~ ,-~d'O l~ V1l~N V1~ V~l~ N pp,~ vwn O ~ O O O
d'~ N ~ 0ol~ l~l~\D O ~ ~O~ V1,-,O l~I~~ M O _,
O O O O O O O O O O O O O O O M O O O O
a ~ a ~ a ~ a ~ x x ~ ~ ~ ~ x
O
-~ cd
O O
~' O
~ ~ a
N ~ op
M
N
N N d-
a\ ~n
M
i i
N~ M N
a1 d w n
M M
N O ~n
O1
O
w
x w
x
M M
257
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ,-i,-r,-i
i
N ~ ,-i~ ,-i~ ,_;r ,~,-i,-i,~~ r-ir-i,-i,-i~ ,-;p~ ~ ~ d=c'~M
~ M ~ p p ~ ~ N
M oo O d' 0.!O p '- Wr'~ ~ ~ N ~ x ~ O N ~'1
O o 0 0 0 ~ 0 0 0 0 0 0 0 ~ o -- '~ 0 0 0 0 ~
d
N ~,H x a x ~ ~ x x x ~ a a a x a ~ N ~ x x a x x
-i~ ,-;,-, ri,-i,--~rir;ri ri~ r;,~ N o0u~d'M cri
p Ov O d'Oi p~~ ~ t~M \O M ~jop ,=i01~ptij~ ~ l~ooa M d'
~ ~
\DN ~ V1O~00 M V~~ O~l0 ~Op l~ O~M 0101 l~ V~d'd''-'l
~ p l~l~l~p l
x p O O O p p I~ "~[,~'~O O O O ppO O O O p ~,a O O x
x a a x ~ ~ ~ x ~ a a
N
.-~,E~-~"~ U
O p O
0oN
O ~ O
O~ O
d\
N
O dp-
M
M M
O
V'7 O
DO O
x r~
x x
M M
258
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~jN N njN N N N N '~,_,,.;''~,-i,--i~"~,-i,-i'"',-i,-;~-i~-i,-i
N N d~'~ p ~ ~ d\~ ~ ~ d~'~ N N N N M ~ U1 ~--i
N d' V1~ 0o ~ l~V~~ ~ M O ~ O M d'~OO O M O ~ \O
x x ,~1 ~ a1~p-1~ ~ o o ~ o ~ ~ ~ ~ ~ a o a a l~
~rjN N N C~jN N N N N a ,-i,-i,-i,-i,-;r-i,-;,~ r-i,-ir; ~--.i,-id-
N ~"'~ N O oo Ov~ a\c~ N ~ O O ~ ~ ViM vj O O oo,--ia
try~OM ~n~ ~O v~v1l~al l~~ oo l~d',-,~ N v1 ~ O 01t~a
N d' O ~ l~ \Ol~l~v1 ~ ~ V1 M ~nN ~OO O O ~ -~ V1l~r;
O O O O O O O O O O ~ O O O O O O O O O O O O O ~
O G7 ~ v'i
d1
O
l~
00
O
O
259
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-iri r-i'""~'''~i ~--i,.-i,-;'~ ~ ~ ~ ~ N --i'"~'--i~ r-i~ r-i
l~D
~ ~ ~ ue O
o a1 ~ ~ ~ ~ ~ O N ~ ~ ~ fx ~ p N d ~ ~ ~
O "
~ ~ ~ ~ ~ ~ ~ '~ ~ O ~ t~
l l O t l ~OO ~ O N ~ O O \p tn
a
r~r~ r~x x ~ ~ r~O x N ~ H x x x r-aa r~
i i ~ N ~
r-ir; '--i,--~-,-i,--iri'--i r-; .--ir-i N ~ '--i~--~r-; r-;
M O N O ~ O l~d1~--i~ cvj~ M 01~D ~ lOpl~~ ~D O N
d'01 OvN ~id' d'V1O ~ d-~ ,~--,t<1p1 ~ M d'~ d' ~ ~O~ O~
O
l~ l~~ ~ l~ l~l~\O ~ N O o ~ / O ~ ~ ~ ~ ~ p p
O
O ~ ~
~ x x ~ a x ~n v~ x ~.7
d'o0
dl M tn00 ~ O
~
O O O
O ''_'
O
M ~p00 ~O
-, N M I~ ~
i ~
o
:
H U C~~..a~
N
N N
M M
M M
M
M 00
M
d\
N ~'
x
H
x x
M M
260
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r;
01 pv~ M M N N N N N N N C~jN r-i.-;~ ~ r.;~-i~-i.-i,-i,-i
O
O d'~ M ~ ~ ~ M O M ~ ~--iM V>~p ~:~ Q M Q1M V~
~/ O V'7V1~ O M_d'pp ~ ~ ~ d'00O ~ ~.~ M V~~ M \
~ O O p~ O ~ O O O ~ O ~ ~ ~ M ~ O O O O O O
~; N x x a x x x a w a x w x x x x x x x x x
vi m wjwj N N N N N N N N '"''"''.-~i~-i~ r''~'~ ~"''r'
'-' l~ 00p~p~ ~ 00d- 01~Ov1O d1~ ~ O O ~ N '""'~ V7
O o d'~--~'~~ptn M M ~p O lplpM l~~ ~ N \O~ O~ M 00~ l~
~-,a O O p p O O p O O O O O O O O O O O O O O
x w w x a a ~ x ~ ~ ~ x x
M d-
O1 d1
O
N N
O '-'
O
M M
N d'
d,
M 00
N N
a, d\
dw p
z ~
a
o x
w H
x x
0
M M
261
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
.-iN
-i-i '-irir-.;r; ~--iri,-~~-iriri riri,_;,~-i~ N ~ [s [~ ~ ~O~p
~O
M cn N O d'O ~ ~ ~p v'ioo'd't~d'pp.:~vi ~ O M _.. ..
N M ~ ~'l0O M M \O l~N ~O d'~-id-M ~ x ~ O ~ 00 ~ V7~
O N O N ~ ~ O
~pI~ M l~\O ~ O ~ l~ V~ C/~O tn ~ V7(~
O O O O O O O ~ lD
O O O O O O M O O O 'C x O O O O
x x x x x x x ~ ~ a a ~ x x O
,~ , x a ,~ ~ ~: ~ ~ x a ,~
a
~
O~~ ~ N ~ ~ ~ N N V'i~Oh ~ ~ t~O oo~O~ ~ t~o0 ~ d\
-,oo ~ ~ i '
~ l l n ~ N ~n ~n~ ~ d ~
p O O O O O O O p O O O p 0 O O O O ~ x O O O O
O
x x x x x
~ a
N
~ 01M
p (V~ ~ -~ N
.- N
_~"~ ~ ~
_ _ i
O
O
O ~ O O O
p
dlM 0O
~ O ~
N
_~ Q.~ ~ _ _~_~,
C7 ~ ~ ~ ~UC7~U
P.
d,
d1
M
N
N
M
d'
M
d\
a
x
N
M
262
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
v'iv1 d=~1'd=d' d=M M M M cn cnM N N N N N N ~jN N N N
N
i ~ ~- ~ ~ ~ 0 '~~ ~ ~ ~ ~ ~ ~ ~ ~i N oMO~ o0
r o
_ d 0 D O O O _
O O O O O O p O O O O O O O O O p o O O O
x x x x x x x x x O
a a ~ a x a H ~ ~ a a a a x H a
a
Viv'itnd-d=d= d=d=M cnM ~.,jM m M N N N cV (V~j~j N N N
o'd"oN dN'~ M N ~ N ~ ~ N'O ~ N ~ ~ ~ O ~ ~ N d 0~1~
N d' V1~ ~ V7 d-d'~O ~ d O ~D~Od'~ \O~ M ~ O O ~ V1N
O l~ M
' ~ O O O a O x O x O O
~
xi ~lx x ,. x ~-i C/~~i x
L, a
O ~ ~p
N M
~U E-~d
O O O O
M (~
N N M M
~ >,
C7~ a d
263
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N N N ,-i'-i.--i,-i,-i~ r-i,-i~ ,-i'-;.-i,-i~ ,-i,-ir; ,-i~;,-i
M ~ O 01~ O ~ '-'~ ~ ~ON ~ O ~ N d'~ d'~OM d y:,-;
~1d- ~ 00_l~~ d'v1 M ~ ,~~ 00V>l~ d'O M 00_N N p~~-i
O O O O O O O O O O ~ ~ Mp O O O O O ~ O O O O p M
a x ,~ ,~a x x x x x ~ ~ x x x x x x ~ x x x x x iI~
N N N N N ~j ~-i~-i,--i,-ir,;,-i,~ ,-i,-i,-i,-i,-i~; ,-i,-i,-i~-i,-;Op
~ijl~~ ~p~ p~ ~nM v1 0ov.j,--iN Wit'M_01 lWO p oocVN N_,-ixa
~Op ~ ~ ~j N ~ N ~ p M N ~1O O dN"O p M O t< O p ,-i
O O O O O O O O O O O O O O O O O O O O O O O O ,-i
~ ~ x a ~ x ~ x x ~ x x x o0
~i'i
dN-
O
O
264
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
a
i i i
- ,--,--r;r-ir; .-i~-ir-i,--i.-i,-;,~,--i'"'r.-;~"~,--ir; ,--ir.-i~--ir-i~-i~-
;
tjj
cdn~ ono ~ d'N l~ onO d1 O ~j~ O ~ d-~y d'01M ~"oo~
o N l0 ~ \Ol0 O V1O ~ V1~ M ~ ~ M V1~f'~ ~ O O
O O O p O O O O O O O O O O O O O OMp O O O O O l~
x x x x a a a a a a a a ~ a x ~ x ~ ~ a a x a a Ob
a
00~O~ ppVjp N ,-icn ood'~ ~ o0O N ool~op en\Od\ ~ cVVi
M ,---iV'7M Old' l~I~~D lDO O M ~ ~ ''i~ N d'd'l~ ~ O\\D
O ~ tn O ~ lfll~l~M l~0000 '-id'~ ~ V~'''O l~I~l~ ~ V101
O O O O O O O O O O O O O O O O O O O O O O O O O
x x v~ a a a a a x x v~ a x ~
O
O
a
265
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
,.;~ Vjd=d'M N N"N N N N N N ,-i,-i,~~ -i ~ r-.i,....;,-i,-;,-i
~ V'1l!7~ ~ d' M ~ M ~ ~ O ~' ~ '~'~ ~ M ~ N N ,-;
~ '~,'o p O O Mpp O p ~ ~ ~ 0 0 0 0 0pO 0 0 p O O ~
~ ~,x x x ~ x x x ,~,~ x x x ~ ~ ~,x x x x x ~ M
Op
xx
v7~ d'M N ~jN N CVN N N ~ r-i,-i,~,.~,-i,-i,...;r.;,-i,-i
O O Vj~ O l~~ M_ Q~00Q1 ~ N d'~ M \pM [~~OQ d'00r;
,-~aV1~ v~ ~ p O o00p ~f't~tnLDV7 ~ M M~ d'O ~ O ~ 00
x O O O O O O O O O O O O O O O o ~ O O o O O ~:rj
~ x x x ~ x ~ ,~ a a ~ x M
p
O
o
x
n
0
0
a
a,
a,
M
M
M
N
N
O
d\
O
H
M
M
266
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
'"'r-i,-i,-i,-i,-~r-i,-i,-i~ '"'~ ,-~,~,_;'"' ,-ip~~1"M c~CVN N
N
Vjd'd' V~r-i('~j~O~ M .~;cYj ~D M ~ M . Vjri
~O1pd1O V1dl~O ~ M d' due'~ N O ~ t/7v~ - ~ M M
'-'
N O ~ O O ~
O O O O O O O O O O O O O O p ~ '' p p O O
x a x x x ~'x ~i
l r~r~ r~, ~l~lC/~ ~j N ,.~, r
,
-i ,-i,-i,-i,~ ,-~,-i,-i~-i~ ~ ,-i,-i,-i~ .-i SriM ~rjcYjN N
(V v0~OM ~ ~OOvN d'N ~ O 01~pM ~ ~ M l~~ 0101'"'~~
d'l~\O ~ 01 \O~ ~ d'~ d' ~ ~ M 'd'
M
~ N ~pl~l~ t ~ l~ \O~ V'1l~I N ~ d'O O ~O~O ~ l~O O
d' l~~O I~O
O O O O O O O O O O O O O O O O O ~ ,~O O O O O O
p
a ~ x a ~ ~ x ~ a x
O
~
~ O '"'riN N
~i ~ ~
~ .,~ O
~
O
O O O .~,O O
d'd0-~ a1,-r
lp l~r'',-,'-'N N
i
C~ C7~ x ~ C~
d>
M
d'
M
Q1
O
d'
W
d'
M
267
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N ~jN -i'--i~ ~ ,_;,-i,-i,-i~--i,-ir.;,-i,~-i.-i,-i.-ir-i,-i,-i,-i
Oll0 ~ ~ ~ 0~0O ~ ~ ~ M V'7-iM dl N M ~ d'lpO_M_ M ~p,-i
O O O j O O O ~ ~ p O O O O O O O O O O O O O O I~
a a x p x x x ~ ~ x x x x x x x x x x x x x a a N
N N N ,~N ~""'r''.--i.--i,-iri,-i,-i~--i,-i,_;,--i,-i~-i,-i,-i,-i,-ir.;O
O W v'i~.jOv ~ ~ O ~ ~ N '"''~ ~,~ O ~ M d'~Oood' 01 O
O O ~OO I~ ~ ~ N ~O ~ OvM oo ~ ,-~~ ~n N ~ 0001 N ~.a,~
00~O ~ M l~ N ~ d'M l~V'1M d'N V1 ,-i~ V1 ~ ~Od'~f'V1 ,-i
O lp a M ~ x p 0 0 x x x ~ x p x x p x p x x ~ ,-i
~ ~
~
I
~~
268
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
wi o --W o ~ ~ cn
N o
O t~ M oo dwrW~
v1
l~ l~ ~ oo d1 ~ O~
00 O 01
O O M ~p V1 [~ d'
00 O
N M M d"' S~" \p
00 O
M
M
r~
Q.,
d>
r-~iO ,-i M
,_;,-~,~r-i,-i~ N .:.iN ,-~~"'V1 01 O
O
due'~ ~ ~ a1O d'a\N
M
r~r~ x ~'~ a x x ~"
~
cat,--~N cd l r.-,
--i,-~~--~r-i'--i,--i,-i cj~--~r--~ ..
(V
N p
O O O O O O O ~ ~,'S,'O O O ~ ','1~,
G7 ~
O M
_~ _~ ~ ~ _J~
p H p p ~ ~ H
~O,~ .i-..4 ppO
O~ N '"-'
N ~ ~ ~ O _~
H
M
M
N
l~ ~O M
N M
d'
M
N
in O ~O
t~ N
M \O M
O O l0
N N l~
00 M 00
d' O1 In
N
O
x x
M M
269
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M ~f' [~
~
N oo d'
N
~ N N
O O O
O
N ~ ~ O
d1 N N '~ d> r-i~ cn(~j(~jN ,~;,-i~-i,-a,..1''~r-i
~ tN~ ~ ~ ~0,,~ ~ VN'lN c~~ ..--i
goo ~ ~ ~ ~ ,.~o o o o o o 0 0 0 0
a x ~ .~x x ~ ~ x x ~ ,~x 00
N '~ N N ' ~ M N N N ,-i~ ,-i,~,.._;,-ia
a
,-;
,-;
'"_'N ~ M O\'",~ ~-iQ~pip01~ ~ M ~ O O o0~rj
O ~ ~ l~ ~ O O V~O p ~ p ,~-~N M O
W -1 O O O ~ O O ~ O O O
--mI' M
-i ~ O~'~ d."N '"'
N _i, Q. M ~ tip
O ~ ~ ~ O O
V~M
~ O~~
y
x d C7~ v~v~ E-.
O ~ N
d\ d1
01 a1 al
N
a1
M M M
O
O M V1
N
x x
~1 U
x x x
a\
M M M
270
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0 0 0 Srid=d Wo
~n ~no a\ t~t~
o .-Vo 0 0~a,~n
l~d101 N N
N N V1t~ 01d1O
M
N
C
N
M N ~--,M O
O~ ..N ~ ~p '"' .. M ~ ~
p '"'ro ,--~ ~ ~pd1 ,.-~ C~jN ,~ '"~,--i,-i,-i
O x O ~ O O O ~ . O O .--iN o0 ~ 0o ,-i
O ~' O ~ ~ N ~'O O OWI'
~ N ,~ O -~~ x ~ ~ ,,~o O O o O
; ; N x 'd~O N N '~ ~ ''~Vj r-~'Vj,.._]O
~ 1 ,-i,-~ V1 ~ ~jN N ~ ~ ,-iO
~ ~ ,-i_.. _w eel~ ~ \p r~
N1 ~ ~ ~ d'~ ~ ~ CO/~ ~ ~ N ~ ~ N O ~-i
O O x ~ x O O ~ 'O~'~ W a O O O O O ,-i
x x x x a _
O
O
~
M
ri
N M
' O ~ Q
' O
-~Od. ~.~0~O~
N
' '-; N
~%~ ~ C/~~UC~
M 'CI" V1 \O
d\ O\ ~ d\
d\
M
d' V1 V7 M
O1 ~ i
i d'
00 ~ M
N oo N M
N
O ~ N M
00 00 00 00
M M M M
M V1 O1 O
01 ~O d' O
M ~O M O
O V7 lD M
00 00 O
N 'r'
N ~
_
x x x x
O ~ N M
M M M M
271
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O O O O O O ~n O O O O O N O O O
00 ~OO tryO O r O O O O ~DW O O v1
m D r N ~nN N ~ v~VW n 01d~ N O N
~no0 010oO d' N O O O ~ON O a\M
o ~ M M d'~ ~ ~ r r r r 00 M
N
M
N
a'
r
d
~d ~ N
~
cd ~
'"' ~ N 01 N N N ,--i,-i'-'
" ~''O ~ ~ ~ O O O
O
r~ ~lE-''~ H
-i N N N '"''"'''"'
.. pp
01N ~ O '-iM N v0 O O r ~
''
_ _
O ' O O N ~ ~ O ~"'~D
O O ~ x ~ x o O ~ O O
~ ~
0
O .
M
O
r o0
d\ D\
d\
M
O
d'
i
i M
M
.d.,
V~
M M
r a\
r O
M ~--i .
O lp
r r
d' 00
M
d
V~
r , r
M M
272
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r;
i N ~ -~ N -;
- -' ,
,_...; ' .. ~
'--a
ri,-iri,-i,--W -i r-i~ p~ ,-i~ '"r~-; ~;
N O O
O O ~ O O N
O O O O O O ~ O "d~ ~C ~
E-i x
r~V7~.-1 -i x ~ ' ~ ~ '~ ~ N C/~
C/7
~ ~ d - O ~
i N
-i,--r-ir-i,--i,--.i,-.i .. ,--;,-r ,-~ ~
~--i
Dl~ ~ ~ ~;pv N~ ~f'O Ov
o M 0 0 0
o ~ o ~ d ~ ~ d - Q N 0 0 0
o d
o ~ ~ ~ ~ x p ~ 'nx ~ 'i' ~ R~P;~ O
~ ,
-1 ~
01N '.'.'
O
M ~ l~ ~ ~ V~00
~ i i i
O O
O O N ~ p O O
p
.,.~d- ~nO ~'~ ~ d'O
(V _
~ ~ ~ G ~ ~ N
N , .
ra C7E-~~'~' ~l'U
d\
O O O
N tn O V1
00 ~ Q1 M
M
i i ~ i
N N ~O M
M
M M M M
~t d- N
M O1 lf~ V1
r"' N 0o N
o
o
. ~q
~
W
a\
M M M M
273
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-; p ,--,- ~ o;
~ ~ ~ ~ ~ ~ .. ,-i'~ d: o cYin
"~
ri,-i~ O y j <-i' -i ~ O c
CVO p O dM.N --il0 _iwt'~h O O ~ O O ~ due-O
'~ , ~ , ~ h x ~x te o
o ~ ~ o ~ ~ o ~ M ~ o o a;
O O '~ ~ x O O O O O O O O 'C~ C/~O M x O
~ ~ ~ ~ a a x a x ~ a a ~ M a o o x
~; N , .. ~:
r-i,-i,--a f~jN ~ ~ ,-i,~~ ~ ~ ~ ,~-~,.~ ~ ~ cri
~ M N ~ h
d N p d ~ d ~ o t<o ~ ~ ~ ~ 0 0 ~ ~ fx ~ N
" ' " o o
0
0 0 0 ~ ~ 0 0 0 0 0 0 0 0 ~ ,"L',0 0 R~ p ~ a O
a ~ ~ ~ ~ ~ ~ a a x
~O d: d= N ~i'iM
'", ~ M V1~OO
i =
p ,-~ ,-i,~ d ~ ,-,,~,~N ~ ,-id'a1
~ W ~ N ~ ~ ~ ~ o a;
~ d
. b ~ . ,- ~ ~, , ~ Q.o ~
0
_ a E~ ~ o ~ ~ ~, ~ ~, ..~
~ C7o O ~ ~ ~ a a, H a
0 0 0 0
0 0 0 0 ~ ~ 0 0 ~ ~ ~ 0 0
p N ~ ~
~ N ~ ~ o ~ ~ ~ p , ~ ~ ~ ~ d' ~ 0
p -ii 1
N O ~ b ~ b ~,~ ~
4 A
O , ~.. O z- , ,
~ ~ ' ' '
H r~ P I~.,U d H ~ d C r~ ~l
J
M d' V1
O O O
O O O
01
d.
i
i
M M
O ~ N
d> d1
M M M
M 00
O O ~ 00
\O l~ O
l~ l~ 00
00 00 00
x x x
O -~ N
M M M
274
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
M
N N ,_;~ ,-i,-i,-i,-;,-i,.;,-i,-i'"''"'r-i,~,-m ,--iO M N ~j
N
~ O ooc~jOven~ ~t O ~ ,~ ~tvN O O d O oov'i
v0
~ ~ ''N d ~ O tn~ ~ ~ ~ O ~ fxP~..~ O ~OM ~p
' N
p o p ~ O O O _ O O O O O O O O _ ~ ~ x O O p
O
' O O
'
a r~C1~x r r~~l ,."L~,~ ~lr-1x W -) r~~ M N W -~,x ,-a
t
,
~
-ir-i,-ir;.--i,-i.-i~--~,-ir-i,-i,-~,-i M cVN
N
v'i~pN ~' tntn~ ~ M d'Ov O N oo -~ivp '-' ~ cVN
h ~ ~ M
M ~O N oo~ ~ ~ \O~OO O ~ l~N , ~ON o m t~N O ~
M o l~
d'\O O N O M ~ \O M I~0000 ~ ~OO O M d- O O O O ~Od'~p
O O O O O O O O O O O O O O O O ~ ~' ~ ~ p O O
O
x ~ ~ x x ~ w a x ~ O O , x a
~ ~
M ~;
N N O N Vj
N ~ ~
~'~ ~ _'d N .~ tiAN
C7 ~ ~ d ~ H
p O O O ~ O O O
O O p O
_
O
N M
O N ~ ~
- -~ N N
-,,
te~ 7
a a C d d ~ ~ a C7d d
..
O
O
d1
d'
M
M
pp
O
G7
x
M
M
275
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
,_;N O ,-i~-i
-i,-i~-~,-i,-ir",~~--i,-;'-i,-i'"''"''~-i,._.;,-a~ ~-iQ1 '-'~ Q~~ O
~t M ~lva1 ~ O N w v70o a>
N O M ~ ~O~ ~ pOpo00~ ~ ~ O p ~ ~ ~ ~'O p .-r~l ~ O
~ ~l ~ N
cC (V~ ,~" cd N ,.,_;
.-i,~ri ri~--i~; ~ ,_;~ ~-i~--i~ '-;~-;.-i~--~ '-~''~ V~
wt'O ~ ~ ,-; ~ ~ O O
O ~ O O dN',~-,O o00~ ~ O ~ O ~ ~ ,-~1O O O O ~ ~ O ~ "x,~
O O O O p O O O O O due.'Q O O ~ ~''~ C/~O
~,Cl~~ ~ ~ ~ ~ x x ~ ~ Cf~ ~ c~
'
due'
d
i ~ a',
C~r-
H
O O
O
M
i i
N N
G7
O O O
O O O
d>
i i
N
d' ~n
d\ ~ d>
M M M
d- N d'
O N
M ~ l~
V1
M M M
276
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-. ~ ~ o
M (vj,-i'"''~;r' r-.i,-i.-i'"'~"',-i.oOp~ M N ,--i,-i,-i,-..;~ ,-i
cn~ ~ oo~ ,~~p~f:~ ~O ~O O ~ d' ~ 'd'~ ~ ~ O
~ ~ O v~ ~ ,-.-y0 ~ ~Ooo~ ~ ~ ~ ~ ~ ~ ~ l~in l~
O O O O O O O O p p~O O o ~ ~ O ~p l~l~~O M O
O O O O o
~ a a x x x x ~ ,~,~x x ,~~ ~;a x a a ~ ~ a
--..
M M N ~j ~ ,--i,-a,-r,.,r,,-~,-,~,,-, d,eV ~j,--i,-i,--~N
p viv~p cnp~,-.-i,=i,_..;~ ~ ~ d:~ ~ ~ N ood W0 c~ i
~ ~ ~ M o ~~r1~~r1~ ~ -~ vM1p ~ O p N tr~ 000~ O
a O O O O O O O O O O O M O fxa O O O O O O
~ x x x x x ~ a a
O M
N N
~ O M O
l~
O
~ N M
~ i :
~'.,b~0~
Ci~~ d E
O
O O
01 N
M N
N
O
01 D\
M M
O O
dl
x z
w
x
x
M M
277
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~
~OW J=M N N N (V(V N N (~j'~ ~ ,-i~"'''-'i,~'"'r'~ ,~ ,--i,-i~.;
,-i
O .d d'dt~"~_~ ~ 0 ~ ~ ~ ~ ~ ON~ ~ ~ N oMOl~OM CNnd0-~ ON
O p O o O O O O O O p O O p O O O O O ~ O 0 O ~
tria v~x x ~ ~.;~ ~ x ~lv~x ~ v W; x x x x v~x x x O
en
V1 V7M M N (yN N N N N '"~'-',~~ '"',-~,-,,-~,-i,--i~ ,-i,--~
~ 01d'~ O O M ~ ~ op~ ~O CVpp~ ~O,=-id' O p oo '-~idvO
l~~ V1O ~ ~ oo~O~ ~''~d'N ~ ~ In,--~oo~ ,--,,~~ N OvM .-i
O O O O O O N l~\O d'I~O l0 ~OM l~ d'd'O V7N d' V'7~O~
-7v..-1~ ~O.]o O ~ O O ~ ~l~i xi~ x O ~ d'
V7
~O
O
'~
O
N
dN~wr1
C7
p O 'aO
O +'
O N
~
_~~ _~
C7~ ~ C7
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
ri,-i,-i,-i,-ir; ,~,-iri '"''~r-;,-~,-i,-;,-i,-iri r"'~ p~ N ,~riri
M pp 00
01d' (Vu~i~ ~O v'i01d' ~ '-''v0 O CSCN ooN ~O M O O ~ ~ ~ 0~1
l0\O l0l~l~O M o000 ~DN O tnl~V~ V~\OO_1N ,~2ip~
O O O O O O O O O O O p p O O O O O O "~~ ,-r0-1O O O
r~r~~ r~r~x x r~G7 a ~ ~ ~ ~ ~ x ~ ~ N ~ raO
~
r~
'-irir;riri ~i~i~i ~ ri~ ~i~ ~ ~ir;.--i~i.--~ ~i~ ~-i
r-i
O ~ ,--i~ ~i'i~i'i01l~V'iO cV'd y1~Dl~ V'iool~ cri(V'-'N oo~jN
N ~O N t~O v~ v>~OvD l~t~O M V~l~ V~O ~ ~f'N V1M l~
V'7l~ V~I~00l0 \OM l0 ~O~Ol~ d-l~l~ I~~O~O V7d'O O O ~
O O O O O O O O O p p p O O O O o O O O x x O O ~p
a a ~ x x x tn
O
O
0
0 0 0
N
O
i
01
M
M
O
Q\
N
C7
a
x
a,
M
279
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M ~ M
N r-i,-ir;r; ,-i,-i~-i~ ,~ ~ N ~j ,-ir;,-;,.;~ , ~ d:
:.i N
O vp O 'd'l~ p~~ ue i 0 O
O
~ ~ ' n ~ d ~ o ~ ~
d t '
0 0 0 0 0 o 0 o a o ~ ~ o 0 0 0 0 ~ '~ o
0
a
x x x x x x x x ,~x M a x x a ,~ ~ M a
x
M ~ ~ ~
-i M ~ ,-,,.~,-i,-i,-',-i,_;.--i,-.i f~jN ,-~,--ir-i,-' trj
cV
~ ~nm cn d yjp O O oo N l~l~~ y 0 y r N O Ov~ ~ 01
~ O ~ ~' ~-~ ~ N ~ ~' ~ ~ ~ O ~ 0 ~ ~ 0 ~ ~ O O M
u d d p p
~ o 1 0 0 0 0 0 0 ~ o 0 ~ d
0 0
o x 0 0 0 ,~ 0 0 0 0 ,~o
x x x ~ ~ x ~ x x x ~ ,~ ~ x
., N
~
O d=O N c'nV7,~ ''~,- ,-i
' N vo ' -~ d.
- '
~' tip a, d a M a ~ i
C
~o D a.A , f
.
p p
O O O O O O N O
p \OM V~ 00 0oM N M V7
O ~O
M N ~ ~ M ~--~N V7 '~~ M
'
R.'~ ~ N
~
M d' In
O O O
01
M
' '
M M M
N
N
d0- due- d0-
N
d
-
d\
O O O
d, al a1
N
w
x x x
x
O ~ N
d1 01 01
M M M
280
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
b
-i
N j ~ -i; ; '-',-i; -ii i --i ~ ' i ~
~. , ,- r r..., ,-,- ' ,~ r ,-,-iO O
N ~ O ~ 0 ~ ~ O O
M oo ~ m ~ ~ ,-O
, 1
O p O O O p O O o O O O p ~ '' ' ~C
O r~,0 C
G7x x r-aa r~r~ ~ia ; , a a
~,
~-N
N N N ,-a~~ ,--i.--~,-i,~,-i,~,-i,-i,-ir-i ri ,-ir;,--i
n N O N ~ ~ N ~ N ~ ~--~~ ~ p ,-,
N n o o ' O O ~N O ~ ~ ~ 0 0 0 0 ~ ~ 0
o o 1
'
I~ V~N ~ O ~ O N 0 0 0
O O '~ O ~
O
O O O O O O O O O O O ,~O O M O
G7~ ~ G7
o
"~v~ ci~
~
U ~-
l
0 0 0
0
l~N
C7H H C7
M
O N O
M
i i
a\
N
M
O N O
d' ~ d'
O o0 00
al ~
l~ O O
~ O1
M
~
_
r~
M d'
d\
M M
281
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O ~ o
=
--i ..d .,.,., " ., c~3 ..d:
01 ,-~ M N N N ~ ~ ,--i,-.a,-,,-i'~ r-i,~r., '-'' M N
O ~ O ~ N ~ enl~ ~ ~Ocnoo p ~jr''d:v'iO O M ~ N
~ ~ ~ N 0 ~ ~
p ''p O Q ~ ~ d d N ~ ~ 1 ~ Q O ~ O
' ' 0 '
x ~ x O O O O O O O O O O O O O O , ~ O O
~ x ~ x a ~,x x x ~ ,~x ~ a a , a x
. ~ " , ~ ~
~i d. M N CV ,-i~ ,-,.-,,--i,..~,- y..;,-;,~ ,-i M N
O '"'~ oho,-aOvt~~''~~OO cnO oo~;.~~.iO ~pi~j~ ~ oho~ l~
~ ~ ~
O O ~ O O ~ ~ ~ N M 1 O ~ ~ ~ ~ M ~ O O ~ O
V
VjO ~ ,.~O O O O O O O O O p O p O O O ~ ,~ O O
x ,~ .~ ~ x x ~ a ~ ~ ~ x ~
O
N
cd ~,,_,
is~ ~'~U
O O O O
N
d
s~,v~ ~ i. '
_ _
E'-~ra 'UE-V ~U
~ ~ O
_ _
O O O
N
i i
M
O O O
d' d' d'
M tn
m
U
M M
282
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ~ O r-'
cd M .,.. .." cd ,~M
N N ~ ,-i,-ir.;,,~~ ,-i,-i,~ ~ N ,-i,~~ ,-i,-~,_;~ N
~ ~ p '
d
M ~ M ~ O Vj'~ d'VjO O ~ 01 ~ v'i,--~,-'t~M cn O N O
d\~Otn fxO ~ ~ ~ N ~ ~ O 01 ~ ~ ~;
,
O O o 0 O p p O o 0 0 ~ x 0 0 0 0 O p o o ~ x
x a ~,x x ~ a x a ~ a a x x x x a ~ x
~;~: ,
N r;,-i,-i,-i,_.;,~ r;,-;r; ~ N ~jr-i,-i,-i,~,-;,-i,~
M ~pO O oo~rjv'ip v0N l~~ N O op~ ~ d'01cn (Vd'~ ~ v'i
~ M ~ ~ ~ M
N M V ~ ~ ,-,-~ ~ ~ ~ O O V ~ d ~ ~ ~ 0 '~O O '
'1 -ii 'l - d
0 0 0 0 0 O p O O 0 0 0 ~ "1~0 0 0 0 0 0 0 0 0 ~ L"O
~'
~ x x x a ~ , x x x . x
, ,
,
~ ~ ~ ~
N ;'~ O N
~Od; N d"
,~
'~ C7
p~ C7
C7
O
O
O O
O
.--itI~
bD~.'~ ~
i..~ ~.,"~,i
~
~.,v~ _
L7
N
N N
O O
N
i i
N
d1
O O
d' d'
dl
M M
at
d. a\
x
01
d>
M M
283
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
Srio ~ ~ ~ ,-;cYio ~ oovo v_or
~ ~ ~ ~ h r
1 1 O ~ N o N d
0o O M ~O 0 r 0 oo O ~ o N '
tW d' ~ N
O N M M d'd"\p00 O O O O O
M
M
N ,-i
-..;,-io ~ ~ r d' M M M M ~jN N N N ~jN N N N
N
O N ~ M \O,--i .. ..
O ~ l~ r p d'~n ~ O t~ M d'~j\p Srivp,~
M
O dm n '~~ x ~nd- d-~n~ ~n M M N O ~ ~ o
'
r o r r
x x x x x x x x x x
x
N x x ~ ~ ~ a ~ a a
N ,....;~;,-, ~ d' M M M M N N (V N cVN ~j N N N
N
lp00~ ~ O~CJ"tnO ~ d' ~ O l~ ~ ~ 00\p O~M 1f1
M
O O M O ~ O O ~nN N N N N cdnt~rW~r~O O due'
,~o 0 0 ~ x o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
x x x x x x x ~ .~~ x
0o N M r M
0 ~' ~ ~ ~ ~
0 -~cn p ~ N
00, oo ~,~p o~ ~ ' i b
~
_c_ . y
tin''"
~C ~ U'H
~, ~
O O O O O
O +~o
~n~ v~ ~ ~ m n
O~ M ~ dl
~
cd~ ~,~ cii
a ~ ~ ~ ~ ~ ~ ~ a ~
M d'
N N
O O
r
M M
r r
r
N
M
M
O ~
d' d'
O 00
V~
dl
U
x
w
x
0
0 0
d- d-
284
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
V7o W o ri-~
cri
N O I~M ood'
v7
at~
O N cMM
M
M
C~
.-i~-i~--i,~~ ri~j,--i,--i~-i~ r-i~--mr-i.~w -ir-ip 01
~ N o~od' l0~ ~ N O O
O O O O p O M N cnO~
p O O O y O O V~O O O O ~ N
x x x x ~ x ~ x x x ~ O O O a x x x
,~,~ a a
'--i,-;,~-ir-.i,~.-;ri ~ ,--i,-ari r-i,-iriri .-i'-i~--~
I~d' M cVoo O in~ criN ~ ,=i~ d'I~M ~ ~ON
00 0oO v'Wn t~N ~ t~ O
~Ot/7V1d-d' V7~nd' N N ,~~ ~ pOp~ ~ O ~ due-
O O O O O O O O O O p O O O O O O O O
x x x x x ~ ~
N
O
N
O
N
d'
N
d'
x
N
O
285
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
o t~ oo ~o
~O
V1 M
O d1 N N d'
0o
0oO ~ N N
.-~
0oO O O O
O
ITjri
=i~ ~ ~ d=M cYiM N ~'1N N ~jfV~j (VN ('1
N
O ~ ~ N ~ ue'O ooa\ ~ ~ ~ N cri~ ~
O
P~fx d
O p O O O O O 4 O p O p O O O
O
~ ; a a x a a x x x x x x a ~ a xa
~ ~ ~ ~
l V1cnc~ncn ~.rjN N N ~jN <j njN N
N
'-'~ criVjv0d'~ ,-ioot~ v'i,=i~ ~ d'd'cn
Ov
tP'7tnd'N_\O tnM N l~~ ~ l0 p~O l~
d'd' ~ d'
Y O O p O O ~ V1d- ~ t~oo~O
G P~ fx O O O ~ ~
,
x x x a ~ , .a
~ ~~
N h O
N ~ o O
o
ue ' N
N d O ~ ~ ~ ~ tip~',s~
- p
~
P~H ~ C7C~
~
O O O O O
M
~
00
a; , ~ N
,
~
a a w ~ a ~ ~ ~ a
N
O
d'
M
d'
M
d'
d\
U
W
x
M
O
d'
286
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ,-i,-~,~~--i~-i~ ri,-i,-irir; H ~-i,~,--i'--i~-i,-iri~ ~ r-i'"''r;
~pN ~O VjO~O ~ ~n~ N N N ~ ~~~ O O m l~ a\~ O ~O~ o0
p N M ~plpN ~ O M M d'd,-~~ 'Cyp ~ pOp~ l~ 0
p O O O O O O O O O O O O O O O O O O O O O O O O
~ ~ ~ ~ x ~ x x x x x a x x ~ ,~ a a ~ a x x ~ x O
N rir; ~;,~ri ~--i,-ir--iriri,-i,~,-i~--i,-;,-i,-i,~ ,-iri~ r-iri~,a
M v-iop~pvi cVd'~ O v'iO .~O 01M ~ ~ ~p M d'O cV~i'i,_;
0oO ~ d-oo d'N I~ ~ ~ M ~ d'V~~p ~p p oo~D~ l~v1ri
O V1M ~,-~O d' O O O V1\OO M O O ~ [yp pp [yp \O \OV1~j
O O p O O O O O O O O O O O O O O O O O O O O 01
~ x x ~ ~ x x ~ x ,tea ~ x ,~
O
M
O
287
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~ ; i
r.;,-i,-i~--~O M N N ~"',-i ,-,-,.;,-;,,~,-i,-;'"'~',-i-i
O ~p
d O ~ d'x ~ o ~ ~ ~ ~ O d-~ O Q ~ d'inO
~ M V1 ~ O o ~ ~
o
Q ~ ' x ~ a x ~ ~ a o o O p o 00
a .. x d a x x a a a x x a a
a ~
N ~ ~ ~ ~ ~
,.-;,-i'--i,-i,-~'-' cnN N N r.;,--i,-,,-m--i,.~,-i,-i,-.i,~ ,-i,-i,....;
,-i
a\cn N ~t~ ~ N O u'i~p ~,j'~ v~vi~ d'M Wit'O~~ N oo,-i
M ~ O a1N O l~ N M ~ON oo~ ~ '-' ~O~O O O
'
O ~ \O ~ d- O ~ ~ ~DO N O M ~ ~ M I~ o000~ ~ p O
~ O O O M
O ~ a O O lpa O p p O O O p O
~ ~ x a ~ x'V~~
,~
N O V7
M N d"~ ~ ~.,~N N
-i c
~ p ,--i,-i,-i, V
N M lpa;~ ~ ~ tip~'t~~!s~
,
~ a ~ ~ ~ _ ~ ~ ~,
~
~ a a~.
H
~ ~ O O p O O O
O O O O
~ ~ h
~O~ I~M N d' o N M
o
,~ ~-,N ~noo~ ,-,,-,,--~,-~N N N
~, a~a~~ N by~ a,~
~,>,~-.~ ~ N ,-..w cn
w ~ c~ a c~ ~ ~ ~ ~
a w a a
N
O
N
d1
N
d'
d'
M
d'
z
x
U
x
d-
0
d'
288
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
~
,. _..
01 .-i- W O ~ criM .rjcnN N N ~jN N ~j~.jN ~j~j~j
,-i
, / ~ CV O CV 01 ~ ~:,,j~.rj01 wjN ~rj
N O N Vj
N V O ~ N ~ ~ d O V1~ ~ v> h ~pp~M d-~ d-
1 ' ~O
_ ~ 0 O O O O O O
0 0 ' O O O O p O ~ p p ~ p
~'
~ a o ,,x a a x x x x x x a a x x a a x
x
~'
.a r,.._,,-ia ''_' <j=cfiM trjN N N ~jN C~jN (VN ~'1N N
r''
'''N M pp00 ~ ~ ,-i<r d1d'O O M p M ~jVjUj00 V1 ,-i
~f'
N o ~ ~nd'~ o N v1v0 ~n~nh ooM ,-,~D
~
d- O N h ~D p h h ~ h '-'~ M O O O ~ l ~ ~ ~
0 \O
p rx x O p O ~;,..-~v~O O O O O O O p O o O O O p O O
O
x a ~ a a x x x ~ a x a
0od=N d1O d'V
7
i h = O _
r- ~jcri ~ N N N ~ M 'd'
R b ~ ~ ~:~ O
Q.. p , ' ~ ~ _
'
' ' ~ ~ CJL~~ ra
a d ~,
~ ~ ~ O O O p
O O O O p
h N ,~in~O
V1O O ~ 00 M p~N ~pO~O
,~d' h ~ O~ ,~,--~N N N M M
i ~ i i
i i i N i i i ~ i
~ ~ ~ ~
, , ,~ , ..fi
~ a ~ a a ~ H ~ ~ ~ ~ a
N N
O O
N
N
N
M
d' d'
h
h 'd'
N ~D
N N
a\
O
M
O
O O
d' d.
289
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
r',~ ~-ir;~"~r-i~-i~..~r-ir;r;r; ~ ~ ,~ ~--i.--i,.,..j~,~r;riri ri.--iri
~O O ~ ~ ~ can~ N ~ O ~ N M ~ N .M-i O ~ O \O O\d'~i
O \O~ ,-, N N ~ O N d' O
x ~ ~ d' oo~ O
M M l0O ' O O ' " O O O O O ~ ~ O V7 ~OO
O x x x x a x x ~ x x x H x x O a a x ~ d'
~j vi~pnjc_nO l~~O 0100M cYicnl~ ~i'iV ~p ood'~ M '""~00
O N OMO N ~ N dN"O M ono~ ~ ~ O N d'~ N M a\~D V~N l~
O O O O O O O O O O O O O O O O O I
x ~ x ~ ~ x x x a x x x x x ~ p p x a
00
01
d'
t~
290
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
V7v'id- M M N N N C~jN N N N ''_',-i~ ,-i,-i~--i
Ov~ ~''~ O (~O ood' N ~ d: '""'O ~D 01'-'l~cn '-~O '-'O ,-i
l~~ ~ ~ ~' a O l~~ ~ I~M O ~ op ~ ~ l~V1 '~l0~ M \ON
r~x t~ ~.,.j~ r~a ~ ~ r~~ r~a a ~ ~ t~~ ~ ~ O r~r4~p
ri~ r-i v'i~jd' M rrj~rjN N ~j ~.jfVN N '"~,-i,-i~ ,-id.
t~
,-i
r;
,'~~,CV~jO \O~ ~ ~ _l~.'--i\O0o,--ioo ti'd'pp ~ O N
O O M o O p O ~ ~ d'dM'~ O l0~ ,-Ni~ ~ ~ ~O,~-,~ ~OM N
O O ~, ~ O O O O O O O O O O O O O O O O O O V7
~ x ~ x x x ~ x a ~ ~ x O
p
: ~
0 0 0 0 0
\ o
M l ~ ,--i
i
L7
O
M
O
O
d-
O
N
D\
O
x
O
d'
291
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
-i,-ir-i,-i~ ,-i,-i,-i.--i,-i,-i,-i,-i'~.-i,-i~-~dM'~ d'N N
.-i
v'itVd d'N ~.j,=iood'~ ~OOvO ~ ~ ,~ t~O O ~ O 000op~
~
N ~ ~- 0
O d ~ ~ ~ ~ ~ ~ ~ 0
0
x x x x ~ ~ '~
x a a a a ~ a a x a a x ~ ~ x a
N ~
-i,-i,-i~--i~;r-i,-i,~,-i.-i~-i,-i,-i'"'i,-;,-i,-ir-, O oho d~M N
,-i
h ue'~ ~ oo d'M 01vi M Ov~ N O V7 l~~ ~ ~ O ~ d'~ ~O
~ ~ N
o d M M ~Ol~d-l~ V1V~[~ N d'V' WnO O ~ ~ OlM ~D
o
~ _ O O O O O O O O O O O O O ~ ~ '" O O O
' O
O O O O O ~j ,t
.,
G7
d'
dl
>
,
O
O ''-'-,-,
r O
., ~
O
o
o
00 _
~.~ O
~, C/~r~
M
O
O1
M
DD
N
d,
C7
z
x
O
292
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~--i M
r-iO ~ N ~--~~ O
O ~
"' -;_..;-i-i-i -1"''; -i t~,_i ~ . ~ ~ Ov '
00 00~ ~ ,-;~ ~j~ ~;~ o ~p ~ O O O ~ N
~ 000~1~ ~ ~ ~ x,~ ..~~ ,M-~ ~ O ~ ~ O
O O O O O O O O p O ~ ~ ~ p --~ ~ a cV
C/W--1,~~-1r.~~lx C/~~-1~ ~-iN ~ x \O ,~-,x~ ,-; ~
N \pM a O
N ~ ~ ~ o~~oO ~ O O vN~10 ~ B ~ O ~OO p O
O ~,Ox ,O~,~ ~i~' O ~ ~ ~ ~ .'~O
f-~, x
x
V~
M
~l
M ~ ~ '
d' , ,-d cry p
~ -i~ ~ ~ M d'
~' , , .~_~,~ N ~ ~" ..~~'N
E~~UO N ~ W E~~l
~ O ~ O N M ~ O O
~
- ~D O N l~, N '-- O 01
~ ~' ~ '~'-~O N cna;
d ~ N s.:
H ~U ~U~ ~ s;n ~ C7C7
CW
N M d' V1
M M M M
O O O O
a\ d~ d'
O ~ ~ ~O
M N ,-~ ,-i
O O ~ N
v
_ N N N
d' ' d d
d ' '
~O O ~D V1
0o d V~ N
~
_ ~
O ~ d
-
M M M M
01 dl
H
U
x
O~ O ~ N
O
'd' ~. d.
293
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N N hjN ,....,,-i~; ,-i,-i'~r-~,-;.-;~ ~ ,~,-i,~,-.i,~,-i,-i,-i~-i
~ dM'~ ~ ~ M oNoO ~ ~ ~ p p M ~ N ~ ~ ~ ~ ~ ~ ~ ,-i
O O O p O O O p O O O O O O O ~ O O O O p p O O ~
x ~ a a a x x ~ ~ x x x x x x ~ ~ x x x x ~ ~ a N
N N N N N ,--i,-i,-i~ r-ir'''"~,-i,-i~ ~.;,~,-i,-i,-i~;,-;,--;.-~O
d'~ ~ \DN ~ N ~ ~ l~,-i01 ppl~~ O \Opp,-iO d'O
tn~ ~ !nY7 ~ ~ rt N ~]M ~ 1r7[wOl ,~00M 01~-~M I~ O O aa
p V1 [~[w \O,~N ~ N d'O ,~d-M M l~O O lpp M 0000,~
O O O O O O O O O O O O O O O O O O O O O O O O ,-i
x a x ~ ~ ~ x ,~a ~i'i
O~
O
~7
00
\D
O
O
294
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O O O Q ~ ~ Q
i O ~ o N d d d
O - ' -
O O O O a1M o0O O O
M M ~f'~f'00N 00O O O
O O N N M o0 0od101 01
M
c~
N
N ,-i
cd ..,..-, .. ..
..-.i,--i~--i,--i,--.;,--i'-.;~--~ ,--~_, 01''-,r;r-i
..-i
d~.'O~MId~M o~oN ,N~ O , O D 0lM O O
a Q ~ l\ .; ~ O
x a ~lCn a C~~ ~ N ~ ,_,.; ~ x a ~
~ M M ., --i
~ r;ri~ ~ ~ ~ N '"1~ ~ r;
V o0 \pO N ~ d'N ip O ~ ~p o0'..;v
~ ~ M O t~ x O O ~ ~ M
O a p ~ O ~ a O O ~ O ~ ~Y.,~
x
dl~ 00 M
M N M o0'~~ op N
_~~ _~
~C U ~ H ~. O
O O ~ M ~
N 01 ~'..'d' N l~
M ,~N oo'"~' oo ,-,
O ~ O
C7f- C~0.,~C7C7 ~C f~
~
v~ 00
O O N O
N
O
in ~ ~ d.
i i ~ i
M N
d'
O N ~ h
o
o
M
x H
x x x
M d' V1
295
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
'C o ~ ,-i ,-i,-,
~ ~ ~ ~ '~ .. '"'cd N ~ ~ ~ cn..cn ~
-i r'',-i,-,,.-i ,~ r'' p~..~ ~ ,-.i,~ d-,-,.. ~jN N ;
,.-i
\O r.
h ~ ooOv oo t~ ~ 01'~t ~0
N
~ o ~ ~ ~ N O x ~ ~ v
o 1
O O O O O ~ i O ~ 0 O O O O ~ ~ O O O
' ' x -1 ~l O ~
r
~ ~,r.~.,~,,~ ~ x N x ~i''~',~ ~ N '~~ ~iC/~
N i ~ i N ~ ~ , ~
~
,- ,-,-,-~,-i,-~ ,-i,-i ,-i,~r;,-;~ .. ~yN ~j~-i
v ~y
j .... --~p ..
N o
O O O p ~ ~ " O O ~ ~ O O ~ p ~ ~ O O M O
d
0 ~ x o ~ ~'O O O G~;~ O
r O
7 ~ ' ' o x " o x ~
x ' ''
- ,
,.; M ri
N
b~JO~ p;~ O~
O ~ 'U n ~nC7 L
P-i va0., a P~ ~ O O
O O
O
~-'''-'''--''p O ''' O l~ ~O
~ ~ ~ O N
N O>,-,,
-,
~. ~ ~ p p cC~ tip~ R.
d ~ C7a~~ _ a
d
Ov O
O O O
O M O
,_
..,
i i
N
M
d- d. -
d
O d1
dl dl
A
d' d' d'
296
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N
~i
r;,-i,-i,-ir;,-i,-i,-i,-;~ ,-iO O\~ d=c'~N Cj N N .-'~"' ,~~-i,-i
.-i
O O~oo~j~p cn01cn ~ ~ O O ~ ~jv000~ d=O w ~ O v00o
N V1 M M ' ~' ~ O~
N d V~00\O M x CY,O N V7N M LD'~'N tn00~O
p r~ O O d-\O \Ol~~D l~d' ~ N ~ O \O \Ol~O M O M !I7
l~
l0
x x ~ 0 0 0 o p o ~ N r o ~ a ~ x
a
a ~ a a ~ ~ ~ , ,
~ ~
-i,~-i,~,-;,-i,-;,-i,-i,~ ~ '-i,~ trjM N N N N ~ ,-i,-i,-;,_;
. . ri
O ~ON _ ~ ~ ~ ~
tn O
O t~ N ~ V~~ ~ ~ ~ ~ ~ j O p ~ O ~ p opodM~ O O O ~
O O O O O O ~
O O O O O O ,~ O O O O O O O O O O O
x x x O
a ~ ~ ~ ~ ~ x x x
M
a o
N O
C7~
O
N
i
N
dN'
O
M
d.
O
h
x
297
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
'"''~ 00
~--i~ N t~ ~Od=M ~.rjc~M N N N N ~jN N N N N N N ,-i-~
~ ~ ,
~ ~ ~ ~ ~
N ~ ~ N ~ ~ n M N ~ O ~ ~ N ~ o ~ o
t o ~o
x O O O O O
~t~~ p O p O ~ ~ o O O O O O O O O O p
x ~ a x ~ x ~ x x ~ ~ x ~ ~ ~ a ~ x a ~ x ~ ~
x
M o , , , , , , ,
--, ..t~ ~ trjcn criM M M N N ~j N N N N N (VN N
W rj~ l~~D ~ ~p~n O cri,-i~ oo~n~j O M V'i~ON lW0 ~'1O ~.j
V'i
0od'Q N ~ V7l~~ oo,-,~ ~ O M O l~l~l~ \O~ d'V7 d'l~op
O
O V7 I~l~N V7O O ~p N ~ O t~M M l~~ l~l~ ~ '~N
~ O O O O O O O o p p M
O O x O O p p O O O O O O O
O
x a ~ x x x ~ ,~~ x ~ x x ~
x
N
~ bn ~
~
U
a~ ~,
O
_ O
d'
s;
H ~ 0..Cn
M
d-
O
dl
M
M
O
M
M
d'
N
N
O
N
d'
298
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~-;~i~ir-ir; '--~~--~,--ir-iri,~ r;r-.i'-i~--ir;r-i~-;,--it-;.--ir--i~-ir--i
010 o ~ M O ~ ~ ~ O ~ N ~ M N o~o~ ~ N ~pO O o~o '-i
~ ~Dd'~pO ~nO O ~OO N O ~ O ,-mn~n ~ 000o t~~
O O O O O O O O O O O O O O O O O O O O O O O O ~
x x x x x ~ x x x O x x x x x x ~ x x a a ~ a a ,-,
~;~ ~ ~ ~ ~ ~ ~ ~; x ~ ~ ~ ~ ~ ~ ~ ~;~ ~ ~ ~ ~;~ O
ON1~ O ~ N ~ ~ ~ p ohoO O
~DO M ~ O O M d',~ O O O ~ \O\Ot<1N O ~ ~Olfll~ ~ l0~x
O ~p O O O O O O O O O p O O O O O O O O O O O O ~~
a ~ x x x x O x x x ~ a
z ~O
O
O
O
a
299
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O '_'~r",i '"~M
.. N .. N " .. ., ~i N ..~ M .. '."'..~p
,.-.i,~r.;,_;r.;,-i~ ,--i..~--y.;,-~,--.y;N p~ ,-W-.,~ d-,-, ~--iO~ Q\
V'1dM.~ ~ O O ~ ~ O d'o ~' d-~ x ~' p d'~ dN-~'',fx p ~ ~-1R~
O O O O O O "'ad ,~,'O O O O O 'z3d ,~,''O O Np"Cfd x O 'L5d
x x ~ ,~~ ~ ~ ,~ ~ x x x x x ~ ,~ ~: x ~ ~,
-., .. ,-
O ~ ~ l~~ O .. w ,-, ~ N ~ N
~ \ O ~ o ~'~ <''~'~ N cn1 ~ o 1 "''
O ~1 d'v~a1 ~O~ d'~n N I~ O1~ ~ ooN ~pd-~ M
~OV> ~ l~~ ~OO O ~ N ~ N ,-i~ O O V1~ ~p~ O O M M O
x O O O O o O ~.;x O p O O p O x x O O p O x x O O x
x x ~ ~ x x ~ x ~ x x
x ~ dN'-
O p a;
O ~ O
O
0o M N r-'d~
.--t ~ M
M
a x ~ a
'~ o ~ 0
o 0
~_
i V1 \D M
i i
i
M 0~1 N
N M d-
dM' dM' dM' dM'
O in d- 00
due" N N
N M
a> d\ a\ d>
O
x O
d U x
x H
x x
N M d'
dN- dN' dN' dN'
300
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
b
d~ ~ ~ ,--~ ~ o N
M i ~ ~ ~ N , . . , d
~ "~.-~ O ~ O ~ -~~ ~ ~--I~ r-1~ ~
~ ~ r"i ~O ~
O p M ~r '_'i Iy ~ O l~M ~ 1 O~O000l~ D '7
M Op ~ ~ ~ Q~,~ O O ~ x O O O O p O
x ~ ~ ,~ r0~, ~; x x ,~N x x x x ~ x , ,~,~
i N ~ d' N N
~
.-i~-,.-ir; r, ,.~,-i~--i C~j,-ir.i,-i,-i,-ir.;,_..;
--iool~~.j~ ~ cYi'"~ '-'~ cV ~ M ~.jO o0 v0~ M O~ ,-;
..-yesM d'd-o M O ~ ~ [~O~O _ ~ ~ ~ V1V1 0000~ O oo
O O O NpI~ o p lx ~ a O O ~ x ~ O O O O O O O
x x ~ ~ x x x ~ x N
d'
O
O
O M
N N
_~ p
U f~, o
O O
C7
0o O~ O -
d- dw n v~
O O O O
~n
01 d1 ~ M
i O1 ~ 00
i ~ i
N
M M M M
d' d' d' d'
N tr1 v> O
N n ue
d o o\ d
' o '
a1 ~ d\ a\
x
o w z
x x x x
301
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0
d'M (vjN N -i '-~''-~,-;,-iri,-i'-''"'~ .-i
O ~ ~~d'01 l~(V, ~ ~ M d' ~ ~ O ''-'O I~oo O oho
~p O
O O O O O O O p O O O O O ~ O O ~ '
'
p
x x x x 1 ''
O
,
~
~lr-7~l~lC/7 .-1~-.l.--1~l ~-,~,..~ r; ,~
O d'M N N N r-;'~.--i,-i,-i,-i,-i~ ,--~,-,r;,-;,~ ~
d'
M ~' fxfxO opO N M 01p ~ ~ 01l~ ~ ~ ~ ootrj
~ ~ ~ ''f'l\d' ~f'd'~O d'N ~O~ l~O~M d-V1~ ~ M ~p ~
' d1
O ~ O l~l~~ l~l~M ~ M l~l~ l~l~~ ~OV~[~l~ d' O
O O O O ~ l~
op~.j,..aO O O O O O O O O O O O O O ,~
O
x ~ ~ ~ ~ ~ ~ x ~ a x
M
d'
M ~ O~'~
~A cnN N
~ ,.a
.~
x
o
O O O
~n ~ inN
N l~
C7 C7~ C7
N M
O O
M
' M
i
O~ O
d>
N O
M
N N
W
x
x x
a\ O
N M
d' d'
302
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d'd' M N N N N N N N N '_',_,,-i'"'~ '~,~r-i,-iri~--i,-i,-i,-i
t~Ov a;~ p O oo~ ~ ~ op~ O ~jOv N cn~j ~.-icVt~ ~Oui,-;
~ ~n ~r1N v~~ N ~ dN-~ ~ ~ opo~ O
a ~ a x ~ a x x a ~rx x x x x x a a a a a M
d'd' M M f~jN N N N N C~jr-i,--ir;~-i,~ ri,-i,-;,-i,-i,-;,-i,--i~
d'Vi M N oo'""~N ~i'i~ N ooO l~~ d'~ ~ cncV O W-i,-iO cnO
trytn O d',-.,v~ ~O\O ~'N tryI~ V~,-~I~~ ~ON d' W O N V W a
t~ oo~n~ ~ \p~p V1V1~ ~ ~O~ ~nd- N O O M I~~n ~OI~
O O O O O O O O O O O O O O O O O O O O O O O ~O,-i
~ x ,~ x ~ x x ~ x a s a O ,-;
Ov
M
o0
l~
~O
O
O
303
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d-
'~"'',-i,-i,-i,~,-i'"'~~ p~~ d'M M ~.jN (vjN N ''~,-i~ .-i.--i
,-.-i
~ a\Ov cniri~'~'O O l~0~ oo(V l~~ O (V t~O ~-icV
0 ~
M M d-V1 01~ N v7lx~ O ~Od' V~O O l~ t~~ d' O o '
0 dw
N
~ O _ 4
O O O O O O O O '~ O O O O O O O O O O O O
O
x x x a a ~ a x x ~ ~ ~ x a x x x x x a x x x x x~
-i,-i~-i~-i,~,-i,-i,-i,-i,.-i ~pd'M N N N N ~'1N ,-i~ ,-i,-i
~-'
d=O ~' ~ v'iO v'i~OM N ~ _ W N cn O ~ ~OO ~ M W d'O ~i'i
' d iv O
I~N d W V1 0oN d N O l~ 01~ O ~O'"'M O M d'o0 ~ N d'
J-
M ~ ~ M [~l~ d-O ~ d' O l~O 00 M ~ O 00 '~'~ [~ N d-O
O O P~ V~
O O O O O O O O ,~ O O O O O O O O O O O O O
O
~ x x x a ~ ~ ~ x ~ ~ ~ x ~ ~ ~x
M
O O
'"~M
i
~
d'
O
' M
N
d'
N
M
M
N
N
w
w
U
x
M
d'
304
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
.-iN
D;
r-i,-i~ ,-i~--i~ ,-iriH .-;r;.-i~-iri'-i,-i'"~"'',-i'"~ ~ \O\O~O
cVO ~ ,--;~ ,-icnN ,=i p ,~.-i~pd'N v'i~ ~ ~i'i~ O O ~ c~jd'
0100'""'00d1~ ~ '"'d' ~ l~~D ~DO11D M ''~V1 M Vj~, O N
O O O O O O O O O p O O O O O O O ~ ~ ~ p
C/7x x x x x x ~ ~ r-ar-ar-a~lr..]~l x x r-~x ~ ~j ~ ~-1O
r~,
~;~ ~;~;~ ~ ~ ~ ~;
Ov01 ~j~ l~ N oocs ~OM 01 N ~i'id'~O ~ ~ l~ cnl~~ O ~rjcn
p O ~n ~ p O N d'O ~ ~ ~ M \Dl~1D inV~~ ~OLD O ~f'LD
z O o x x x a x a x ~ M
O
O
O
x
O
M
d'
N
N
al
U
x
N
M
d'
305
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N N ,~~ ~i~i~--~r; ,-i,-i,-i
'--i~O cnp~,--i~O O M d1 01
O
N p d~~ o 000000
~ ~" ~ v07~l
d'M N N ,--a.-i,-ir-i,~ r.;,-i,-i,-i~-i
cnO ~ ~ d1 cnoo~ ,~ oo~-'N O W
~_N ~Od'd' t
O O O O O O O O O O O l~ l~
~1~..7r~~1~ x ~ a x O 0 V'7
0
~o 0 0
a
0 0 0
x a~~
M
N
O
N
M
N
O
N
a\
306
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
[51] The first column in Table 1A provides the gene number in the application
corresponding to the clone identifier. The second column in Table 1A provides
a unique
"Clone ID NO:Z" for a cDNA clone related to each contig sequence disclosed in
Table 1A.
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 ID NO:X was determined by
directly
sequencing the referenced clone. The reference 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.
[52] The third column in Table 1A provides a unique "Contig ID" identification
for
each contig sequence. The fourth column provides the "SEQ ID NO:" identifier
for each of
the contig polynucleotide sequences disclosed in Table 1A. The fifth column,
"ORF (From-
To)", provides the location (i.e., nucleotide position numbers) within the
polynucleotide
sequence "SEQ ID NO:X" that delineate the preferred open reading frame (ORF)
shown in
the sequence listing and referenced in Table 1A, 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.
[53] The sixth column in Table 1A 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.
[54] Column 7 in Table 1A 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
1A. It will be
appreciated that depending on the analytical criteria used to predict
antigenic determinants,
the exact address of the determinant may vary slightly.
307
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
[55] Column 8 in Table 1A provides an expression profile and library code:
count for
each of the contig sequences (SEQ ID NO:X) disclosed in Table 1A, 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 column 8 (preceding the colon), represents the tissue/cell
source
identifier code corresponding to the code and description provided in Table 4.
For those
identifier codes in which the first two letters are not "AR", the second
number in column 8
(following the colon) represents the number of times a sequence corresponding
to the
reference polynucleotide sequence was identified in the tissue/cell source.
Those tissue/cell
source identifier codes in which the first two letters axe "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 slcill 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.
[56] Column 9 in Table 1A provides a chromosomal map location for certain
polynucleotides of the invention. Chromosomal location was determined by
finding exact
matches to 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
308
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
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.
[57] 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 1A 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.
[58] 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 (supra). 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 10,
Table 1A, labelled "OMIM Disease References)". Table 5 is a key to the OMIM
reference
identification numbers (column 1), and provides a description of the
associated disease in
Column 2.
309
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
TABLE 1B
Clone ID SEQ ID CONTIG BAC ID: SEQ ID EXON
A
NO:Z NO:X ID: NO:B From-To
HFCBB56 24 910073 AC068296 1268 1-225
HIBBF63 75 912715 AC009065 1269 1-70
850-1112
1169-1622
1707-1779
1874-1924
2836-2908
3006-4160
HIBBF63 75 912715 AC012171 1270 1-64
159-209
1122-1194
1292-1527
1593-2446
HIBBF63 7S 912715 AC005346 1271 1-70
874-1136
1193-1646
1731-1803
1898-1948
2861-2933
3031-4185
HIBBF63 75 912715 AC009065 1272 1-547
HIBBF63 75 912715 AC012171 1273 1-547
HIBBF63 7S 912715 AC009065 1274 1-424
HIBBF63 75 922715 AC005346 1275 1-547
HIBBF63 75 912715 AC012171 1276 1-419
HIBBF63 75 912715 AC005346 1277 1-424
H2CBH45 90 963811 AC068243 1278 1-267
1540-1640
3095-3380
3393-3556
3901-3967
4137-4639
5287-5856
5916-6588
7029-7876
8324-8414
H2CBH45 90 963811 AC068243 1279 . 1-309
HBGQT03 93 908173 AC024045 1280 1-218
i
310
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
457-549
660-819
2039-2238
2529-2763
2876-3033
3631-3810
3941-4058
4184-4322
4727-4851
5161-6181
HBGQT03 93 908173 AC024045 1281 1-176
HBGQT03 93 908173 AC024045 1282 1-461
960-1030
1194-1959
2041-2516
3037-3122
3396-3455
4055-4366
4547-4599
4967-5216
5321-5461
6521-7174
7564-7841
8311-8758
8829-8969
8997-10118
10257-10910
12058-12385
12438-12953
13729-13873
HCEPH71 97 522739 AL365319 1283 1-494
HCEPH71 97 522739 AL390715 1284 1-494
HCOOZ11 100 965306 AL022238 1285 1-121
899-983
1445-1513
2166-3430
3550-3763
3 859-3972
4449-4595
4960-5152
5385-5529
311
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
5744-5972
6327-7067
7097-7152
7210-8073
8079-8680
8772-11399
12956-13517
13736-14155
14311-14753
16294-16357
16648-16806
16874-17059
17685-17787
HCOOZ11 100 965306 AL022238 1286 1-540
HCOOZ11 100 965306 AL022238 1287 1-665
HCWFF88 101 506577 AC025670 1288 1-300
HCWFF88 101 506577 AL157951 1289 1-624
HCWFF88 101 506577 AL157951 1290 1-409
HCWFF88 101 506577 AL157951 1291 1-83
HDPFF24 104 909232 AC020910 1292 1-353
359-468
787-861
1877-2199
4963-5089
5342-5440
6133-8734
9933-10319
HDPFF24 104 909232 AC020910 1293 1-814
HDPFF24 104 909232 AC020910 1294 1-437
HDTKQ14 107 886936 AL359542 1295 1-140
1249-4264
HDTKQ14 107 886936 AL023653 1296 1-140
1249-4264
HDTKQ14 107 886936 AL359542 1297 1-499
HDTKQ14 107 886936 AL359542 1298 1-145
HDTKQ14 107 886936 AL023653 1299 1-499
HFTDF15 113 657020 AL365277 1300 1-406
HFTDF15 113 657020 AC024511 1301 1-406
HFTDF15 113 657020 AL365277 1302 1-430
HFTDF15 113 657020 AC024511 1303 1-430
HFTDF15 113 657020 AL365277 1304 1-526
312
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HFTDF15 113 657020 AC024511 1305 1-526
HLQDT35 117 839777 AC010998 1306 1-44
540-884
1203-1261
1994-2178
2303-2474
2991-3088
3592-3757
4262-4364
4742-5802
6235-7057
7126-8472
HLQDT35 117 839777 AC013357 1307 1-44
540-884
1203-1261
1994-2178
2303-2474
2991-3088
3592-3757
4262-4364
4742-5802
6235-7057
7126-8472
HLQDT35 117 839777 AC010998 1308 1-768
HLQDT35 117 839777 AC013357 1309 1-6035
8430-11057
HLQDT35 117 839777 AC010998 1310 1-278
HLQDT35 117 839777 AC013357 1311 1-278
HLWFN63 118 908437 AC006599 1312 1-30
1525-1711
5428-5502
7038-7273
7590-7735
8960-9049
11665-11800
12889-13194
13907-14119
14889-15043
15926-16164
18759-19079
20581-20693
313
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
22531-22783
23817-24956
26153-26283
26791-27141
28145-29220
HLWFN63 118 908437 AL033378 1313 1-30
1525-1711
5428-5502
7038-7261
7590-7735
11665-11800
12889-13194
13907-14119
14889-15043
15926-16164
18759-19079
20581-20693
22531-22753
23817-24956
26153-26283
26791-27141
28145-29220
HLWFN63 118 908437 AC006599 1314 1-2939
HLWFN63 118 908437 AL033378 1315 1-2939
HMSCD15 120 918133 AC027008 1316 1-1190
HMSCD15 120 918133 AL158207 1317 1-130
923-1252
1765-3269
4138-4483
6546-7734
HMSCD15 120 918133 AL158207 1318 1-371
HPMFL08 128 959569 293016 1319 1-477
HPMFL08 128 959569 293016 1320 1-650
HTEAG49 135 954614 AL390796 1321 1-1310
HTEAG49 135 954614 AL357045 1322 1-1310
HTEAG49 135 954614 AL390796 1323 1-627
HTEAG49 135 954614 AL357045 1324 1-627
HTLBH67 136 751985 AC008439 1325 1-62
293-400
452-976
1016-1058
314
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
1463-1534
1886-2026
2110-2249
2401-2463
3324-4027
4192-4288
4694-5330
5485-5650
5813-6262
6273-6401
6475-6559
6728-6847
6979-7205
7573-7676
7730-8146
8334-8866
8885-9392
HTLBH67 136 751985 AC008781 1326 1-85
254-371
505-731
1098-1201
1255-1671
1718-2387
2408-2915
3113-3244
3382-4278
4504-4538
4650-5645
HTLBH67 136 751985 AC022420 1327 1-62
295-403
455-979
1019-1061
1466-1537
1890-2030
2114-2253
2405-2467
3328-4030
4195-4291
4697-5333
5488-5653
5816-6265
315
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
6276-6404
6478-6562
6731-6850
6982-7208
7575-7678
7732-8148
8195-8864
8885-9392
9590-9721
9859-10754
10980-11014
11126-12121
HTLBH67 136 751985 AC005368 1328 1-64
294-399
451-975
1015-1057
1462-1533
1885-2025
2109-2248
2400-2462
3323-4026
4191-4287
4693-5329
5484-5649
5812-6264
6275-6403
6477-6561
6730-6849
6981-7207
7575-7678
7732-8148
8201-8868
8887-9394
9592-9723
9861-10759
10985-11019
11131-12126
HTLBH67 136 751985 AC008781 1329 1-292
HTLBH67 136 751985 AC022420 1330 1-323
1372-1431
1657-1821
316
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
2377-2485
4488-4700
4954-5061
6224-6547
6819-6965
7268-7333
8088-8593
9897-10068
10109-10623
10645-10680
10812-10871
10982-11123
11345-11383
11877-12000
12310-13467
HTLBH67 136 751985 AC022420 1331 1-292
HTLBH67 136 751985 AC005368 1332 1-292
HTLJC7I 137 922923 AC009516 1333 1-2009
HTLJC71 137 922923 AC007957 1334 1-1747
HTLJC71 137 922923 ACOI875I 1335 1-2009
HTLJC71 137 922923 AC023490 1336 1-2009
HTLJC71 137 922923 AC009516 1337 1-375
HTLJC71 I37 922923 AC009516 1338 1-494
HTLJC71 137 922923 AC007957 1339 1-205
HTLJC7I 137 922923 AC018751 1340 1-494
HTLJC71 137 922923 AC023490 1341 1-375
HTLJC71 137 922923 AC018751 1342 1-375
HTPAD46 138 503313 AC010932 1343 1-3347
HTPAD46 138 503313 AL133510 1344 1-5377
HWMBM13 I44 909683 AL158847 1345 1-1445
1668-1817
1931-2643
HWMBM13 144 909683 AL158847 1346 1-396
HWWDN34 145 911357 AC019214 1347 1-160
713-910
1069-1269
3997-4098
4303-4397
5035-5098
5740-5796
6024-6155
317
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
6697-6813
6937-7029
7110-7349
7432-7571
7573-7601
7834-7907
8326-8490
8712-8804
8894-8979
9090-9171
9368-9467
9622-9730
9821-10012
10197-10277
10440-10562
10668-11103
11203-11432
11937-12052
12251-12312
12794-13183
13257-13343
13483-13996
14001-14146
14369-14483
14587-15046
15053-15302
15470-15534
15624-15695
16128-16212
17904-17980
18066-18189
18298-18394
18494-18574
18668-18771
18896-19043
19245-19364
19650-19925
19968-20102
20205-20354
20529-21648
21748-21816
21861-22129
318
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
22341-22569
22799-22888
23058-23600
23833-23968
24304-24757
HWWDN34 145 911357 AC019214 1348 1-803
1028-1918
HDPVY89 156 827026 AC026283 1349 1-292
353-776
1340-1506
1568-1696
2408-2534
4767-4955
5472-5546
5957-6293
6373-7085
73 86-7445
9201-9273
9532-9672
10470-10641
10873-11481
12131-12705
12990-13214
13351-13509
14119-14173
14445-14570
14879-15004
15604-15844
16133-16253
17540-17867
17944-18254
18356-18755
18 892-19002
20066-20352
21146-21308
23235-23486
23813-24533
HDPVY89 156 827026 AC026283 1350 1-318
HFOXK14 180 603245 AL096870 1351 1-68
218-379
706-840
319
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
1000-1180
1505-2004
2014-2301
3897-3942
4074-4162
4353-4422
4764-4865
4941-5356
5850-5932
6040-6181
6664-6917
7152-7337
7431-7624
8016-8175
8346-8525
9445-9926
10349-10496
10802-10912
10949-11881
HFOXKI4 180 603245 AL096870 1352 I-262
HHFLU06 182 857884 AL096870 1353 1-68
218-379
706-840
1000-1180
1505-2004
2014-2301
3897-3942
4074-4162
4353-4422
4764-4865
4941-5356
5850-5932
6040-6181
6664-6917
7152-7337
7431-7624
8016-8175
8346-8525
9445-9926
10349-10496
10802-10912
320
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
10949-11881
HHFLU06 182 857884 AL096870 1354 1-262
HBIOZ10 187 973131 AC010761 1355 1-543
787-3239
3323-3758
3840-3890
HBIOZ10 187 973131 AC010761 1356 1-134
560-634
971-1b91
2351-2501
2711-2875
2967-3126
3298-3461
3575-4655
5184-5345
HBKDI30 188 729048 AL160175 1357 1-155
743-898
1272-1388
4034-4114
4238-4358
4714-4779
4918-5073
5219-5353
6932-7970
HDAAV61 194 810305 AC007136 1358 1-462
1711-2082
4232-4320
4347-4558
4640-4739
7341-7423
7710-8325
8400-8498
8 890-9085
9717-9885
10451-10717
10747-10793
11067-13460
HDAAV61 194 810305 AC007136 1359 1-138
HDAAV61 194 810305 AC007136 1360 1-113
HE8UY74 202 960914 AL356968 1361 1-2209
HE8UY74 202 960914 AL356968 1362 1-518
321
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HFKIT06 207 934019 AC068353 1363 1-1562
HFKIT06 207 934019 AC026976 1364 1-222
HFKIT06 207 934019 AC026976 1,365 1-294
HFKIT06 207 934019 AF284563 1366 1-1562
HFKIT06 207 934019 AC068353 1367 1-323
HFKIT06 207 934019 AF284563 1368 1-323
HHEHC53 209 921783 AC009427 1369 1-100
1854-1942
3236-3463
4629-4868
5054-5181
5371-5476
5851-5953
6104-6149
6509-6612
7131-8415
8429-8492
8638-8748
8975-9440
9835-10490
10606-10899
11149-11282
11382-11881
12023-12075
12172-12315
12496-12551
12638-12706
12827-12994
13077-13630
HHEHC53 209 921783 AC009427 1370 1-428
HHEHC53 209 921783 AC009427 1371 1-388
466-526
698-906
1023-1922
HMTAJ73 215 813296 AC015698 1372 1-132
337-470
573-666
1313-1765
1962-2257
2433-2599
2611-2991
322
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
3150-4087
HMTAJ73 215 813296 AC015698 1373 1-184
HNTMD79 217 934522 AL160291 1374 1-240
824-922
1460-1771
3163-3311
4244-4385
5252-5359
5721-5781
HNTMD79 217 934522 AL365228 1375 1-240
-
1460-1771
3163-3311
4244-4385
5253-5360
5722-5782
HNTMD79 217 934522 AL160291 1376 1-694
HNTMD79 217 934522 AL365228 1377 1-694
HNTNB 14 219 909942 AC068701 1378 1-414
578-660
871-957
1247-1581
1647-3915
HNTNB14 219 909942 AC068701 1379 1-148
HTEMU66 232 944419 AL022167 1380 1-1796
HTEMU66 232 944419 AC018903 1381 1-631
HTEMU66 232 944419 AC068470 1382 1-706
HTEMU66 232 944419 AL049186 1383 1-912
HTEMU66 232 9444.19 AC006510 1384 1-1150
HTEMU66 232 9444.19 AC022305 1385 1-686
HTEMU66 232 944419 AL049186 1386 1-87
HTPGG25 239 911282 AC020705 1387 1-125
455-594
711-853
934-1082
1618-1727
2487-2898
3420-3558
HTPGG25 239 911282 AC020705 1388 1-924
1085-2662
HWAFG04 244 952878 AC018571 1389 1-36
150-275
323
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
1528-2147
2757-3048
3345-3519
4024-4132
5472-7934
HWAFG04 244 952878 AC046I85 1390 1-36
150-275
1528-2147
2757-3048
3345-3519
4024-4132
5472-7934
HWAFG04 244 952878 AC015651 1391 1-931
1434-1990
3313-3421
3533-3658
4911-5529
6139-6430
6727-6901
7406-7514
8854-11316
HWAFG04 244 952878 AC018571 1392 1-619
HWAFG04 244 952878 AC046185 1393 1-469
HWAFG04 244 952878 AC015651 1394 1-284
HWAFG04 244 952878 AC015651 1395 1-619
HWMIB81 249 955336 AC021719 1396 1-109
636-1074
4114-4301
5473-5527
8202-8368
8491-9905
9927-11792
HWMIB81 249 955336 AC016143 1397 1-109
636-1074
4114-4301
5473-5527
8202-8368
8491-9905
9927-11792
HWHGY45 304 911621 AC021102 1398 1-260
946-1050
324
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HHPDV86 310 522953 AC025928 1399 1-62
370-633
1054-1403
1500-1650
1962-2043
2080-2494
2660-2823
3015-3150
5002-5160
5681-5758
7238-7722
7759-8092
8289-8396
8800-9692
HHPDV86 310 522953 AL109627 1400 1-62
374-637
1058-1406
1503-1653
1965-2046
2083-2497
2663-2826
3018-3153
5010-5168
5723-5800
7279-7763
7800-8131
8328-8435
8839-9730
HHPDV86 310 522953 AC025928 1401 1-137
3556-3999
4417-4578
HHPDV86 310 522953 AL109627 1402 1-137
3556-3999
4417-4578
HTTKF86 318 912689 282188 1403 1-128
_ 933-996
1532-1699
6031-7667
HTTKF86 318 912689 282188 1404 1-282
HTTKF86 318 912689 282188 1405 1-896
~HCESA79 319 912709 AC009065 1406 I-70
1
325
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
850-1112
1169-1622
1707-1779
1874-1924
2836-2908
3006-4160
HCESA79 319 912709 AC012171 1407 1-64
159-209
1122-1194
1292-1527
1593-2446
HCESA79 319 912709 AC005346 1408 1-70
874-1136
1193-1646
1731-1803
1898-1948
2861-2933
3031-4185
HCESA79 319 912709 AC009065 1409 1-547
HCESA79 319 912709 AC01217I 1410 I-547
HCESA79 319 912709 AC009065 1411 1-424
HCESA79 319 912709 AC005346 1412 1-547
HCESA79 319 912709 AC012171 1413 1-419
HCESA79 319 912709 AC005346 1414 1-424
HDTBJ28 320 912714 AP001793 1415 1-791
2172-2708
3318-3396
HDTBJ28 320 912714 AP000864 1416 1-973
2292-2890
3500-3585
HDTBJ28 320 912714 AC008052 1417 1-1228
2610-3146
3756-3852
6044-6512
HDTBJ28 320 912714 AC015676 1418 1-782
2163-2699
3310-3406
5603-6071
HDTBJ28 320 912714 AC008052 1419 1-281
344.-1073
1346-1846
326
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
1875-2279
2562-3367
HDTBJ28 320 912714 AC015676 1420 1-281
344-1073
1346-1846
1875-2279
2562-3367
HEOQA56 324 925132 AC013449 1421 1-104
HTPCQ24 325 925349 299716 1422 I-55
126-186
610-963
1193-1368
2995-3327
HTPCQ24 325 925349 299716 1423 1-135
HWAEI37 326 929481 AL035461 1424 1-125
1059-1213
1474-1578
2527-2806
3656-3738
4150-4303
6178-6277
7576-7777
8753-8841
11399-11733
12324-12409
13930-14406
14552-14912
16486-16637
16878-17075
17331-17733
18153-18539
19403-19618
20219-20612
21057-21087
22106-22250
24542-24846
25416-25943
26924-27007
HWAEI37 326 929481 AL035461 1425 1-902
3219-3309
3397-3514
327
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
4119-4204
4594-4956
5725-5855
6111-6199
6330-6423
6972-7084
7935-8468
8574-8701
12446-12712
HSLEM44 330 506604 AC078913 1426 1-350
HSLEM44 330 506604 AC022123 1427 1-351
HSLEM44 330 506604 AC010357 1428 1-350
HLWBR95 335 734474 AC013252 1429 1-1431
2471-2593
3271-3363
3664-3815
4189-4313
4828-5350
5548-5643
5651-5788
6280-6588
7989-8153
8309-8444
9035-9391
10636-10819
11421-11524
11927-12357
12421-12568
13436-13609
14506-14698
HLWBR95 335 734474 AC013252 1430 1-355
HMSOZ55 340 910911 AC024229 1431 1-44
4837-4955
5209-5280
6713-7192
7207-7601
79'73-8858
HMSOZ55 340 910911 AC024229 1432 1-1660
HMCAV88 347 924874 AC06823I 1433 1-77
341-747
965-1228
328
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
1419-1507
1758-1819
2098-2205
2595-2658
2804-3341
HMCAV88 347 924874 AL357752 1434 1-77
341-747
965-1229
1420-1508
1759-1820
2099-2206
2596-2659
2805-3342
HMCAV88 347 924874 AC005476 1435 1-960
HMCAV88 347 924874 AC068231 1436 1-202
2270-2941
5541-5653
5766-5910
6198-6242
HMCAV88 347 924874 AC068231 1437 1-415
674-737
960-1053
1379-1496
HMCAV88 347 924874 AL357752 1438 1-415
674-737
960-1053
1379-1496
HMCAV88 347 924874 AC005476 1439 1-366
HF'VHV40 349 945849 AC020911 1440 1-149
3465-3490
3536-3663
5417-6105
6912-7217
8423-8493
8847-9176
10098-10233
10536-11336
HFVHV40 349 945849 AC020911 1441 1-299
HFVHV40 349 945849 AC020911 1442 1-110
HEAAE08 351 959970 AC008687 1443 1-66
297-597
329
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
ss4-11
is
1668-2115
2645-2819
2847-3188
3247-3306
3480-4766
HEAAE08 351 959970 AC008687 1444 1-95
HAPRM21 353 963200 AL034374 1445 1-78
996-1169
2915-3039
3204-3252
3307-3664
4437-4671
4859-4972
5431-8861
HAPRM21 353 963200 AL034374 1446 1-498
HAPRM21 353 963200 AL034374 1447 1-495
HTADZ74 358 811489 AC007278 1448 1-164
1470-1572
1892-2030
3973-4099
5671-5845
6588-7389
HAPNZ77 359 887072 AC076973 1449 1-480
HAPNZ77 359 887072 AC023098 1450 1-1520
1808-2468
HAPNZ77 359 887072 AC003046 1451 1-3893
4181-4841
HAPNZ77 359 887072 AC005859 1452 . 1-3893
4181-4841
HAPNZ77 359 887072 AC023098 1453 1-307
HTSFJ40 364 722406 AC006171 1454 1-247
1217-1320
1624-1963
2076-2179
2604-2711
2716-3114
3399-3638
4344-4427
5079-5141
5439-8153
330
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
8268-8798
HTSFJ40 364 722406 AL161645 1455 1-247
1217-1320
1624-1963
2076-2179
2604-2711
2716-3114
3399-3638
4344-4427
5079-5141
5439-8153
8268-8798
HTSFJ40 364 722406 AC006171 1456 1-2213
HSDJH12 368 876344 AC021747 1457 1-76
239-328
886-973
3912-4047
6397-6453
7393-7574
8590-9069
9354-10839
13386-13803
14791-15108
15296-15408
15499-15925
16031-16317
16452-16602
17145-18449
HSDJH12 368 876344 AL359882 1458 1-283
1271-1588
1793-1888
1979-2405
HSDJH12 368 876344 AC046143 1459 1-283
1272-1589
1794-1889
1980-2406
2512-2797
2932-3082
HWLEY40 374 957875 AC006171 1460 1-247
1217-1320
1624-1963
331
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
2076-2179
2604-2711
2716-3114
3399-3638
4344-4427
5079-5141
5439-8153
8268-8798
HWLEY40 374 957875 AL161645 1461 1-247
1217-1320
1624-1963
2076-2179
2604-2711
2716-3114
3399-3638
4344-4427
5079-5141
5439-8153
8268-8798
HWLEY40 374 957875 AC006171 1462 1-2213
HOUBZ94 376 527876 AC068475 1463 1-70
163-330
651-994
1105-1272
1372-1586
2253-2908
2995-3524
3711-4406
4418-4480
4581-5218
5621-5829
6007-6286
HOUBZ94 376 527876 AC005954 1464 1-91
893-1009
1323-1695
1856-2422
3548-3650
3665-4010
4965-5170
5288-5397
6874-7000
332
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
7283-7430
7520-7600
7693-7860
8181-8524
8634-8807
8902-9116
9783-10438
10525-11054
11241-11936
11948-12010
12111-12748
13154-13362
13540-13833
14748-14851
14928-15142
15543-15616
17091-17240
17351-18020
18331-18662
19524-19871
19999-20209
20570-20670
20861-21075
22489-22727
22961-23073
25307-25360
29573-29961
31051-31168
HOUBZ94 376 527876 AC005954 1465 1-131
HCE3W04 379 615501 AC022366 1466 1-565
1503-1718
1838-1933
2011-2097
2265-2335
2588-2693
2905-2975
3090-3726
3809-3889
4080-4591
4847-5070
5355-5819
333
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HCE3W04 379 615501 AC022506 1467 1-563
1501-1716
1836-1931
2009-2094
2263-2333
2586-2691
2903-2973
3088-3724
3807-3887
4085-4540
HCE3W04 379 615501 AC025165 1468 1-565
1503-1718
1838-1933
20I 1-2097
2265-2335
2588-2693
2905-2975
3090-3726
3809-3889
4080-4591
4847-5070
5355-5819
HCE3W04 379 615501 AC025165 1469 1-604
HCE3W04 379 615501 AC022506 1470 1-518
999-1533
1563-1830
2015-2094
2441-3538
4095-4315
4655-5378
HPJAP28 382 686349 AC004794 1471 1-599
769-987
1562-1690
1879-2043
2595-2821
3807-5923
6102-6572
6644-7502
8127-8585
9415-9553
9669-9763
334
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
9826-9989
10230-10322
HPJAP28 382 686349 AC004794 1472 1-97
1121-1975
HPJAP28 382 686349 AC004794 1473 1-691
HIBEC79 383 703000 AC011458 1474 1-138
397-1114
1356-1693
1781-2091
2270-2389
2474-2908
3053-3202
3288-3349
3421-3976
4551-4662
4696-5053
5166-5246
5318-5490
5592-5723
6082-6283
6619-6733
6853-6942
7491-7586
7922-8003
8015-8421
8432-8624
8714-8856
8943-10332
10482-10901
11647-11934
13110-13177
13310-14175
HIBEC79 383 703000 AC011458 1475 1-406
HIBEC79 383 703000 AC011458 1476 1-287
HNFHS82 387 779946 AC010835 1477 1-418
HFPBB28 389 844526 AC016135 1478 1-845
HFPBB28 389 844526 AC018512 1479 1-776
HFPBB28 389 844526 AC073717 1480 1-240
HFPBB28 389 844526 AC002518 1481 1-150
HDQGZ78 399 909735 AC026282 1482 1-238
976-1440
335
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
2143-2356
6769-6910
9591-9648
9951-10098
HSIDQ38 401 909854 AC003070 1483 1-152
3039-3473
4301-4483
4678-4795
5280-5944
6055-6117
6290-6359
6677-6761
8475-9284
11404-11918
12112-12437
12443-13065
13153-13467
13593-13719
13799-14185
14224-16489
HFTBL33 407 910055 AC022366 1484 1-565
1503-1718
1838-1933
2011-2097
2265-2335
2588-2693
2905-2975
3090-3726
3809-3889
4080-4591
4847-5070
5355-5819
HFTBL33 407 910055 AC025165 1485 1-565
1503-1718
1838-1933
2011-2097
2265-2335
2588-2693
2905-2975
3090-3726
3809-3889
336
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
4080-4591
4847-5070
5355-5819
HFTBL33 407 910055 AC025165 1486 1-604
HUFCI64 411 911558 AC004151 1487 1-145
359-443
527-599
798-868
958-1095
1196-1260
1465-1577
1652-1732
2256-3158
4031-4899
4984-5306
5735-6066
6554-6694
6780-6970
7107-7232
7316-7404
7529-7643
7744-7917
8401-8592
8675-8813
9685-9920
9958-10211
10485-11014
11088-11199
11958-15576
16324-16465
16587-16818
16939-17000
17440-17554
17558-17946
18645-18765
19015-19378
20522-20937
22111-22452
HUFCI64 411 911558 AC004151 1488 1-134
HWAFT84 412 911559 AC004151 1489 1-145
359-443
337
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
527-599
798-868
958-1095
1196-1260
1465-1577
1652-1732
2256-3158
4031-4899
4984-5306
5735-6066
6554-6694
6780-6970
7107-7232
7316-7404
7529-7643
7744-7917
8401-8592
8675-8813
9685-9920
9958-10211
10485-11014
11088-11199
11958-15576
16324-16465
16587-16818
16939-17000
17440-17554
17558-17946
18645-18765
19015-19378
20522-20937
22111-22452
HWAFT84 412 911559 AC004151 1490 1-134
HWADR60 416 926487 AC023176 1491 1-178
293-506
542-940
1591-2005
2031-2104
2390-2509
3681-3797
4018-4165
338
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
4267-4381
4704-4736
HWADR60 416 926487 AC023176 1492 1-162
443-739
1067-1458
1745-1877
1976-2119
2816-2883
3171-3294
3727-4154
4340-4442
5251-6126
6708-7176
7418-7880
8134-8752
9979-10164
11234-11413
12532-12666
13313-13459
14761-14898
15208-15308
16207-16518
HPCIG66 419 930886 AC024888 1493 1-36
149-234
537-623
852-921
1077-1728
HPCIG66 419 930886 AC024888 1494 1-61
133-210
992-1107
1310-1644
1834-1905
2133-2254
2927-3032
4154-4254
4482-4683
HPCIG66 419 930886 AC024888 1495 1-63
239-327
574-1064
1763-2190
2394-2604
339
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
2659-2795
3452-4040
5967-6046
6187-6254
HCRPU72 420 931140 AC023151 1496 1-65
72I-1042
HE9RT95 421 934556 AC008439 1497 1-57
311-418
1581-1904
2176-2322
2625-2690
3445-3950
5254-5425
5466-5980
6002-6037
6169-6228
6339-6480
6701-6739
7238-7349
7664-8821
HE9RT95 421 934556 AC022420 1498 1-323
1372-1431
1657-1821
2377-2485
4488-4700
4954-5061
6224-6547
6819-6965
7268-7333
8088-8593
9897-10068
10109-10623
10645-10680
10812-10871
10982-11123
11345-11383
11877-12000
12310-13467
HE9RT95 42I 934556 AC022420 1499 1-389
HE9RT95 421 934556 AC022420 1500 1-62
295-403
340
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
455-979
1019-1061
1466-1537
1890-2030
2114-2253
2405-2467
3328-4030
4195-4291
4697-5333
5488-5653
5 816-6265
6276-6404
6478-6562
6731-6850
6982-7208
7575-7678
7732-8148
8195-8864
8885-9392
9590-9721
9859-10754
10980-11014
11126-12121
HWADD57 426 943039 AC011492 1501 1-303
949-1648
1913-2937
3032-3231
3325-3443
4093-4485
4777-4936
5057-5548
5650-5968
HWADD57 426 943039 AC011492 1502 1-50
852-907
988-1407
1584-1839
2455-2586
2689-2787
HFKHR40 431 952470 AC018805 1503 1-525
612-1372
1476-1730
341
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
1732-2155
2345-2460
2652-3025
3157-3251
3449-3540
3680-3780
3914-4131
4215-4491
4603-4741
4913-4987
5135-5190
5435-5571
5901-6011
- 6309-6423
6922-8294
8370-8522
HFKHR40 431 952470 AC061707 1504 1-527
614-1374
1478-1732
1734-2158
2348-2463
2655-3027
3159-3253
3451-3542
3682-3782
3916-4134
4219-4495
4607-4745
4917-4991
5139-5194
5439-5575
5905-6015
6313-6427
6926-9300
9919-9960
10029-10186
11393-11624
12094-12294
13227-13375
13690-13829
13921-14010
342
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
14362-14486
HFKHR40 431 952470 AC018805 1505 1-343
700-770
HFKHR40 431 952470 AC061707 1506 1-343
700-771
HFKHR40 43I 952470 AC061707 1507 1-277
HWLHF10 435 963422 AC010545 1508 1-40
1661-1891
2119-2199
5160-5349
6239-6607
7675-8566
9450-9516
9675-9752
10110-10274
14154-15055
16384-16500
17055-17139
19941-20453
20703-21216
21806-21945
23638-24171
24527-24795
25564-25656
26644-26787
27284-27438
28354-28612
29247-29591
29597-30208
32018-32539
33187-33942
HWLHF10 435 963422 AC010545 1509 1-721
HWLHF10 435 963422 AC010545 1510 I-610
675-1454
1591-2267
2801-3363
343
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
[59] Table 1B summarizes additional polynucleotides encompassed by the
invention
(including cDNA clones related to the sequences (Clone ID NO:Z), contig
sequences (contig
identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)),
and genomic
sequences (SEQ ID NO:B). The first column provides a unique clone identifier,
"Clone ID
NO:Z", for a cDNA clone related to each contig sequence. The second colmnn
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 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 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).
344
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~ ~ ~r -~ mo ~n ~n o a~ -m o ~ o vo ,-~ 00
wd- d- mn
N ~ oo N ~ N O~ O~ O N ~n O~ O1 ~O ~O a1
d' o0 0o N l~ 00
N d' l~ d' ~O N N ~n ~ Ov 01 M l~ o0 N M
~ N ~n 01 N N
o ,-~ ~ r., ,~ ,-, ,-~ ~ ,-a .-,
,-. ,-~ ,-, N .-, .-~
H
H
z
O ~t O o0 O l~ l~ N oo ~ d- Ov .-, d- M
l~ ~D O~ d-
v~ 'cY cwt N oo ~ N ~ M ~ ~ 01 ~O ~O m>
oo N O 01 .-
N v0 M ~ ~ N ~n O ~ V1 ~ N d' ~n ~
d1 N
x,
W
H
z
o ~ ~ 0 0 0 0 0 0 0 ~ N ~ o ~ ~ 0 0 0
o 0
d- O V'1 ~n 00 01 \O ~ O M I~ ~ a1 N
a1 N ~n ~O d' M M
V7 l~ \O \O \O M M d' N 00 V7 V'7 N 00
M M ~ d' M
V ~
~I H
O Q~ ,-,
. ,
r'' by
O
~ - l \ U ~ \
_ p O D
Op O O ~ pip O
'"V
~f'
~O
Q hA ~O 1 b ~
z ~
i p..~1 y bl~
,
v~ "d
C O . N
H
C. ~ ~'
,
cd
L7 V1 ~
~
A "d "d , ~ "d
n l~ ~
C1' ~ ~.-
~
_ t+-r
'
'~
_,'
w ~ ,
w ~ ~ ~ ~ ~ te
~'
a.~ a~ a
.,
0
_ _ _.
.fl r~ x' ,~ .fl r-~i
N N N
~
a
M ~n \O
_
-, ~' d' ~ d'
d'
00 ~ 00 O 00
~n l~ t~ d' N
p ~O l~ O ~n ~O
U A -~ o ~ ~ oN,
-, ~n
A W
W
~1 ~ N te
a
...
0
x x x x
z
345
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M ~ l~ N N l0 ~O 00 00 00 00 O M M 00 ..-r M
l~ 00 M N M ~ 01 d' d' lwn I~ d' d' ,~ M I~
d' d' ~D l~ N M M M d' N N N M M ~ O~ 00
~n d' O~ d' N N M ~n ~O O a1 l~ oo ~n d- N
d- ~ ~ ~ O due- ~ N ~ M ~ ono ~ ~ a\ N
o No~p~po~o~o ~o ~o ~~ o
~O <''~ O N N l~ t~ O ~O d' l~ ~ l~ ~ O ~O
I~ M O 01 ~ 01 00 l~ ~ M d' M N M ~ O ~n
,_: ~ o
N
W 01 Q1
\O ~O ~ ~-' l0 ~ ~ N
r' ~ d- o U ,~ m ''-' ,--. ~ ~nl ~o U o yt-I
°o o°o~ °o~~o 'r'°~.90 '<'E"'
Pw-as ~bA o Pw-~ ~ P~-. ~ bn ~ Pwa ~ ~ Pw-~ ~ Pw-~
.,-i ,7, ,~~ -S"', o
V .-~ cd by O ~ s-~ ~ N ~ p b~0 ~
~ cd ~ O O ~, V ' ~ S~ c~ ~ ~ ~ O Q-s x
'TJ ,--~ ~ TS ~ O ~ ~ O
~ O ~., O O -N n O cCt p..i O c~ ~1, ~ .~', O
p ~ ~ d' ~ U ~ U '~ ~~ ~ ~ ~l ~ O " ~ U
U
~ N C%~ M ~ ~ p",i 5, N ~ ~ G~ N ~ ~ ~ ~ ~ C%~ N
S-," ~", O M ,~ M .~ U U
f-~~w°~ ~ ~-~ ~ ~w.a~' ~~ w °' ~~ L7 0~ ,-,.°~'.a~ o
Q., ,.Ws ø, ~' Pws Q, .~,' ~ s-i "c3 ~ 'C3 ~ p, w
N (~ N ~.~r..~ N W ~ (~ N (..~L~ N (.~T~ N
c~3 ,--~ c~ ~ 00 c~ ~ o0 cd ~, ,-~ c~ ~ .-~ cci ,-, cB cc3
..~~fl ~ N ~ ~ ~ ~ x .-~ ~ x N ~ ~i N ~ ~ N
a1
d' ~ d' l~ d- oo a1 O
d' ,-i d' .-i d- .--r ,-r N
00 l0 00 lp M O M 00
0o a1 00 l~ O O N
O O O 00 01 d' 00
d- O mn t~ 01 N N
N
dl
O d' O ON1 O1
O
x W a
x x ~ ~ x x x
346
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
m o0 N oo v0 t~ M O~ dmn oo two
O ~n O M N ~ ~O ~n ~O ~O
d' 00 0o t~ l~ ~n ~W O own ~n N ~n
M 00 O N Q1 N M 01 ~ V7 ~O O M
~O M .--~ ~ M ~ M t~ N ~O
N ~ N d- M N N d- N N
o ~ o N ~ ~ V7 ~ V1 o M M
O o 00 ~ ~ d' p~ ~ M ~ M Op
N '-'a
d' ~ ~
O 0.
U o ~ o o U °o '-' o 0
~o ~ 0 0 0 ~ o ~ o o O'
A, N Pw-WbA Pw-i P~-~ ~ P~-a ~ Q, ~ Wn
v~ b~A --_ a~ -N
4a - 'c~~' O 1 ~ O
.-~ ,s," Q, W
i
s.,~~'' o~o~~~,vPx-~ ~ ~~W ,~~o~ P'T'-. W
_o.~ ~ ~v~ ~ ~~ o ~'~~ z
o ~ w '~ ~ ~ ~ w ~'' ° .~ ~ o w w
~ ~ a..~ ~ ~~ ~ 0., a~ '~ ~ .~ N ~ ai a~ ~ w ~ d- a.~ w ~7
N ' (~ N W (~ N W N W W
ri ~
N ~ ~i N ~ x N ~i N ~ ~ .-i ~ ,.~., N x N
O ~ N M
V7 ~ . V7 M '<h' l!7 V~
d' N d- N N d' d- N
d1 ~O ~n ~n M ~O N N
d- ~ r., O l~ 00
01 O~ l0 l~ O d' a1 N
01 01 ~ O O ~O 01
O O l~ M ~ N O N
d1 ~ d1 d1 ~ dl
O O1
d' °o ~ '~ ~n d' M
w O U ~ ~ w
d W w ~ as w
x x ~ x x x x x
347
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
01 M l~ 00 M M l~ M M N ~ ~O O lp
O ~ lp .--i CO d1 ~O N V~ O 00 00
00 d1 ~ .-~ .-~ N ~O ~ ~ ~O 00 00 01 d
~n 00 N M M oo M .~ .~ N .~ N oo l~ Q1
d' l~ ~ M O V7 M V7 ~O ~ 01 00
~n oo w r., ~n N ~ M ~n ,--mn
0 0 o d. 0 0 0 ~ o ~ o M o 0 0
N
a1 M oo ~ ,~ N v~ N ,-~ N ~ o0
l~ l~ N N 01 01 01 d' 01 ~t l0 ~ 00 01 V7
cn U ~ c~i
Pa ,-fl
N O N
l0 ~ 00 ~ M
01 O ~ 01 01 01 O
~O ~ t~ ~O ~O ~O r, -_
~O
~ I~ O a1
p.., ~ H ' bA N P-~ N ~ N ~ "due bA ~
c~
O .~ O ~ n
E-, + E-~ ~ ~ ~ ~ o
~ C7 N ~ ~ U ~~ Q,' ~ '~ v a~ ~~ ~~ w
'"' wn v~
Gq U W
~~rr~~
O ~~OwU''~~ WOZ~~Wr~ ~x w ~~ .~ ox ~n tea, o
W~~~v'~W A'.'. °~W~qW~ ~'~p., ~'~p..,
UU~~~p,pH ~ ~ ~UUr~~~ y ~ ~ ' ~ 0N ~ O ~ o'~.~
~w~~i E-~~a~.,aw.,,~~~W~rn~:~,~aw.~ ~~~ ~~~aw.~ ~~~ s-~~
r~ d- ~ r.~ r~ d-
0o cd c~3 .-~ cd ,-~ cd .-~ cd cd
N ~ rx N ~ r~i N ~
d- TWO
d- N d- N d' M
N
O l~ ~-~ d' o0
~O oo O1 N N
O o0 O~ ~ O I~
O l~ N .--~ O ~O
O
d> ~ dl d>
O
01 M
d,
w ~ w a~.~
w
x ~ x ~ x
348
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
ch M v'W p t~ Q~ N O N ~O N d~ o0 V~
N ~O N t~ ~ d' ~ ~O ~n O a1 O I~ I~ 00
Wit' ~ ~O l0 d' 00 M N M d' N ~ M M M
d' 00 d' M V7 lp M N M CO M ~ 01 V7 d'
O a1 ~n d' ~n l~ ~ I~ GO .~ ~n l~ 00 ~n
~_ o N ~ N ~ ~ M o ~ o o ~ o ~
~ .Md.. M ~ ~ ~ 00 O
N
M M
by b4 M ~p
N
Co 00 ~ d-
d1 01 ,-i ~ M o0
U
o ~q o ~ o o ~ 00 0 ~ 00 0 ~ o pa o
0 0 0 o mr, o ,mn o 0 0
w ;.o"' w ;.o"~ w w . ~ o, w . ~ a, w ~ w ~'-' ~ w
P., ~ a, ~a a~ a~ nmo A-, an ~ p~ en p~ -d P-~
o ~ °
a~ ° ' ~, ~ _ c~ '
V ~~ x c~G ~ x V '~ ~ '~ CMG ;=i ~ ,~ ~~ '~ x ~~
N N ~~ ~ O
~ 'd rw ~ ~ '~ ~~ ° ~ '~ O '~ s-. ,~ 'd ~ v~
x ~ o x ~ o x-1x v ~x ~~x ~~ x ~.~x
~ ~, ° ~,
~~ ~ .~ w U o
w o ~ ~, ~ r.~ ~ ~, ~ w o w
a.~ ,~ ~. ø, ~ w ~ s~, ~ a~ ,.~ a~ v~ ~ ~, v~ ~ a1 ~. ~, -~ a~ ~. as ,~
N W N ~ ~ ~ W ~ W N (~ N
_ ~ _ _ _ _
ri ~
x~~ ~',N~ x~ xCV ~ xN~ xN~ xN~ x
I~ 00 01 O ~ N M d-
~n ~n Two ~ mo
d" 'd- d' d' M d' M ~h d' d'
D\
~O N N M N d' ~O N o0 00
M O l~ O t~ 00 ~D
~O V1 01 ~ 00 00 d' 00 O
00 0o I~ N o0 O~ ~n l~ O o0
~n l~ ~n M ~ O ~~ N ~-~ N
d1 ~ ~ d1
01 d' ,--~ .~ N ~ d'
~t W ~, ~ f~ ~~.., U O
x x ~ ~ a a a
x ~x x x x x
349
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d' O ~ d' 00 ~ ~- I~ ~O ~f1 N V1 V7 M 01 M M V7 01 l!7 d'
N a~ O O~ ~n N N M l~ ~ oo O~ ~--mn N ~ ~ ~ ~O O O
~O N N M l0 ~p d- d~ N d' ~~ O d- ~ 00 \O OWn M V7
d' ~ M N a1 O ~ ~ ~ 00 O~ O Go 0o O l~ N M M W 01
N 01 N O1 M ~O ~O a1 v~
M ~ N N d- N dw--~ N ~ O M N M ~ N
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
'~ \ \ \ \ ~'~' \ '~: \ \ \ ~ \ \ \ ~'?
~W O O O O O ~O ~O N N O N ~-' ~ a1 I~ r-' d' O o0 00
01 00 O 00 d' ~ l~ M d' l~ M l0 ~ 00 00 01
N M r-, fx.~
U ~ ~ ~ o ~ '~ U
-' ~ I~ ,--~ ~ ,-"
00 ~ d- 00
~_bA ~ N N oho _bA ~ _N
l~ pp N d' ~ ~ ~ p
d'
- ~ ~ ~ ~-.' o ~ o w '~ °°, ~ o M .-. ~ o ,~ o
V7 ,..1 Q; t/7 M '-' _U '"'' C_O M '~ O 01 ,-~ l0
O ~d~'MO~O oO~o~oO~d~-NN_O
bJ) o Q., ~ ~ bn d f~., N f~ ~bA ~ ~ bD O p-~ ~bA M ~ bA l~ p
U U O O
_~ ~ ~ ~ O
''O l~ ~ N N
U U ~ 0 ~' cct ~ cct ~ '~ O
c~ t~, v~
n O bA v O bA O
O ~ .N r-i O W--, O ~ .5~, b0 ~ ~ .5~. O b-0 . '~' Sw"
x ~~ x ~ x O ~ .H ~ O
N O
G1 z3 ~ P-, '~ ~~ P~ oo ~
O O N O ~ ~ N O
N o w ~ o ~ rte, ~ o ~ °
i, ate, '-' ~ ~ a~'.~ ~ ~ p.~'., ~x C~~x ~ ~~~~ ~Ts aw..~
N ~ W N W N d' R~ d-
N
cat ~ ,-mt c~ ~ .-~ c~3 ,-~ c~ c~ ~ ,--~ c~ cd
x N .~ ~ x N ~ x N -~O ~ x N ~ ~ x N
a1
01 \O O lp \O N ~ M ~O
M d- d' d' d' d' d' d' d'
O _ oo O N
due. d_- ~ N M ~ N
N ~ 0~1 0~1 ~ O 001 0~1
N O O ~ .-a ,-a O O
01 ~ ~ d> ~ ~ ~ Q1
O .-i
x
x x x x x x x x
350
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
V7 00 ~ tWO vo t~ N ~ ~ ~-i o, ,-~ ~n o ,.-~ ,~ t~
00 N M O \p lp M M ~ M N V1 00 ~ M V1 t~ 00
t!7 t!7 ~n ~O 01 01 d' V~ ,~ ~~ ~n d1 ,~ V1 ,-~ N '~.
D1 01 d' M .--W~ ~~ ~n N ~ ~ I~ ~ N N o0 ~ l~
0o M .--~ O N N ~D d' N ~ oo ~n ~O ~n d-
N N V1 00 ~O ~ 01 O M d- N d-
o ~.,~ o o ~p o 0 0 0 o p1 0 0 0 ,.~ o ~ o
o0 d' 01 \O d' l~ M o0 O d' ~ 01 ~-, t~ d" t~ ~O l~
N M d' t~ M WO 00 ~ d' ~ 00 ~ 00 ~ 00 M
op M N ~ '~ ~ N
O ~ ~ N 001
~ U ~ - Wo
U ,-~ U M ,~ ~' .-. ,--.
a ~ o ~ N a Pa o Pa
w ~ w ~ w ~ .~ 01 w ~ w :°
an w a~ P-. a~ p-, en bn o w 'a w ~
°
°°~° .~ .~ ,-o o ..~ o
C~ l~ V ccf . ~~,..,' ~'' ø'' O x CCi x cd ~, cCi
L7 ~.N ap ~ ~~', +~ ~, ~., ~ -~' a v~
O 'CS ~ ~ O ~ (~ ~ ~ v~ ~ U O ~ V O w °
"d ~ ~ , p "d ~ ~ ~ 'O ~ ~ "C~ r~ ,~ T3 r-~ ~-'~
x tx ~ ~ o°°o ;.n ~ ~ o x ~ o x o °
~ U a~ l~ ~ ~ w ~ ~ w M .~, r~ o ~, ~, a., O ø, ~ a, O x
..~ ~p ,~ p .,~ pp O O O
o ~ .~ ~ ~ w ~ ~ ~ o v ~ o y ~ o
° ow ~r"xw ~ o w ~.-~ ~~ ~, ~w ~ ~, ~w ~
x N ~ x N ~ x N ~ ~ x N ~ x N ~
O ~ N
t~ ~n ~ t~ t~ t~
d- d- d' d- ~Y d'
d
Q1 N l~ N
00 lwY ~n N
0o t~ l~ O O l~
d' d' 01 d1 O 01
N ~--~ O O ~ O
d> ~ Q1 ~ O1
H
x x x ~ x x
x
351
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O o0 00 01 ~n l~ N N -~ ~ .-~ o~ o, ~ .-. ' ~ o
00 r ~ M ~ o d-
~1 d' ~n I~ 00 ~ O M d' d' N O V~ l~ N
~n M t~ ~ a1 M
~Y M ~O ~O N I~ O ~ M M O~ N M ~ O
00 ~O ~O ~ O
N ~n ~ M O N O O~ ~ ~ l~ ~O ~ O~ O~ M M ~O o0
N N O O l~
M l~ ~ N N 01 O o0 V7 ~n ~ M ~n lp tn
O W O V7
d- v~ .-, l~ oo O t~ ..-mn
oo ~n ~ O~
0 0 ~ o o ~ ~ 0 0 0 ~ ~ a ~ ~ o 0
0 ~ o o
O1 N O N 01 l~ M N O ~ M -~ ~ <''~V~ O ~ O
v~ l~ oo N N
~O l~ ~O l~ d' V~ d' N M V~ M lfl ~ d' in m n
~O d' 00 N M M d'
N d' O N ~ Ov
O ,-~ d' N ,-,
01 ~ d1 d1 N ~ - M
~O ~p N ,~ ~
O m O ~ O ~ ~
"~ ~d Mp O .D
" ~ p
~ '' ~ ~ w ~ N
P-~ P-, W Q,
N N
by
U ~ ~
~
_ ~ ~ ~ P o U
w N
~ ..~
+~ v~
N
~' U ~ .-w
~ ' " W
C ~
N~ ~ ~~ ~ ~.N ,-,= ~
~~
~ r~ ~O ~ M N ~ N
U ~~
a-,'_' w a~ N , a~ ~r _ w o
U ~ o ~ ~
.
o o ~ o
~zsH
~ . ~~
w ~ ~ w ~ w ~x ~ ~ w
~ ~ ~
~i ~I U U ~ 'J ~1y p-I ~.r ., p-1
~ p..,fn a ~e \
~ P-I
.
~ ~ ~ ~ ~
N (.. N ( N Z.~ N
L~ [.
N ~ ~ n--i~ ~i .t ~' x ~
~ N N
M ~- V7 lp
l~ O I~ l~ N l~
d' ~n d' d- in d'
00 ~n
d' 01 00 M d1 01
Q\
l~ d' 00 M O 01
01 ~ Q1 d' ~ 01
N -~ O d' ~ O
a>
O N
r..., ~ ,-N~ N N
352
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M ~ ~ 01 V7 00 O M N ~ '-n d' V) O \O 00 01 l
w o0 N ~n ~n ~~ o0 01 d- d' d- ~ d- ~ ~ O~ N v0 ~O
c~ M O~ d- M N ~n M .-~ N N d' d- d' ~ ~ oo l~ t~
.-i ,~ N
Q~ M ~n t~ N M oo ~n O~ oo d- oo l~ ~o M o0 00 ~O a>
M 01 d- N d' ~ d1 00 ~ M 00 M ~ lp l~
<t ~ O~ ~ N N N N ~O
0 0 0 ~ 0 0 0 ~ ~ o ~ o o ~ o 0
O d- N ~ M N d' oo M M O O N oo O~
M ~D tm0 M 1n N M vD M ~ O o N OW 1 N
.--~ M
_ ~ N~
M
O a O ~ pp ~ op
N~
d- N
oU~ ~U cmn~ ow'~I~~c-mn
--. , .-. d- U o ~ v., o ~t-
a\
o d °o o .~ °o o ° o °o
w ~ ~.., w ,.fl w ~ w ~ a, . ~ ~.~, w
0., tin ~ p., bn p., a~ ~., ewo an ~
-..
~n ~
~U a~ °; U
,~~ ~x'n ~, ~N
.
"''_ '_" o ~ H o UP'~..~o v~~~ ~ ~.~ ~oUv ~v
.~ . ~ a~
~~-~~~~d p, ~ ~ ~ °r°, o o~'°~''~ ~~;o~ 0 0 0
c~ °1 .~ a'' P~ ~ ~ ~ W o o x ~
a~ W o ~' .~ ~ o .-. ~ ~ ~, '~ a, ~ oo can
w ~.~ ~~~ ~ o ~ ~ w ~ w'~ ~s
~~~a~-~aw.,.~~ ~U a~'.~ ~'~-d~ ~'~xaw.,;x~ ~~:o.~aw.~
r~ d- ~ ~ ~ d- r~
W N W N W N
ri ~
x ~ ~ ~ x (V ~ x ~ ~ x N ~ ~ x
l~ oo O
~n ~n d~ d' ~n ~n d'
a1 a\
0o a1 0o M o ~ ~n
v0 d- ,- M ~n oo d-
d1 M O 00 00 M O
~O N O 01 (~ cn
O N ~ O M -m O
Q1 ~ ~ D1 d1
W ~O ~ ~ ~ M
U pa ~ ~ ~ ~
x ~ x x x ~ x
353
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d\ V7 N O o0 O O ~n N ~ l~ M ~O O M M ~O l~ M O
N O r-. ~n ~ ~n N
t~ 01 ~n d' N O t~ N ~O l~ 01 M O 01 N ~ d' t ~n ~O
~ l~ ~O N l0 ~n ~W
M ~1 ~ M c~ M O l~ ~ V7 M N O O N
M V~ l~
d> ~ N N l~ N t~ N (~ O ~n l~ N N I~ l~ 01 M M
d- d' N M l~ N d'
CO O ~O N ~n O M M N d' a1 ~ l~ M N ~O oo 'W f' l~
M M O N M 00
V7 .~ 00 01 M V~ ~ M M N N ~ ~ N ~ M 01 01
01 O\ 01 V7 M
ooo~~oo oooo~ooo N ~o ~o~ooo ~
l~ 01 M oo O~ ~O O (~l O oo ~ d' N O p 01 O
V'~ N N ~ N M N d- d'
o~ ~ N ~ N a~ ~O O N O ~ ~ o~ ~O M dwn m oo O
N N M ~ N M ~n
~
N
M \O
~ ~ M .-fl
M
y n w ~ l~ d' N
M .--i ~ 01 M r, ~ M
o '-' o ~ ~ ~ '_" dM' U o
~ '
0 0 . o
o
0 ~ ~o o cn
~ ~
bD N bA ~ p-W bA bA ~ P-i N
N
i
U
0 1a U Ga
N ~ N ~ ~ N
, U d' ~ ~ cCi
~'
, i-~~, ~ ~ x '~'~a
~ ~~'r .~ ~ ~ 1 V]
~ .~
n
.~v ~ y ~ ~ ~ o ~ U
~ ~ y ~
s
U U .~ ~ . .~
a' v~ c~ U . - s ~
~ ~ v~ ~
~
-. ~ .-. ~ ~
o ~no ~o -~ ~, . 0 ,
~ a~
~~~,
~ ~ ~ o~ 0 0
~ u, o ~ ~, o W ~ ~ 00 ~ ~ P
o
0
~ ~ ~ ~ ~
~ w "~ ~ w '~' ~ r- U ~ o w
~ '~ ~ o
~
~ ~ ~ ' ~x ~
~ ~ a w
: ~, ~ >
a
,
~ ~ ~ W
N ~. N N
L~
-N ~
-,~ ~ oo ~ ~ ~ ~
o
N _ ~ r~ ~ ~ o _
~ ~ tr-ii..O
-1
N
00 00 01 0o O
in v'~ d'
a>
M ~ d' V1 00
~n ~n N M O
N N N o0
d' d' ~n D1 Q~
l~ l~ ~ O O
D1 a> ~ a1
N o0
W
W
x
x x
354
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~n l~ N M M ~O M \O N d' ~ ~ 01 l~ Q~ d'
~p \O ~ t~ d' 01 O 01 M d' l~ ~O ~~ O ~ V7
M d' l~ ~n ~n ~ M d- d- ~O t~ N N N
~!'1 V7 I~ 01 01 M V1 '-W~ M O N l~ V'7 .-i Ol
l~ l~ O O d' O d' M N M N ~O d' ~-~ ~n 01
N ,-~ M ~ ~ .-~ ,~ ,-, 00 00
0 o pp o 0 0 0 ~ o o pp o ~ 0 0
M \ \ N
~ o0 ~--~ ~ O o0 d- O d- I~ N ~ O ~D
o, o~ ~ a, M ~o ~n M ~n v> ~ o, M o o~
(,M~ - ~ M
pp N
- ~' ~ -
N ~ ~ ~ ~ ..O
d' ,-, d' l~
M ~ _ ,-, ~ M
pp O p ' ' O ~ ~ O U O p ~ a1
O~ O l~ 00 O ~ ~ N O ~ O _ O ~ N d0-
-,w..o.~o,w ,.fl.~oow ~ w ~ w~N...
O1 p1 bl7 bA O~ p-~ by by ~ p..~ N p~ bA G~ bA ~
~ ,-, ~ n
s-~ s-~ ~ ~ ~ ~ r--~ 'd
~' .~ ~ ~ .~°,' .~5.,"
U ~ 00 U o0 O ~ ~ p"~ 00 O ~ x ~ ~ ~ ~ x ~ cn P-~ 00 O ~ N ~ 'C3
.bA ~.,-~01~ .~bDal~.~~ .~ .~~ .~ 01~ N~v~
a1 N c~ ~ N .,~ c~ ~ U ~,~ ~ a3 ~ N
O p ~ N O +~ .,-. N O ~ O +~ ,~ y~ N +~ ~~ N O ,-~ N O '
o~ w ow~~ ~'~w, ~ ~ ~ ~~ . -~~ ~v~,x~ ~.~w
° w ° ~ ~ w
~.' P..ms ~' wr ,-~ pw.r .fl ~ ~ s~ f~ P1 ~ ~ s-i P-i ~ ,.W r N P-~ ~ Q, vWU
N ~ (~ N ~ W N ~ N W N
-N
ri
M d' ~n ~O I~
00 ,--~ oo N o0 00 00 ~n
d' ~D d' ~ d' d- d'
l~ 01 O
N M O N N (~ M d'
N a~ ~ M N M ~W D
~O ,~ oo N l~ oo .-~ d
N a1 N ~n N N ~O in
O ~ ~ .-i ,--i \p
d1 ~ d> ~ d1 d1
N v~
O1 N
w
x
355
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d- d- I~ ~n oo d- ~-~ ~ 00 o N ~ ~n o0 0~ oo ~
01 p1 M l~ ~ O O t~ 00 lfl N M M N l~ 00 d'
M M l~ O ~ ~~ ~ ~ lp o0 N O\ O 01 ~O 01 V~
H
O a1 ~O l~ l~ a1 M l~ ~ ~n ~O H N ~ I~ d' O
H oo O~ N O N N 01 0o M t~ ~n d- I~ a> ~ l~
M ~ ~ t/7 tn H ,--i d- O d' d' ~ d' a1 M
0 0 0 0 0 0 0 0 0 0 0 0
M \ ~ \ \ \ M
~ M o0 00 ~ O O~ O ~t N t~ ~ M
01 l~ l~ l~ N Do ~ 00 01 01 ~ 01 d- ~ ~n
N H
~I
.-i _ l~ ~ ..fl
M ~~ d- .-N~ ~-'~ O
N Hb-D ~O d- 00
H ~ pp H M H ~ ~ ~ ~O
-_ o ~ o o ~ o U ~ ~ o U c-°1n o
o °~~o ~C °o -fl ~~ °o ~ p°-..,q °o
' bn ~ Pw-~ 'ion Pw..~ ~ ' on o ~ ~ ~"' U Pte.,
°
O ~ O ~ ' ~ L~
f,
o ~ o ~ ~ o ~ o .°~' ~ F"' o °? A"' O p",
°~ ~~O~a~~~ a~~~~O~aO~~~O~~~~~~f~f~°
~ N s~-min G~ s.~, ~ ~ ~ ~ ~ ~ ~ ~" W .Vs .~ P~ .~,' ~ ~ ~ P~ ~ a
N ~ (~ N W N ~ (.~'L~ N
k
H ~ r-1 ~N
r1 CC3 CC~ ~ CC3 00 C~ CC3 CO CC3 CC3 00
x ci ~ ~ ~ ~i ~ x ..-~ ~ ~ x ,--a
0o a, o H N
a, ~ a, a, a1
vo d- ~r ~ dwo d-
d' M l~
l~ 01 V7 N M V7 O
N l~ M M \O H 01 O
01
l~ l~ ~n N l~ N 01 N
O .-~ M ,..._, H H
d\ ~ ~ ~ H ~ ~ a>
H ~ ~' C7 Ga
'~'~ W r.~ r~ W t~
356
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d' M M [~ O ~O l~ \D O 00 O d' ~ d' d1
O~ O O ~ oo ~ ~n N a1 O N oo N N l~
~wh dW v0 ~ ~O d- ~O d- d- ~O l~ lwt
d- ~O ~O l_~ N o0 <t d' t~ ,~ oo O~ ~ N M
~ o0 '~ oo cT O~ N~ a1 ~ gyp.. N N
o ~- 0 0 o M o 0 0 ,-, o o ~p o 0
N \ ~ \ ~ \ \ \ N
M \O \O M N I~ ~n t~ M ~' a1 O
01 l~ 01 ~ l~ O~ d1 N~ d1 01 N 01 O
~--~ M ~--t
N O
H
H I
H ~. H ~ M
O M N O ,.fl ~ .d.. ,..fl O
p ~_ l~ _~ ~ p bA ~
M l~ CO
l~ N o0
U o ~' o ~ ~ ~ o o U o
O ~ ~ N p f~ ~n d"' ~ ~ O ~ p ,
;~ w ,~ ~., ~ w ;.n'~ .'~ ono w .~ w
a~ ~, en ~ ,-. p.., -d un ~n P-~ on P-~ a~ ~ bn o
rn 'd o
.~, P-r ~ ~ N ,7., ~ N ,~ ~ ~ P-~ ,~ ~ ~ P-i . ~ ..,~~0 O
o ~ ~, ~ o ~ ~ r, ~ A-' o ~ ~ Gq ~,.~ A-' o C7 f~ ~-., P'' o y C7 N
° ~ ~ ~ ~ ,-~ ,-V ~ cps cd ~ ;' ~ ~ cd ~ ;' ~ cd ~ ~-; o
~ o w ~ ~ ~ H H ~, o ~ ~ x ~ ° w ° ~ ~ ° w °
~., '~ ~ 'r ~ ~r ~ ~ P-i ~ ,~ ~ ~ ~ W r ~ a W s .~ ~ 4-mr S~, w
N~.,~T,.~N~WN~~NWN
c~ ~ o0 cd c~ ~ oo cd cd ~ o0 cd ~ o0 c~ c~
H ~ ~ x H
_ M d'
l~ d' l~ ~ l~
N _\O
O ~ M N ~ V7
.N-~ ~ ~ N dN ON1
N O .~ ~ ~O O
a1 H ~ H ~ d> H
O
O pp
O Q1 00 H
x x a
o ° ~ ~ ~ a
x x x ~ x x
357
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O ~ ~ ~ d- N M d- ~n M o0 ~ t~
d' ,~ r-.~ ~ 01 V1 a1 ~ 00 ~ M O O
M M d' d' v7 d' V~ ~O ~O ~O M d' d'
N N M M D1 l~ 00 d' M M N M M
N a1 N ~ ~ ~ O
cal N N
'":\°\°~\°\° ~?\ \ '~ \°
0~1 NOOOOO~o~ N0~1 O ~ 0~1
U ~ U
-, ,~ '~ N
l~ ~ dW
00
~bA ~ p bA
O od-o 'O N N ,--yn
M ~ ~ ~ M
o'y ~ ~ ~-~ U o- ~ ~ ~ U
O N
M O ~ 00 o0 O O d' ~ ~ ~ d'
P.~i b1~ 01 f~, "O b1J N P-~ b4 bA ~ P-, "O bA ~ P-i
~w bn en
o ~ ~ ~ ~ ~ o ~ 0 0
O ~ N ~ ~~ ~ ~ ~~ ~ O ~ ~ O ~ ~ ~ P.i
~ P1 '~~' ~ ~ Q-, cd ~ p.., cd x ~ ~.~.' 'Tu' ..~~ H
~ O LJ N 4~ ~ N FU O 4~ CJ O
M c~i ~ ~ ,..~0, oS ~ ,~p, tn O c~ ~ O (1, ~ c~ ~ i'
V7 A-I O ~ v.1 M a ~ M O ~ ~ O ~y ~ ~ ~ V7 A.i (~
~ bn ~' ~ ~ N o ~ ~ y-' ~ 0 ~ ~ ~ 0 ~ ~ ~ ~ ~ '
o ' ~ a~ ~ ~ a~ a> +-' ',
~ ~'~w~w~ ~ ow~~ w~~-~w~
~ ~r ,.o ~ ~, v~ P-~ ~ a ~ Ss, P-~ ~ ~e Q, v~ P-mr ø, w vW, w G-wr Wn
d- ~.., d- ~ ~ ~-,
N (~ N ~ (~ N ~ W N .-~ W N
_ ~ _ _
r~i N ~ . ~ ~, N ~ ~ x N
~n ~O t~ 00
dl ~ ~ al ~ d1 ~ a>
d' l~ l~ d- l~ d' l~
O O O
N ~ .-~ O 01 00 01 l0
M ~ d- 00 l~ N O M
0o I~ d' tn d' ~O o0 00
N N M N ~n N l~ N
,~ ~ O ,
d> ~ ~ d1
_~ U U ~ ~ O O
W
x x ~ x ~ x
35~
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
t~ ~ ~ N N l~ l~ .~ ~' N ~ O O oo ~ O ~ M
t~ ~O 'O l~ l~ N N o0 l~ 00 M ~ dw0 ~n d' d' M
~O v0 v0 00 0o d' d~ N ~ M ,--~ N M l~ I~ d'
H
d' ~ M N N O O~ dlMVIOMOO~Ip N M
~Wn d- O\ \O ~O l~ ,~ M N O\ N d- M O ~ 01
H N N N ~ N .--~ N M M M D1
0 0 0 0 0 0 0 0 0 0 0 0 0
~ \ ~ \ ~ \ \ \ \ \ \ \ \ \ M
O O O d1 - O M ~O O O H M v7 H l~
O M O N~ a1 ~ O ~O l0 M I~ i~ 00 00 (~ O 01
N N
O N
0o O
a1
M ~
H
O ~ ,_,
_ _ ~ _ _ _
M
N l~ l~ l~ N I~ l~
o U o o ~ ~ ~ o U o
a~ H o ,~ o ~ o N o o .~ °o
w ~ w :~ w ~ .~ o w ~ w
bn o P-, a~ a.~ -cs w bn bn ~n a.~ a~ p~
cd
° ~ ~, ~ ~, w N . ~ ~, w bn ~ ~ ~ ~, w
0
~t ~
-, ~, rx ~ wo w
C7 o r, w d.
a~ a~ ~ ~ ~ ~.,~ ~ p y
°c~ ~ w ~w~~~~~x.,o~ ~o~~ , ~~ wo~~ow
t~, vW -a P-, s., P.~ ~r ~ ~r p..~ a ,~ vW., U -~/-i i-i s-i P-i ~ ,.D w.r
Cd ,~ H CC'S ~ 00 CC3 00 CC3 CC3 OHO
xN~x~ ~ x~ ~ ~ x
a1 O ~ N
01 01 O H N O O
d' ~n o0 00 ~n ~n
~n ~O N ~--~ ~ t~ o0
0o t~ ~ oo m d' ~n
N t~ oo N ~O O~
~O N N ~ l~ N M
H ~ ~ a>
a1 Q1 a1 d> O a\
N
v-, ~ ~ W ~ ~ W
r~ ~ r~ x
H ~ H H
x x x x
x x
359
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
00 ~t ~ N ~ ~ o~ oo co uo O ~n M O~
l~ ~ N l~ oo a1 Ov O t~ l~ Qv t~ Ov ~
d- O OWO O~ N N M N N ~O d' d' ~
M M d' O t~ N M ~ ~ d' V1 lp l0 l~
<71 01 lp Q1 M d' ~ 00 V7 00 .-~ 00 l~
01 l~ ~O d' D\ r., d-
0 0 0 0 0 ~ o o '~ ~ o ~ 0 0
00 d1 d' V'7 V'1 ~ d' 00 ~ O d1 ~ d1 00
01 , -
pp O
_00 _ O
N 'O O
01 N
~n~0~~ l~~pl~U~l~
o ° U M ° ~ ~° ''_' °
O .~ ~ O O
"'-' ~ N o
Pte., ~ ~. Pw-.. ~ ' bn o° P~-,
A-, '~ W L'7
O , ~ ~ ,~r, E~ ..fl
p_, O ~ '''' ~ o ~ Z ~ ' ~ p,, . ~ H ~ ~ P"' v
~, p.., ~, N 4-W, by ~ 4-a ,.. ~ ~ ~ O H
-' ~ P-.ms Q, .~ ~ ~,' ,-, cn O ~ ~ ~ c'~~ yn ~
N~~ ~/~W. ~OU ,~'_,~., M~~~uU ~, ~u..-U,
S-ate" bA ~ ~ ~ ~i
.-r ~ ~ p N .i.., .., ~ ' 4j U
o ~ w o '~ ~' v' O ~ ~ .° ~ H .~ ~ ~ ca o .9 0 0 ~ o ~ ~ 0 0
wU.r .~ ~ ~ v~ ~ ~ ~ ~ ~ ~ ~ 'd ~ a U ~ ~ ~ U ~ ~, ~' ~ a ,-fl ~ Q., ~'
N ~ W N ~ W N ~ (~ N
0o cat cct ~ ,--, cd cd ~ .-r cd cd ~ co c~
N ~ ~ rx N ~ W
d' O W O ~O O
00 ~n oo m oo m
a\
O 01 N N N l~
d' ON1 ~ ~ N v~o
N N N N 0o
N ~-~ N ~ ~ M
W
w w ~ ~ ~ ~C
x ~
360
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
l~ ~-~ l~ O ~ ~O N N 01 O~ O M t~ M O ~n ~n ~
d- ~ ~ N ~D ~-~ ~O ~ 00 00 .-y~ ~O o0 ~O M wn
I~ O t~ l~ l~ Iw V'7 V7 00 00 M M ~ d' ~-~ M d
N d- ,-yp .-, o0 .-a ,.-y~ d- N .~ O ,~ O ~n M
OW t o~ o~ N o0 0~ t~ ~ oo cT co ~p M tW O O
M l~ M M l~ M N ~ M d' ~ N ~
0 0 ~ o o ~ ~ o N o rM, o o ~ ~ ~ 0 0
t~ d' wn to N ~"' O ~ O ~n 01 l~ O M o0
01 CT ~ 01 l~ d1 ~ O~ N O oo t~ oo l~ N d' M
d-
- -
a> ~ ~ ~ v7
d
O
N M ~ d' .~ 00 00 ~ 00 d1
d O ~ N uj O ~ O ,~-,..~ O ,~-,~ O
w ~ . ~ a, w ..o w .~ w ro w ,.fl
P1 tin bn a\ a~ an a~ z: as ~a p-~ bn
a, o~.~ a~ ~ ~.~ o ~ o ~o
~ (~ .~ ~'"' a ~, ~ ~ ~ ~ ~ ~ ~ O V7
00 ~ ~--, ~ ~ ~ v~ M O U ~ V "'
~., ~ N ~ V ~ ~ V A-i ~ x Cl~ M ~ C/~ M ~ .-~,
..~ .,-r lp ~.,, _~ '~''
bA N 47 _~ _V~ 4-~
"O d'
c~7~~~~;~~ ~~~a~~ ~~
N ~ (~ N (..~T~ N W N ~.T~,.~ N
x c~i ~ x ci , ~ x '--~ ~ x ,--~ 's
a,
t~ 0 00 0 0 0 0
a,
d- V7
~O M N ~-~ N ~ M
O ~ 00 00 d' ~~ ~O
00 d' o0 ~n o0 0o a1
N N l~ N N M ~n
N l~ .-i ,--i ~ \O 01
d\
~ M N ~ t!j
r~ M ~ ~- z
U
361
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
t~ ~n ~ .-, o
o ~--~ 00 0~ ,-, o~'o ~ O~1 ~ ~ N oho ~ o
M O l~ l~ ~ l0 M M V7 lp 00 d1 V7
~O ~--mn M O~ ~n d- N d- N M ~n N l~
M r-' ~--a N d' ~D .-~ ~ d1 M d' O 00 00
tn lD l~ d' N M l~ CO M
\° ~ \° \° ~ \° ~ ~ ~ N \ \°
O\ ~ M M O N ~ ~ ~ N ~O d' O N
VWO 01 01 d' O~ d' d- e!' 01 l~ O ~
d' p ~ ~ N
d-
00 00 O r, 0 00 ~' 00 00 00
w ~ 00 - ,~ .-, r-,
O~ 0~~~'';O~ O VOOO'-'
O (~ O ~7 [w ~ M O ~ O O O ,
r-°~ 'o'-' r-°~ ..fl o ~ ~ °w ~ r.°~ ~ °w
°w
P.~ ~a P-. bn M an o ~, bn P-. a~ P-. A-.~ do ~
by N ~ ~,' O ~ U ,~ pp U ~,C,' '~",' v~ ~ bD
Q, . ~ CC3 ,. .S", ~ ~ O
o 'rr, ~ bA ~'" ~ W U ..fl W tU-~ sU-i '~ ~ bA r-.,
C/~ M V~ ~ T/] ~ ~ ~ 3~ C/~ M ~ i"'' C/~ O ~/~ M Vl M ~ ~ ~'',
, ~ O . S~ S-~'" _M ~ ~,' . ,~ ~,' ~ ..-, OM ~G U
o ,_, w o ~ ~ ~ w ~ o x ~ ~, o w o ~ ~, o w ~ w o w o ~ a~
4-~ N ~ "O a ~1, v~ ~ ~r U a 4-~ ~ U P~ "O ~H ~ U ~ P,i 'd G~ "T~ a ,.fl .,
N W N ~ (.~I~ N W N
~, ri ~
~i~~ r~N~ ,~ r~~~ ~N~r~'~
O
N M d- ~ v~ ~p ~ 00
a1 ~ d1 ~ d1 a1 01 a1
O d
d' ~ ~ N oNo oho M N
M ~ O M l~ O l~ v7
.-i 00 ~ 00 01 V~ N l
O1
d>
M
H M ~ CO ~ V7
w a ~ ~ a x H
~_
U ~ U
x
362
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~O Q1 M O M O 00 M O d' M M l~ l~ l~ M M N ~--~
~ 00 O l~ -~ M
~p 00 .--i O M ~Y l~ .-i d' M 00 ~!7 N l~ V~
~O M ~ ~ M 0O M N M 01
d- M M o0 0o N l~ ~n N o0 ~O ~ ~O ~ I~ M co
t~ l~ N ~ N N N
l~ ~ d' O O M o0 O ~ N M l~ d' M .~ W~ I~ ~D 01 M
l0 ~ d d d' l0
N ~O d co ~o O~ ~O O~ 01 N t~ O ~n O t~ ~n oo N
d- M M ~ ~ d- ~n N
M M ~ l~ l~ ~ \O '~ ~ I~ ~ ~ l0 \O ,--.~ M d- ,--W~
.~ ,~ ,--i ,--,
o ~ ~ 0 0 0 0 0 0 0 0 0 ~ ~ o o ~ ~ ~ ~ o o ~ 0
o o 0
V'~ oo O o0 ~ d- lmn oo N a> N ~n ~ ~O d- O~ ~O
,~ ~n o0 00 00 M \O
~ N ~ V7 M M dw un d- N <t M M M N d' av d- ~n d
M N N N M
N
aA
~ N
_
O O .-_,
O
O
bA bA N
~, N
~J ~.,
_ ,
O .,s0-~
'~
N N '~'
~ ~ . 'T' O
-!'
O
~'
. ' . by ~ ,~
~ r
~ ~~''
a
x'' _ N b-0 ~' ..~
I~~ c~,
C/~M V7cd c~
~ yn
n ~ n s
.
N .~O O . ~ u,
~ ~~,
. ~ w . 'd U O
p ~ ~
0.'
,
~f'
N .-,
a1
a1
v~
M M
O
w
U
U
x
363
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M N O ~n N ~ O~ ~--a M O ~O O ~ N 01 l~ 01 0o
~-a d' d' m N ~ o0 00 ,~ ,--r ~ ,.~ N N d- v~ d' d
M oo d' N N ~n ~-a d- ~t ~ Do O O M d- t
r--i 00 V~ V1 M a1 N O d- ~--~ M .--i V'1 ~ 00 00 O d'
00 l~ d' ~-~ d' ~ 00 d' ~O ~ 01 d' d' ~ ~ O 00
O ,~ d- .-, ,-, ,-. ~ N ~ \p ~--, p1 ~ r.-~ \p
~ \° \° \ N \° N M ° ° N ° \°
M \° l~ °
o d- .0 0 o N o ~ ,_, ~ ~ ~ ~ o o O
M lp M M O M O ~ M '-'a O 01
~O ~ d- ~t N ~ O d' iN t~ O N ~O m N v~ ~ M
O
U
p ~ ono ~ ~p t~'n
N oo N .-N-~
M
00 ~ oo . o0 00 ~ oo ~ N N .-~ o0
,~ ,-.
o ~ o U o o U o U M ~ 00 o U
0 0 0 0 0
r-°~ .~ °w ~ °w r.°~, ~ w ~ r-°~ ,~ ~ w
a-~ on a.~ ~ a-~ a.. ~ a., ~ w en o a.,
N
V V N U
bD'A ~ ~ b~'A ~ ~ O b~'A b~'A 'a ~p . N ~~,' V> ~ 9,
Oca..~,~ 0~~,~,~ O O ~O ,~~,~~~~~ O
O ~'., ~ O O W ~ O O O O cd O ,-~ O OO O
~ x
0 N v~ ~ h ~ a
~
~ "C3 ~ ~ ~ ø' t.~ ~ oMO O ~ N ~ ~ oMo
C/~ M ~ ~ C/~ M N N ~ M C/~ M ~ ~ C/~ M \p ~ N ~ C/~ M
N ~ U ~ ~, '""'
~ ° ~'~ N ° vs W
w o'ø.,~ °w oa ~WW~~f-~~ oG~=, o ~~w o'~ ~f-~~ U~yf~ oa
w ~ ° ~, x a~ -~ ~ ~. L'7 C7 ~ ~, -d a~ -d ~ ~ a~ ~s ~ w ~ ~ ~ a-. ~ ~
N ~ -~C W ~ .'~,~ W .~C ~ _ N ~ -'~~
cn cn vwn . cn v~
00 ~ 00 ~ 00 00 ~ 00 ~ ~--~ Cd 00
-fl ~i ~ r~i ~~ ~ x ~-~ ..fl r-~ N
N O ~ M M d'
O O .-~ O O O
N 'o l~ ~ M N o0
N N
d> Q1
N ~O O ~ N O ~O
a1 O1 ~ al a1 a1 a1
N o000 ~ ~ N M
U w ~ ~1 w aU.~
x ~ ~ ~ x x
x
364
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O M \O V7 .--~ M l~ O O M l~ l~ l~ M ~--a O ~ I~ '~ \O V~ ~ l~ V~
~D V7 d' ~ 01 .-~ N I~ M ~ M M N M CO l~ 00 N I~ GO [~ l0 l0 M
~t ~n v~ ~ N vO d' ~t ~O ~D ~O d- d' d' ~h d' ~~ ~ N M M d'
M ~ O 01 ~ ~n M d1 M d' N ~n O N N O N 01 O O ~ I~ a1 c0
O\ 00 M M l~ d1 O 00 O O 01 01 O 00 ~ V7 M V7 ~~ ~ O 01 ~ ~O
N N ~l" d- l~ 'O ~ ~O o0 I~ l~ ~ v~ ~n ,~ v> d' N ~ N
0 0 0 0 ~ 0 0 0 0 ~ 0 0 0 0 0 ~ ~ ~ N
00 ~ O \O ~n ~O O a1 O o0 01 ~~ 00 l~ l~ O d' ~ I~ d' ~ N
d' ~ O ~ l~ \O l~ M d' M M d' M M M ~ V) ~ I~ d' ~ 00
U
r., N
--~ d' d- O
00 ~ 00 ,~_, - 00 00 ~~ ,_.., 00
-, N ~ ,-.~
O ~ O ~ O ~ O
M d' M O
R.., by G~ N ~ by O R., N ~, ~bA M P..~
4-i
n O p U n .~
v~ ,_"_, _,-r v~ O O
N N
~ .', s-m, O
~ cd, O ~ ~ p O ~ ~-' S~ ~ '~~'' v, O
,~ M
~ '~ ~ v ~ ~ v~
0 0 N <n 0 ~' O ~ ~ O fT~ .~ O ~ 0 0
C/~ M ~ ~ ~ C/~ M ~ ~ '_', v~ N w ~ ~ U
a N .H, lD a O ~ C/~ M 0 ~ V~ M M " C/~
~O_ ~ _~ ~~ ~ .~ o ~ '~ o ~
° ~ o W ~ c~ ~ o '-a ° ° ~ ~ o O ~ ~ o F~'' ° f-~~
s~,a~~~~~ai~~ ~,~~ a~~~~aa~~ ~a~
.~c
x
0 0 0 ,-t o ,-.
M O~ O N o0
00 .--m-.; O ~-,
O1 ~ dl
d'
d N ~ ~ N
W
H 'U
r~
365
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N l~ M ~O d1 M M 00 V7 00 01 lp M 01
M N o0 00 ~O I~ O O ~n ~O o0 00 00
~' 01 d- d- N d' N t~ ~ N M d- ~' d
d- Iw0 00 ~n M co v0 ~Wn ~O ~ ,-~ N
~ I~ O ~O N O M l~ N d'
00 M ~ ~ .-i V~ M ~O N N M
N N ~-~
o N ~ ~ ~ ~ M o V7
d' ~O ~ 0~1 l~ ~ d' O ~ 01 01 ~ 01 M
M _ ~ N
ON1 ~n O o0
ono ~ ono U ono oHo ~ N ono
o U o o O ~n U ~o U o
°o .-fl °o ~ °o °o °o ~ °o ~ o
w ~ w ,.~ w w w ~ w ~ w
-o a~ ~ a~ bu a~ a~ a~ ~ a1 ~ a~
N
M
O_ .,~ "-'
O ,~', b~A ~ ~.~ c~-'C O bhp ~', ~ W O ~, '+~~
U ~ o ~ ~ ~ ~~ N O
~cd O M ~ ~ ~~ ~ ~ p p ~' O (Z O ~ ~ ~ O
O .N ~ O ,~ ~ ~ x ( ~ O . ~-U-~ .y~",,
O '.O ~ a ,.O ~ w s1 (~ U U O
0 O U ~ _~ ~ ~ .-~~ ~ _ U U U ~ ~ ~ O ~ ~ U
M O ~ C/~ M ~ ~~-~ ~ N ~ ,.M~ O ~ ~ M C/1 M ~ N N ~ N ~ C/1
N ~~ O ~ ~~ O N O ~ U ~ ~~ ~ O ~, ~ W
~~~o~~a~~w~~ wM~~~~~a a~,zz.~~
o ~ ~ w o .~ ~s ~ ~ w ~ x ~ w o w o w ~ ~ W W ~ w ~ w
'Ci ~ a~ ''C< ~ ~ U ~.,'' w ~ ~ C/~ .~.'' P1 'T3 a-~ T3 W r wr CJ C~ vW a P-i
N (.~x~ N (.~i~ N ~,~i.~ ~~T..] ~..~T~ N (~ N
c~ ~ ,-a c~
~ r-~~~ ~N ~ r~i~ r~'~ ~N ~ r~N ~
~n N M ~ ~n ~O
N
N ~ ~n O M
N O oo M Q1 t~
00 ,-.-W~ N V~ v~ d1
\O ~ V1 M \O M M
dl d> ~ D\
O CV M
o ~ ~ a w . a a
x x ~ ~ x x x
366
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
00 d- d- \O Q1 ~n 01 W V7 ~-., 01 ~ O 00 ,~ O N N
N M a1 M l~ I~ O ~ V~ V~ ~ ~O ~n l0 O O
d' ~ O ,-~ V~ ~O d' ~-~ d" d' ~ M N ~-~ M d' 00 00
N V7 ~" ~ M M t~ O \_O ~---~ .-~ ~ l~ l~ 00 V'1 00 O
N mn 'd d d~° ~ ~ M N dN" ~ N
o ~ \ ~ O o o \ ~ o ~ o \ ~ o ~ ~ o
00 '~f' ~ 00 01 00 ~ l~ d' N 00 ,~ V1 \O
a1 ~ d' N ~~, 01 N N ~ d- ~ O~ ~n d'0 l~ d' O~
N
r.,
-i ,-a - ,
lfj _~ ,--~ .r,
N ~ O
N~ ,--, d' O Ono l~
Q1 d' a1 O l~ d1
o~ ~ 00 0o co 'd' oo M r., 00
o U o o ~ o ~ o ~ d-~ o
°o ~ o o ~ °o °o ° °o
w ~ w w ;.fl w ~ w ,~~ o w ;.~'
'~3 P-i N P.~ /~ TJ P-~ bA P-i hA M P~i 't~
O
U
b~A O ~ O b~.p
_+",~~_O_0~00~,~0_i O~O
O0a300 x0~~0,~.~ O
U .°'
p bA ~ 000
M ~ ~ U~ M \p " ~ M ~ M 01 ~ C/~ M ,-, O ~ ~ M ~ ~ C/~ M V7
~, 00 ~ ~ ~, 01 ~ ~, ~, O ~ ~., O p.a ~ ~, O ~.,~ ~
O .,-W..~ '~ d' ...a .,--i O ~i ~, ~,~ M ~ .'r M U fir., .,-, O -S~,
N N O ~4j ~ cd cd O ~4j N ~ O ~ U ~ N ~ N ~ O N
a o ~ ~ ~ ~ ~ o w ~ ~ w M ~ ~ ~ w ~ y, ~ ~ ~ o
o ~ ~, ~ w o ~ ~ w o w o ~ ,~ ~ w o ~ x w o ~ ~ ~ w o ~ ~,
~s ..~. s~, ~ w Ts ~ ~, ~ ~, ~ .J ~, ~ a., -cs ~ v~ ~ w ~a .~ . ~ ~, ~, ~ ..~r
N WN(.~1~WN WN (~N (~N
00 ~ ~ oo ~ ~ oo ~ co ~ ~ oo ~ ~ oo ~ ~ ofl
x~~ x~x~~ x.~~ x~~ x~~
00 01 O ~ N M
N N N N
M d' M 00 00
d" .-~ ~ V1 M 00
00 \O 00 lp ~ M
O V7 ~ d- ~ ~p
O~ 00 d1 [~ 01
M O1
w H ~ x
r~ ~ H
x ~ x x x
x
367
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~n d- O~ N N t~ O~ Q~ oo ~O oo O 01
M
.-~ ~n d- M M N N d- ~ d O~ M ~ N
a1 ~n d- --~ ~ d- ~n v~ oo N N d'
~ ,--~
l~ ~ .~ oo l~ O .~ ~O N ~O O~ d1 N
M
N ~ M M N N M ~ N N
~ o ~ M o o ~ \ ~''? o ~ t~ ~o o~
_ _ o~ ~ o
00 00 00 ~ p~ lp p~ M 01 ~ d' Ch
N .-, 01
~ M ~ M O ,-.r
~ M
t~ _ ~
H l~ ~ N ~ N
~
N
0~1 ~d~. d- ~O ~ d1
due' ~ 0~1 O ON1
O~O y---iO ~ 0~O ~ l~ 'N M ~ ~ ~ 00 00 00
~ ~ M
I ~ o o
~ I
~
I
o ~ ~ 'n ~ O '-' d p M o
~ ~- O O - O _ r., O O O
N p~ tn _
~p pp
w ,WO .,yn w ~ .,~ w "fl w ,.O w w w
C~~ l~ N
bA aA P-r by bA ~., by ~ by ~ P-.i
d' d- O~ O ~O
~
I
N .-i ,-n s"'0 O
~ ~ O ~ ~
~.,''s.-~ ~ O ~ ~ ~ b b
y O .~ O , M ~ M cCt r. A O 0
.~ ~ r~ O O
o ~ o o ~ U ~ ~1 U 0 0 0
x x o ~ ~ U ~
, ~ ~ W~ ~~ c~~ ,- ~~ 0 0 0
o~
~r~ ~~ ~ ~~ .-. ,-, N
a~ a~ ~
N N
O ~ ~ O
V ~
N N U ~ ~ 0 00 P-~ .-M~ ~ ~ C/~
U r, M ~ 0 ~ ~ (-~ M M M
~ ~
~ M O ~ O ~ N
cct .~''O O O w ~O ~ cd ,~
,--mnO p r, .~ cti
~ ~ ~ O
y ~ wov wov ~~ w~ Uo ~ Uo a wow
~
, w ~ ~ ~, w ~~ ~x w ~."~L~~~ ~ ~ w w w
~ a ~, ~ o ~ -~ -
~ a
~ ~ .~~,~~~,~ ~~ ~ ~~ aa , ., a P a
., ., ,
~ W ~ W ~
N N N (. N
I~
~
~i ~ ~ ~i ~ _ x ~ r-~ ~ ~ x W
N ~ ,-flN N H - ~i
d- ~ l~ ~O oo l~ oo a\ O
N ~ -~ N ~ N N N cn
H ~ VW ---1V~1 v-1 v--1v-1 v-1
00 00 ~ ~ 00 M d1 V~ O
0o d' ~O a1 0o O1 ~O N o0
01 M d- O v~ N ~ O H
N ~n v~ . ,-~ 01 M l~
00
d' t~ M .-~ O -1 v1 N ~
01 Ol 01 ~ 01 01 01 l~ d1
a1
H
N ~ x a d'
~ ~ w
x ~ x x
x x x x
368
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
l~ M o0 00 00 .-. 01 ~ oo N O ~n ~O ~O a1 O O~
~D CO 00 O~O N M ~ ~ M ~O ~ ~ 00 01 00 V'7 M lp
N ~ M M ~-~ ~ N ~ l~ N
M M ~O N ~n ~ l~ ~n N ~O N M O l~ o0 N t~
00 N 01 \O t~ l0 .-V ,~ V~ \O d' 01 d'
d' N ~ N M ,~ ,-~ N ~O
M ~ ~ ~ M ~O M ~ ~ 00 d' ~ d' N ~ \° 00
00 O c<1 ~'? M M yn t~ ~-, °d. '"' 00 ,°-, \p N I~
o~ M M ~ d= ~ pwt- M ov o~ d- ~ ~n ~n N ~o
'"' N v-i d'
t~j ~O V'7
M N d'
~O d- ~ d-
00 00 00 00 M ,~ 00 00 00 00 00 ~ 00
U t~ U U U
w ~ www.~~°w°ww ~w°w ~°w
a-, ~ a1 a1 w bn ~r a~ a~ a~ ~ w a~ a~ a~
U
rte, ~ +~' ~ ~, ~ ~ ~ ~,
,5.; .,--i
U U ~ O ~ O O O O ..~ ~~ O O ~ v O O
ai -~-' ø, ..-~ .-r .-a +~ ~ ,--~ .--. .-
~ O O O ~ p O O O ~ ~ O O ~ ~ O 0
0 0 0 0 ~ x o 0 0 ,~~' 0 0 0 ,~ o 0
l~ O U U U I~ '~ U U U O O U U M O U
i.~ F.-i i-~ ~ 3-i 3., 3.r M x ~ P"' pp
O a C/~ M U~ M U,7 M N U V~ M V~ M U1 M O a ~ M C/~ M \p C/~ M O
M \p ~ M Cf1
w ~ ~, w o w o w o ~ ~ ~ w o w o w o ~ ~, w o w o ~ ~, w o
w .J ø, a~ ~a ~, -~ a1 -~ ~. ~, ~ ai -d a~ 'a a~ ~ .~ a~ Ts a~ -d .r a~ ~d C'7
N W W (..~L~ N W W W N W (,~L~ N W N
x N ~ r-~ ~ x ~ x ~ ~ x ~ x ~ x ~-~ ~ x ~ x ~~ ~ x
01 M O v7 ~O l~ o0 01 O
M ~ M N M M M M M d'
V~ ~ V~ .-a ,~ ,~ r~
d' O ~ ~ 00 N ~ 01 V~
M ~ \O \O 01 d1 M _M M
d ~ O o~0 ~ ~n N O ~ m
a1 ~n ~n ~ a1 ~ a, ~n a1 a1
Q1 ~_
O O M 41 I~ ~ \O O
y wt v0 U d-
x ~ ~ x ,~ ~ O
H ~ H
x x x x x x x x x
369
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O1 ~O l~ M l~ O~ ~ V7 01 V7 ~ t~ M ~ ~ l~ l~ M d' 00 N
~n O et- co O ~ V~ ~n ~ N d° 01 00 ~O M oo ~ N ~n t~ ~O O
I~ oo N M N wt N N M M M v~ oo d- ~ N M ~n o0 00 0o N
00 \O I~ V~ M 01 M ~ ~ M V1 d1 01 00 V1 ~ M d' ~O ~ 00 d'
O ~n oo N ~-~ O 01 O~ O d- oo d- O ~ N M N oo ~ 00
\O l~ ~-~ M M N M V'7 \O d1 M (~~ ~ M ~D
0 0 0 ,-, 0 0 0 0 0 0 0 0 0 0 0 0 0
dN., ~ ~ ~ ~ 0
O M O d' N M ~ O O ~ M N O ~ l~ N ~O
00 '~h' ~ l~ l' l~ M l~ O d' ~n V~ o~O d' ~ M M 'di d' ~O
d1
~n ~ d- ~n N
O_
M
M ~ O O\ ~O d"
00 ~ oo w ,-, N o0 00 0~0
o r,
O ~ O ~ M O ~ O ~ O ~ O ~ O
w ..o w ~ ~ ~ o w ;.o'-' w .~ w ~ w
a-. bn a, ~ ~ ~n ~ ai ~ a~ bn a~ aA
°+'' '~ o
en °' ~'n o ~ ~ en ~ ~ b~'n ~ bn
o ~.~o~,~oo~oo,~o ~,~o
o a~ ~ ~ o ~, ~ o ~ o ~ o ~ ~ o
.5~-~~pO~~~UO~V0~0 ~~O
_ Cf~ M ~ "C~ p C/1 M ~ ~ N ~ _ ill M N O C/~ M ~ ~ M
~~ I~I ~ ~' '-' ~ ~ o 'ai ~ '~ o '~ ~ ~~ o ~~ o ~
w o ~ ~ N w o ~ x ~ ~, ~ w o ~ ,~ ~ w o s~, w o ~ w
+~-. -N
N ~ ~ ~ N
IM IN d' ~n IM
N N oo N M l~ I~
O d' M 00 00 ~ l0
~/- ~ ~O \O M
~O O ~ 01 Q1
N O~ ~ O O -W ~
a1 a1 d1
M
w a d' ~ M t~
ya ~ ~ ~ a
~r w ~ ~ U
x
370
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N M d O M ~ ~ ~ ~ ~ N ~ O N ~ ~--~ Co
41 ~ O ~ d' 00
N O~ N ~I- oo d- M H O M ~ ~n H l~ ~O O
O~ d- N ~n ~n ~O l~
O
M ~W O ~O ~t ~ ~O O ~ d- d' ,--~ d- N
~ .-, H H cY l~ -W H
~ ~
H
N ~ ~O O H l~ oo d- ~ 00 oo d' O N 01
~n N l~ 01 ~n N H
~O M
lp o0 d- l0 V1 o0 O l~ d' M o0 ~ 00
O~ tn CO N \O l~ O
.~ V7
V1 ~ \O N V1 t~ M M H ~ ~ M lp
l~
o ~ 0 0 ~ ~ o ~ ~ N o ~ ~ 0 0 0 o
0 ~ o o 0 ~
00 .-~ ~p oo ~ o0 01 N d1 H O
N O M ~O ~ l~ ~n d
O .~
00 00 l~ ~ I~ d' ~ M V~ \O l~ V7 O~ M
~ ~ ~O l~ ~!1 M M M
\O M
N w d- o,
-,
. ~
~
I
00 N ,.-:
N ' h ~ b
~
M bA d o _bA _ U
N o A
d' ~ w o ~ ~ ~ N
o
I_~ N .--y~ l~ l~ ~ O
O '~ O ,-, O O O ~ H 0 tn
~ ,--~O
O ~ O O O
-fl ~ ~ N
.,~ N w ~ d- w w w ,..0 .,~ 01
N
by 00 pi bA ~ ~, L~ bA by 01 bA
N H
~r ~' ~ ~ ~ U
O O O O
~ ~ ~ 0
S~ N'~ O Ny 0
~
, ,~ ~ O O O ~ O
~ ~ O
O
,.L;~ O ~ O U cd
U
~
O H U H U U U ~ O ~ ,-,
~ ' ' ~ ~ "-' % % ~ ~ r~ ~D
'~' ~ ~ ~ ~ ~ ~
~
N N ~ v~ N N ~ C C C a
v~ l ~ N ~ N
" N N
~
O ~ ,~ O ,~ d ,~ ' .~ ~ U p,
' ~ c~ cd , .5 cCi ~ ~ ~ ~'
N ~ ,..I. ~ ~ c~ C!~
O cd U
~ a3 ~
w~0 ~, ~0 ~ ~, ~~ , ~p
o ~ ~ o w ~ w w w ~ ~ ~
o x o o o
~, p ~ p
'd'.r wr U ~ P.~ w.r P-i ~ ~ +-~ ~ .~-",U
'd U ''t3'd "L~
~ ~ ~ ~ ~
N N N
N
0oc~ cd ~ cd ,--~00 0o c~ c~ a3 cd
~ ~ o0 ~ ~ ~ ~i
x
H .-~ N ~-~ -
r
l~ ~t V7 01 ~D H l~ N
d- N N d' N v~ N ~n
w n ~n ,~ ~n ,--~ ~n ,-,
d' M d' l~
N N d- d' O~ M N l~
01 ~O M ~O oo d- H N
0o N ~O l~ ~n O N V~
N --~ N v1 -~ 01 O N
.-~ H V7 ~p .--1 O O O
H ~ ~ ~ ~ H H H
O ~ N
"x N N
a w ~ ~ ~i '~ ~ w
x x x
x x x ~ ~
371
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
\O ~ ~O ~--~ ~O ~ .~ 00 ~ V~ ~ M V1 O M V7 V1 ~ I~ 01 ~ I~ V1 t~ 01 M V1 \O M
(~ l~ 01
O d' O d' O M d- ~ M M d' 01 ~ .-~ p1 V1 tn O V7 d1 d' ~ ~ ~ ~ O~ d' 00 01 (~
l~ 00
~O l~ ~O t~ ~O t~ l~ ~O oo t~ t~ ~n ~O a1 ~n d' ~O ~O N m ~ N d' N N v> N M v~
d- ~ N
M ~ d- \o ~t ~ O M d- N o0 ~ d1 l0 00 I~ 00 O t~ N M ~ M N 01 \O ~ .~ 01 t~
tWo
~n ~D 01 ~n ca m M l~ 01 N oo N o0 00 ~ N N oo N d- v~ N M ~ M N N ~ M ~t
O O 01 O o0 00 O O O O .---W
0 0 ~ ~ o ~ o ~ 0 0 0 0 ~ 0 0 0 0 ~ o o ~ 0 0 0 0 ~ 0 0 0 ~ 0 0
00 O N N N ~ O O o0 0o O O O d' ~ l~ N O d- O oo d' ~ ~n M oo ~O o0 O l~ O a1
N M M M M M M M N N M M M M N N M M M M N M N M M N M N M N M N
O
N
372
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
v7 N ~n ~n 01 l~ M -~ oo d- ~n ,~ t~ oo N ~n .-, d'
t~ .- M ~ M .-~ .~ v~ N
~ oo .~ oo ,-~ .-, .--. N ~ N ,-~ ~ d' l~ 00
M
~ ~ ~ ,-, M ~
o
O
O O ~
~p co N ~ ~n ~n O~ ~o d- N d~ N ~t ~o 00 00 ~ 0~ M N
,-mo O ~o O O~ ~n oo
~n d' ~ N N N ~n W t d' M a1 ~n N O~ d- N oo .-~
N m N O~ ~n N N
~0 00 ~O ~ v~ ~n ~O ~O v0 ~ ~n ~n ~O N ~n ~O N N N
V~ N N N N -~ N -~ ~
0 0 ~ 0 0 0 ~ ~ ~ o o ~ ~ o ~ 0 0 0 0 0 0 0 0 0 0 0
0 0
N 01 ~O t~ N M O O N d- M O 01 0o O .--~ O l~ d' Ov 01
M ~n M ~ d- N
MMNMMMMMMMMMMMNMd'MMMMMCfiMd'V1 d' d'
O
~
_ ~_
N
N
O
0
H
w
M .-i
a
N
O
' ~ O Cl~
a O 'J-i O_
O
U U ~
~
~ ~.
d- d-
M CO
in N
en
N ~O
a1
N O
m n
O O
H H
a a
E-~ H
373
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
.-r .~ M N ~ N ~O
N M ~ M 01
-, ~. d.
l0 Q1 01
o M o 0 00 00 O o
O N t~n~ 0 N 01
'_'d bA 'L3
M
N
M O
O ,..N., - ,~-, - O O O O
''; O O O O
v7 O O O N ,~ ~p ,-, O O O O
O l~ 01 O N ~ .~ O O O O O
tw ~ P-, ~ t~A ~ ~ ~ P~ P-~ P-. P-~ N
~
tw ~~ ~~ ~~ ~~~,~ E'.' U
,_, ~. ;~ . o .... . o . o . o ...~ +~ v~
a a <n ~ v~ ~ ~ ~ ,~ ~~~ v~ yn cn ~ po ~ v~ v~ ~ v~ "O
+., +~ U N O cd +~ ~ "~ N U N N N N U N Q~,1 ~
v~ ,~'' ~ 4-y, ~ O w ,~ ~ cn ..~ --wn ,s.'' ~ ~n ,
U U ~ U CCS ; F-' . "'~ ~ ~ . "'' CC3 ~ "'y CCS
~o ;~a~,~ gas ~ ~a, ~ >a~ ~ ~w ~ ~ o~' ms
~N N 00 .N ~ ~U ~~ ~O ~~ 'TJ
f.., ~.-r ~ +~ ~,-i O ~ w ~ ~., ~ ~ U p ~ O ~ ~ O ~ ~ O ~ '~"'
Q., v~ ~ ø, cn P-r c~ U ~r v~ 'd ~ ~1, vW p., cd U ~ cd U P-i cd U p-i c~3 U
C/~ ø, ,W r a
W d- ~ W W W W N
.D ,~, .~ ,.fl ~ rx ~ ~ N x W -~' N ,~S'7-
d' 01 tn O l0 ,-, 00
~n N ~n M ~n M W
V7 .-i V~ ~ V~
d' O
l~ N O l~ \O d-
M ~ oo ~ N l~ o0
00 00 d_1 O d' 00
due- ~ OO N ~ due"
01 ,.-~ l~ 00 d' 01
M
MM 00 O~O~N
374
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O ~p M 00 .-~ M t~ d' O H 01 O 00 00 V7
t~ O N O \O a1 .~ .-~ t~ d' l~ ~O t~ d' 00
t~ N t~ N a1 M d- ~t d- d' N .-mt- l~
H M \p .-~ V'7 ~ M O ~O 00 M M N H 00 N
01 O V1 01 t~ l~ O ~-i C~l M 01
..-i 00 ~--.~ d- ~O ~--~ .-1
o ~ o ~ o ~ ~ 0 0 0 0
d' O~ N ~O M M M l0 ~ O O l~ O
01 N 00 ~ M ~ 00 d' l~ ~ O 01 01 O
M
O ~ d' ~ tn
_o~
o~t;-oNO'° °'oo'°~M
.-, N ~ ..~ N ,_, N ,~ ~n
°~,~°o~°o°,~o~:°oo
~oo~ ,-, o o d o d- oo ~ ~ o Wn N m
w 'en ° aw-, ~-' ~ 'b'n N 'bn ~ ~ aw, 'bn aN, 'i n
.~ a, ~ .~ ~ o
~ ~ U ~ .~ ~ ~ ~ ~ ~ ~ ~ x ~ ~ ~ ~ ~ ~ ~ ~' o
~ E"'' ~'' '' H '+ H '+ o~ '-' O E-r ~~ E-a '~ M '~ N
"C3 U N Q~, "'' ~ Tf V 'd V 01 ~ ~ ~., TS V "C3 V ~
s~, U.~~a~~ ~a~~so~ ~~, ~a~~s~a~~ao~o
~, . . ~ s~ . ~ ~, a, .~ r-' ~ - ~ ~ ~ ~ ~ ~ s~ a1 o vo
.U ~ 'L~ N ~ ,~, ~V .-c~, .U ~~ O U O .N N .U ,
O,-.C~+-, UQ~,O~~ ~O~w~ r~',"'."'i~°~~O,~w~,w
w ~ ~ E'.' ° ~ W w ~ ~ w w ~ ~ ~ ~ ~ ° ~ w ~ ~ w ~ ~ ~ o ~
A-i c~ U ~ ~~., v~ p., c~ U ~ P~ cCi U ~ ~ ~ ø, v~ p~ cd U P-~ cCt U 'r .s," a
d- ~ d- W t d- p~ ~., d' d
x~ ~ x~ ~
(~l O M ~ d' N V~ ~D d-
cr1 \O M 'O M ~ M M
V7 ~ In H ~ ~ ~ V7
.~ ~ ~ O tn
c~i oho d~-oo NNm oho
~n oo Ov ~ t~ t~ o d- O
~n N --r ~ l~ O t~ at ~n
d- ,-~ oo N ~O ~ N
M
N x M M
H L-1
a a d a a a
x x x x x x x ~ ~x
375
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
00 ~ l~ ~ M a1 ~ O lfl N ~ M
M ~
N l~ ~O ~O M M O ~ N ~O M 00 d- O
M ~n
d- l~ ~ \O l~ l~ l~ l~ ,-~ ~ N N M
l~ t~ ,--i
N N
d' Vm n O V> M d' ~ d' I~ O l~ 01
d' ~O d'
N oo M ~O ~O N ~ O ~O ~D ~n cn
l~ N O
N -~ M v~ ~o v0 ~n ~n ~ ,~ ~w 0
~O ~O
N
0 0 0 0 0 ~ ~ o
0
O d' N ~D N ~ _ p ~ ue
v~ ~ ~
~n 1 o d
O Wn ~O M d' o "
N 0
N N
N
NI NI
~
p p ,~ ~ ~
~ N N ~ ~
~
I~ bA d bA
"
O
~ ~ ~ ~ ~
M O ,_, O ,_, 00 O
_
N ~ _ N _ 0~1
''-' oo ~ oo '-'
d-
O O 00 00 M O 00 l~ '~ '~ O
O M d
o r- ~ ~~ w ~~ ~N w r- w
~ o ~
N ~ bA bA N P-~ bA bA p-i p..~C1, by t~
N N ~O
U r- ~.., y.., U
~
N ~ 4~.1 ~ ~ ~ O '
,.a ~ .S-'.W.i
~ ~
'y .~ ~., ~ ~ ~ 'r' ' c
.'., U +~ a3
.-
_ _
~ ~
O ~ :~ 5-.i -~1,'d ~ U N U p . ~
. ~ i-i ~ ~ ~ ~' 4 N
~ ~ ~
+U-~~ 'T3 5 .~ 5 ~ -- + ~ v1
~ Y ~ U U W
~ y W
0 ~ ~ . . . ~ U o ~ ;~
0 o o - -i ~ ~ o :
o ~., ~ s~"
~
.o
O
h ~
N N
~ ~O ~ ~O ~ ~ ~ ~ ue
W W O ' ~ ~
"
. v~
. ~ ~ ~ ~ O s
' ,
~ '
~
O bA ''~ O bA N d- O ~ ~ ~ ~
~ ~ O ~ G~
w ~l , ~ ,.-~ ~ ~l U oo . 1 ~ ~ cd
~ , ~
~ ~
-~
oo wa~ ~o~ ~~o w ~~o ,~~o w~, w~ wa~ oo~U
P ~ '
;
U -~ ~ ~ ~ -r~ P-i a ~ W G-W-,P-i ~ U +w.r
,-, .s U -N P-~ s..~,.~
.,..,
d' d' ~ d' ~ ~ fx ~ d"
0o cd c~ ,-~ cd c~ .-. ,-, 00 cd
r~ ~ ~ r~ ~ ~ '~ ~, r~'
~ N N N -~
t~ ~n oo ~O ~ O
M \O M ~ M d' d"
N
N
M O d- N N o0
o~ d- O o ~o ,--..
N l~ 00 ~O o0 l~ o0
a1 I~ 00 O ~ 01 00
d' -~ O ~ 01 N O
d1 ~ a1
v~ N
x
L ~ ~ ~ U
7
x
376
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N d' d- d' a1 v0 l~ Omn M ,.-mn N
N I~ ~D O N ~n ~w0 0o N ~ ~O
M N M 01 N N M N ~ d- ~ N
00 O 00 ~ 00 O l~ l0 V7 00 M
~D o0 ~ (~ l0 00 M l0 O d' O O ~O
d' ~ N N N
0 0 ~ o o M o
d1 ~ 01 t~ ~ ~ O ~ O O ~ d
M ~ ~ M I 00 00
"O 'T3 '~ N ap ~ bD ~ ..fl
,"_, ,-, ~ ~ V7 '~ ~ ~ by bA
d_' _ ~ d' _ l~ _ ~ ~ M ~ ~ M ~ l~ ~ t~
Vo '-' N ~i '-' N '~ N M ~i ~ '~ N ~ '-: N N N N
N O ~D N O d- O N ~ o0 ~ O oo ~ O '~ O O '-' O
d- O ,~ dye N O ,~ M in ~n O m ~n ~ ~ O d' a~ O
w .~M.WO w .WO .~o,w .~o,w
bA ~O bA N P-~ bA N bA N t~ by N P
'-' ~ ~~ ,~ '-N
't1,
p ~' O c~ N ct3 '.-i cCt cd ,--~ cat cd "'' cd
W ~,~~ ~O ~ 00 ~''pON -,-V-~ O ,~ :"'N
a m i O ~ W ~ ~ ~ O bA '~ O O ~'' O 'T~ O O N 'd ~ ~ O
'O ~ ~ ~~ ~ ~ ~t~ U ~ U
.S"r x ,~, ~ ~ ~ S~ ~ ~ ~ ~ by ~ ~' ~ bA ~ ~i V~ .~'r x
V ~ O ~ V .~-i ø'' ~ O N ~ O ~ ~ ~ O O r ~ W ~ W ~ U
N c~-'n ~ . N O . N N '~ .~' . N +~-~ ~ . ~ ~ .ii ~ , ~ ~, ~--i ~--~ ,.ti
O
r-~ ,-~,., .i--~ +-~ ,.., ~--, ~,-, -,~ .~, vw,r O +-, +-' O +-,
o ;--. ~ ~ ~ o ;-r ~ o ~ ~s ~ o w ~ ~ ~ ~ w
U ~., ° Aw-, .-~ U u, ° ~ ~.~ ~ Pw.., ,~ v ~ ~ ° . ~
ate'., ~ ~ ° . ~ O ~ O pw.., ,.~
~r ~ d- d- ~ ~r d- ~ d- d- R.,'
-.
x ~--a ~ ~ x ~--~ o 0
00 N d\ M O d' .-~ V7 l0
~O d- ~ d' t~ d' l~ d-
n ,-, ~n ~n
N ~ 01
l~ O M l~ \O O d- O ~O
~o N N M d- ~ t~ M M
~n oo l~ oo ,--~ N o0 h o0
O oo O oo V~ 01 d' v~ 00
O ~ O .~ d- .~ M O
O1 ~ O1
00 O ~ d'
O
M ~' O
o, a a a o
x ~ x ~ x ~ x x
377
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
01 ~ O~ d' 01 t~ a1 00 ~t o0 t~ ~n N O
N O oo l~ oo M I~
O d'
00 O d' ~ l0 00 ~ -~ O 00 01 l~ O \O
01 ~ 01_ l0 d- M N
O M
N ~ -V N v~ vy0 ~O ~ tn o0 ~ d' ~n d'
d- N ,~ N O ~
00 I~ t~ ~ ~n l~ O 01 O t~ M -m 0 O~
l~ ~ O ~O d- ~ ~O
~ N
\O M V7 I~ N d' N ~ M 01 01 00 M M
~ M 01 I~ O1
~
d' N M M N l~ M oo N N N
~O ~ l~
0 ~ ~ o ~ 0 0 ~ o ~ o ~ N ~ 0 0
0 ~ 0 ~ o 0
0
O N N oo ~ a\ ~O ~mn M ~n ~ a1 M d"
O ~n N M
d-
d' ~ d' l0 ~ V~ ~O M ~ V~ ~D ~ t!~ 01
V7 O ~O W' M tn 00
M l0
~
_
_ U ~..'
,
,
M ~ I~ d' ~ l~
'-' N N o N M ~ - N ~ N N o '"' ~"'
'"''
'-' p
M O N ~ N I~ r-, N N N ~ ~
d- ~
v O O ~ p ~ ~ ~ 00 ~ ~ ~ M ~ d
O O t
c
n
w .~~ .~oo w ;.fl w w ..,~
o ~ ~ '
''
b
n ~, A-, can bn o a., z3 a~ a~ tin
o, a,
U
~ ,~ ~
+~ c~i ld~ ~ ccf ~ O x ~ O ~ ~ ,.i~
N ~-' T
0 ~ ' u, ~ ~ ~0
S~, O O ~ O ~? .~, O.'~, O O ~?
,--mn Q, +~ r''
~ v~
V O V
v ~ ' ~ d' ' _
~ ~ ~'
fl
y ~ ~ ,. O .S O
~ ~ ~ ,
~
N O ~ O O'' O O
~ ~
S~
,
yz ~ o~~,
w ~ w ~ ~ ~
v P P v P ci~ ~ ~ v ~ v ~ P
~ ~ ~1 P ~ ~
U
-~ -~ ,. -~ -~ , -~
.
~r ~ ~ d- ~ d- d- ~ ~ ~ a- ~r
-- W W .--~W ,-~ ,~ N W ..-1 ,
cd ~ y--~cd ~ ctt cd ~ c~ ~ ~ cd cd
~--~ .--~ o0 ,--~,--~
rain~iN ~ xN ~ ~ x~ ~ rxN r~N ~
M l~ 00 \O 01 l~ O 01
l~ d' d' l~ d' t~ ~n l~
tn In .-~ ~ .~ V~
O O
O 01 V1 ~ ~ l~ ~ V7
0o M N O in oo d- ~n
d' 00 00 d' O O 00 M
N ~ dl
M O O ~ ~ t~ O
d\
N
00 ~ O 00 O d'
O
V~ r C/~ ~n
~ W U
W ~ ~ ~ C7
x
378
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
l~ ~n ~O d" ~ CO 00 ~O 00 M M d' d' l~ 01
O~ ~ ~ ~O ~f
Q~ d- ~ M O O l0 ,~ .-W O ~ ~O \O d\ O
01 01 N O
01
~n d' ~O a1 d' t~ N V1 M M d- ~n N ~ d'
~O ~ ~p M 00
d- ~n ~ l~ M ~Y l~ 01 O O ~O d- ~ N d'
O N ~ O ~O
00 d- M O~ 0o N ~ M ~ ~ ~ N ~ O l~
~ M ~
d' N N l~ --~ ~ ~ M M d' M
~O ~ \O 'O
o ~ o ~ ~ ~ ~ ~ ~ 0 0 0 ~ 0 0 0
~ o ~ 0
M O~ l~ 00 ~ ~ ~ d' ~ 00 I~ ~ 00 ~O
l~ O O 01
O
00 ~ ~O I~ M ~ ~ ~ O 00 00 ~ ~O V'1
l~ d' O lp M
d'
M
M ~
I
O
' "d bJ~ d'
'd
_ _ _
01 O
01 d1 pip O\
N N ~ ,-~ ,~ ,-~ ~O ~ ,..., ~O N
O O O O O O O ~ O
~
O O O O O M o O O
r0 M O w w w w w .~ ~o w
: ~ N
p-, bA N l~ Pa R.~ P-~ P-r b.0 0o P-~ b.0 00
O
0
r~ ~ ~, ~,
u ~W ~N ~N ~ ~ ~'dv~ .~ l~
~
~ O O ~~ b O ~ N
A
cC3 ~, ~ U
U
c~3
U ~ U ~ U ~ ~ ~ ~ ~ ~ cCt ~ N
~ ~
cd N N N cd
.~ ~'~ .~ W W ~ X' W
~ U ~ - ' ~' '
d. ~ ~ , ~ O ~ ~ O
, ~ ~
~w ~~ ~ ~.~ ~~ ~ ~ ~ ow ~ w~
P ~ ~ CJ U~ U~ ~ P U P (:L~
U U U P "~ " ~~
P P P ' j ~
-v ~ -i -i . -a p, -~ 'r
, , L .
-~
~., d' ~ ~ p~ ~ ~ d- lx d'
~
r~ .9 t~ r~ r~ tx. r~ . ~ r~
N N N ri -i
O -~ N M d- ~n
~n o0 00 00 00 00 00
N ~n M d' (~ N N
M d' O 00 d1 ~ 00
0o N I~ oo ~n M l~
0o M I~ I~ N
O O M v7 M ~ N
01
\p pip M
~o O ~ ~U ~U
~
'"~ o w t
7
x x x ~ x
379
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
00 00 N 01 V1 V~ M M [~ tI~ O O ~ l0
(~ t~ a1 t~ \O O ~-~ N d' ~O ~O \O M V7
N N ~--a M M N d' M M N N N ~t
01 N 00 00 M M ~ O O d' M M \O
M 01 .-~ O 00 ~ O M 01
N N N
o o ~: o N O I~
~t ~O ~ lp ~N, M OM ~O ~ o~o N
l~ M
U M
U
M
01 ~ 01 ~ d1 d1 01 Op Q\ p°~ ~ 01 01
O M O ~ O O O ~ O ~ O N
0 ~ '"' O ~ 0 0 0 ,~-, '..'~ O pip N O M
~L, GA O p-i bA P-~ P~ P-t bA M P-i by d1 P-i
N n '~ ~ r,'~ '
~O ~ ~ O ~ ~ ~ O O O ~ O p O
p, ' bA ~. "" ~ ~ ~ S~, 5.~, ~ p 5~.., .'~ ~ U
U'-',~UbA~.~,~UUU~NxU cdU
' 0 ~ U ' ~ ~ 4--i
cd . r, c~1 ' ~ c~ cd v~ M ,--~ cCt ..-~ cd
cd x cd ~ p U 'T3 x c~ c~ ,", c~ ~ x U d- c~3 ~ ~..~ c~3 r~
O
W ~° ° o W ~°- c , .~ U u, o W ~ W. . r°a W
~°a ~ ~ ~ ~ ~ W '°a ~ ~ q W r°d ~
N O ~ N ~ ~ U N N ..., ~ p 'T3 ~,' U U 4a U U7 01
aw-~ ;~ ~ ' ~ ~U ~ U a~.~ ~ aw..~ ~ awr ;~ ~, ~ ~ w ~ a~'.t :~ ~., C7 ~ a~.~ ~
~
r~ d- rw ~ ~ ~ d- r~ d- r~ d-
x~~ x~~ x~x,~~x.~~ x,~~ xN~
~D t~ oo a, o ~ N
~ a, ~ a,
M ~~ 00 V7 l~ d' 00
M d° ~ M l~ \D
O .-~ 01 M O
N M O~ ~O 01 ~--~ N
~O l~ N O O .--i M
a1 a1 h ~ 41 a1 a1
N
00 O O W oo ~n
'-' °_ ~ W ~ H
x
U U U
380
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
0o N a1 .~ O N ~n ~n M ~Y d- ~p oo N a1 d' oo O N O o0
V7 ~ O ~ d1 01 01 d' M M M N ~ 01 ~ l~ l~ N O l~ ~
M ~n o0 N N r, d' l~ l~ ~O .-m0 V~ 01 ~n ~1 M ~-i d'
O N 00 lp I~ ~ O ~ 00 M M .-1 ~ O ~O M ~ O M M N
~O M ~ M 00 .-~ N ~ l0 ~!1 M d' d' c<7 ~O
N M l~ M ~O N N ~o d' N
0 0 0 0 0 0 0 0 0 0 0 0 0
N ~n l0 .-, N ,--i _. (y v~ 01 M oo d- N M N tn
(~ N in l~ d- ~O ~ d.. 0~1 p ~ ~ 01 0o t~ (~ d- D1 a1 0o M
N
W ~ U
0
- ~ o ~ ~ ~ ,~ ~ ~ ~ ~ ~
0 0 0 0 0 ~ o ~ d- o o
t~ ° °, a o 0 o M °° o ~ o °~ ''_'
o° o "' °°
w w w w '~'Mw :.fl~ w '',Mw w
b0 d' p-, P-~ P-i P-i bA O p..~ "O P-~ bA ~ P-~ ~ b4 O
O .-~ ..~ ..FN., ..~ .+N-~ O ~ '+.N, .
0000 O Q .~'.,.U,00.'~,
by U U U U U w' ~ 5.1 ~ U U 3.-i ..r
O ~O O O O O O '-' ~~ U O 'O O
~,x ~~ x
W '~ W '~ W '~ W '~ ~ ~~ W ~d ~ v~ ~ 0.' ~ ~ W -~ W r°d
~ o _~ U ~ a~ ~ a~ ~ U ~ a~ a~ a~ N a~ ~ ~ a~ ~ a~ a~ a~
w :x~ w :x ai ~ a1 ~ a~ 'x~ ~. 'x'~ ~ a~ ~ x w ~ as ~ ø,
r~ r~ ~ ~ d- ~ r~ ~r- ~ ~ d
'"' W W W W '"' W N W ,-'
_~ ~ Do ~ ~ ~ ~ ~ ~ ~ ~ o0
-fl r~' ~ ~ x ~ r~ ~ . ~ r~ ~-~ ~ r~ N ~ rx N r~ N
M N d' ~ ~ l~ 00 M O
d1 V~ 01 01 01 01 d1 tn O
M ~mn d- O ~ t~ ~O N
l~ ~--~ O N N ~ N O I~
01 d- M 00 V~ l0 O ~ d'
M d' O O d' 01 a1 ~!1 d'
M 'O ~ 01 M
DD d1
N 01
U U ~ ~ p.., p.., a ~ H
w w ~ w ~ ~1
x x x x x x x ~ x
381
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
01O~ M l~ l~ O ~ O l~ l~ ~ ~ ~O ~O d'
M M
O
O 00 M O O d\ ~ n ~ 00 00 d' ~ ~ ~O
--~ 01
VW
~nN d' ~n d- N -~ l~ oo N d' d' d'
dwn N
a1
N ~n t~ oo ~i- t~ M M a1 ~ M ~O vo t~
~ I~ N
oo
d1 ,-~ ,-, ,-~ ,--ypl~ dW ~
.-i ~ t
d' d' ~ -~ M d' d' M
d' l~
0 0 0 0 0 0 0 0 ' 0 0
0 0
O ~O ~O ~O V7 ~"'~M d' ~ ~ \D
M l~ 01
O ~ 01 ~ ~D M d' H l~ ~ l~
l~ M 01
l~
N M o0
U
O_1 M -~ ~ M
~
d ~ r; O O '~ O ~ '~ O O ~ ~ O
M
o ,. o v o ori o ~ o
-,M o~-t
O M ~ O M N O ~O O O M d1 O
d'
bA 0o p..~~ bA p..,~ b4 P-~ bA p., ~ bA p..,
V~ d' o0
~, ~ .S~r ~,
,.0 ~
~ . . . ~
O ~ O O O U U O ~ O
. ,-U, f' ~
~ .- ~
U O
'~
'
i'~ .~ ~ ~ ~ j t? ~ . t~ ~ Q
~ ~
C d-
U , . , , , . ,
U "' U .,' U ;' U i-' O U U
9 ' ~' ~ ~
. ~'
, ' , ~O ',~ O , U M O p O
p O ~, v~ . ~
+~ -~
. ~ z ~ ~ .,
- ~
.
~
W ~ ~ W ~ W O N
cd O O ~ p ~ ~ ~ W ~ ~ W
'' ' ' 'd W
N N . o ..., ~ p . O
O v d ~ . d O O ~ 'O
~ N 00 ' ~ . ~ c~
O N ~ O ~
N
c~ a3 ~ w Q~ ~ c~ Q~ ~ cc3 N , c~i
w ~ ~ cti a3 c~ ~ ~ cat ~ ~ w Z,
~ ~ ~ w ~ ~ ~ w w ~ ~ ~
~ ~ ~ ~
p~ .~ U P-~ '. 'v~ W .~ ~., .~ ,~ fi, '~ P
~ ~3 :~ :~ ~ x ,~ ~, ~ :~ ~ -~
~ U .~
~ ~ ~
W W r., W N W '"' W
t~~ ~ r~~ ~ t~i~~ r~N ~ r~
N IN IN IN IN IN
00 d- M (~ N 00
~t mn mo w
(T 01 M 01 l~ I~
01 O d' 01 Q1 a1
O \O l~ M O O
d> ~ ~ O1
z° ~ w
N oo a1 ~ H "'~~.,
x x x x x
382
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d' ~ ~ O O 00 00 l~ M M ~- ~ ~ 00 00 l~ d' N
M ~ l~ l~ l~ ~ 01 01 O ~O t~ I~ t~ lp \D N ~ ~n
~O l~ I~ cal N ~-~ ~n l~ oo m d- ~ I~ t~ Wit- ~-~ N M
N N d' O o0 d- ~O I~ ~ ~-~ M 01 O O t~ oo ~ ~p
~O M N ~O I~ l~ N O \O N M O ~ ~O O\ ~ ~n
M lp l~ ~ .-~ V) V7 M .~ .-~ M d' M 00
0 0 ~ o o p p~p o ~ ~ ~ ~ o 0
M \O I~ ~ O 01 O M O 01 M ~ ~ 01
d' d' d' M V7 ~ OO 0~0 l~ l~ ~ 01 ~ M M M ~ 00
N
V7 M
N
P~
N
00 ~ d' ,--i
by ~, ~bA d' ~~-, ~bA 000
~-_ ~N ~~N ~ ~N-~~N
O ,-i O M O p ~ ~ O ~ O ~p '""' O
w O ~ O O ~ ~ O ~ O N ~ O O
ww.wow;~ w.woww
'gin ~ P~-~ 'sue w P-, bn oo p~ -d w bn M a~ a.~
.~ .~ ~ .
ø, cue, ~ ~ Q, ~ Q, ~ ~ ~., ~ bA ~ gyp., . ~ M
O ,-, U ~ ""'' U U O U V ~ U ~ ~ cC3 U CCi U
.,0.~,,pOO 'pc~jO'~UO~~~c~OpOC
o°~:~~W.~° ~v W,-~oW,o~'-~:~W,o~~~W~oM~pWpE
~ ,-, yn ~ _ ~ N ~ 'd ,--.
O~~N~''~~ bJ1~U~~~ ~.-~-i~O~~O~''~~~0~dj,-fl~
~~ ~w-rl~- °~ ~ci1 c~~''~~ ~U o '~~ ~ w
~.~ s~,xaw-.;~ ~,~ ~~:x~~;x~~r~~pw., ~~
"' W~ WW~ W~'? W~ WW
r~i ~ ~ x ~ 'r~i N ~ N
l~ 00 01 O ~ N M
O O O ~ ~ .-i
N N N N N N N
d\ 01 M I~ O V1 d
O 00 V~ ~f' 00
d' d' ~~ d' 01 0~o d1
M 01 N d' ~n ,-.
a1 d1 a\ ~ a\
W W ~ ~ ~ H
383
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d' M d' O I~ ~O lp \O t~ M V1 l~ t~ l~ l~ l~ l~
01 00 O O ~ ' ~ I~ ~O N l~
00 t '
' ~
'
M V1 n ~ d l d ~ ~ ~ V1 t!~ V1 ~ V
01 M ~--~Q1 O\ V1 t!1 ~--~V7 M V1
M N N I
1 M d
d' ~O lp \O \O lp \O
~O \O ~ ~ ~O
d1 O~ d' V~ M M 01 lD lp 00 .~ M M M 01 M M M M
M d1 d' l0 O 01 ~ l~ M M M 01
O M l~ d' ~ V'1 V1 V1 ~!'1
V7 ~O ~O V7 ~ V7 V7 tn In
M -~ ~Y d- N N ,~ ,~ ~n ~n v~ ~n ~n ~n ~n
N ~ ~n v~ V~
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 .~ M ~ ~ ~ 0 ~ N 0 0
.. ~ \ \
\
O~ d _ ~n N M l~ l~ ~n d- l~ a1 v~ O
N N N l~ 01 v~ M
~ N N O ~ ~ ~ M ~ ~ ~ d1 00 l~ l~ ~O ~O ~
N V~ M M M M
M O \O
d-
by ~bA
~
U
0
~
O O O O p M ,--~ O O d1
oo O o o d-
N
--. w r.~w ~l' a1 ~O M M
d' ~_
~O p.a P-i~ by P-i bA M P-i P-~ by ~
O
. .
~
.~ ~ -V-i.V
.
-, O O O r., O ,~ , , ~C3
O O
.S-',
c~ Cd C~
x
W W.~W- ~ W,. ~1 ~ ~C~ v
~ W W
~ ~ ~ ~
o ~ ~ ~ o ~
~ ~ ~
~ U ~ E~ ,...-.
w ~ a ~x w a ~ w ~ ~ ~
~ ~ ~ ~ ~ ~ ~
a a a -, ,
., .,: ..~,a
w ~ w ~ w ~ w w
x~ x~ x~ ~ x~ ~ x~ x~ ~
N N N N N N
M ~O O N d' N
N ~ ~
d' ~ 0
1
d- M o~ ~i- ~ o~
M ~ O M ~ O
d>
M 0~1 O d-
'-'U
H H
x x
384
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
00 l~ O M '~w ~ M d' M M d' d1 N ~ 00 ~ 00 00 M
M ~n l~ O~ N ~ N o0 0o N N ~ ~ d' d- N co d' N
V1 ~O M d' a1 O~ d' M d' d- ~ d- ~O M ~O d' lp N M
N ~D oo ,--~ M ~ ~~ t~ t~ ~ ~ N ~ ~ oo N N M M
~ 01 M ~O V1 ~ V7 N ~ ~~ O t~ 00 d- l0 M M
V~ ~n ~ I~ t~ N ~-~ ~--~ N d- M M ~
0 o M o 0 o N ~ o d- ~ o ~p o 0 0 o N o
01 ~ d' ~ O ~ ~ 00 00 M 00 ~ I~ ~ ~ 00 ~ d1
l~ N o l~ oo M ~ ~ 1~ d' N 01 ~ 01 0o t~ 00 l~ M
a,
N ~
N ~p '-'
01 ,--i d'
N
O
d'
O ~ O O ~ O O .~ O ~ O
P1 ~ ~ P-~ ~-.~ ~~ P-~ P-~ N P-~ "~d~ W N
.-, . ~ . ~ . ~ +-
0
oø,~oo.~oo.~o'-"o
~~ o .~
N N
W o ~ ~ W o W o o ~ W o W o N W o ~o o ~ ~s ~ W o ;~
°~' o ~'~ ~i
a1 :x ~ ;x w ,~ w :x ~ o a~ .~ a~ ;~ .~ ~ :~ ~ a~ .~ .~ U ~, ~s ~ a~ ;x~ :x~
N(~~N (.~I~N (~N
oo ~ ~ oo ~ Do ~ ~ co ~ oo ~ ~ o0 ~'~'
r~,~~ r~~ r~~ ~ rx~ r~~~ ~~~ ~N..~fl
O d- N M d-
N V1 N N N N N
N ~ N N N N N
~D ~O l~ 0o I~ M
~o ~n M ~n N l~
O1 ~ 00 O M V7
l~ ~ ~ oo ~ dN- d-
d1
w W
w W
O ~ aU., U
385
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O d' N M ~ M ~ ~ 00 O M 41 M CO M OO O N ~ M 01
o0 ~n 01 0o d- M a1 ~O d- O Ov O d' N ~O d- d- ~~ N N d-
M d' N ~ N N M l~ CO .~ M O N ~O O1 O1 M M M N ~O
M N ~1 O1 .-r M M d1 00 M 0O N O ~O M d' 41 01 ~ 01 M
O N a1 O oo ~O N cal N l~ N ~ O O ~ I~ 00
M ~ ~ d- t~ O ~ l~ O dW0 \O N ~ l~
o ~ ~ ~ o ~ 0 0 0 0 ~ ~ o o ~ o o ~ o 0
O M ~ O ~ O V7 d' V7 00 ~ ~ lp 01 ~ d1 d1 ~ d' V7 d'
tn 01 M t~ oo ~ 00 ~O oo M O d' M N ~ d~ N ~ d- v1 d'
l~ ~n N O ~ 01
N
01 O
t~ ~i
d1
'"' ~ ~ ~ N ~ O
O O O ,~-, ~j O ~ - O ,--n O O ~p tn
O 01
O O O M ~ O O ~ O _~ ~ O _~ O
w w w .,-_, M w N \O w ,~ l~ w .S~ w ~ O ~ M
-~ Q., bA O P-~ bD ~n p-~ bA O p-~ bA P-~ bA ~O bA l~
"d
.a, -a~ .a, H ~ a~ +~ a~
Q. p, Q, W ~, ~ U vWø,, N ~ ø, ~n ø,
c~ x-, U
..~ v .~ ..~ ~ .~ x
0 0 o W ~ o ~ o -~-~ ~t o ~ o ~ o
v, c~ ~ ~ W ~ ~ W ~ ,.~ c~ ~ r, cd ~ ~ ~ v~ vo ~ ' ~" aW n w c~
c~ c~ ~ cd c~ V a c~i . "' ~' ~ ~' ~' r.,
o W o W o W o ~ W ~' W o ~ ~ ~ W o ~ ~ o W o
~c~n~~~ ~~O~dj"fl~~~U~~'dj~
~ w .~ w .~ r~.~~, .~ ~ Z ~~ QQw;; .~ ~ ~ o r-~~.~ .~ ~ ° ~ ~w' .~ W ~
w .~ ° o
a ~ ~ P-~ '.~, ~ .-, U ~ a P-i .-~ ~'', ".~ ~,' P~ .~, ~ ~, a P.~i '~, ~ .~,'
~ .~'., S~, ~', U ~,
W W W ~ W '._' W N ~ N
_~
~i ~ ~ ~~ ~ r~ N ,~ r~i ~--~ ~ x ~ ..~~ r~i ~-~
N N N M M M M
N N N N N N N N
N
01 d' M M CO 01 M
lp O1 01 00 O ~ d' O
0o N V'~ ~n M d' o0
M ~~ ~ N M d' 01
N ~~ N M ~n d- O
dl dl
O
N M ~ O M
H
W W ~ W
x x x x x H
x x x
386
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N V~ ~O ~-~ O M O~ I~ M oo N l~ O~ N ~fi 01 ~-~ M ~p O O
l~ ~ t~ t~ M t~ t~ l~ N ~D Q\ 01 M I~ ~ t~ N M M O~ 01
l~ M 01 ~n l~ M l~ 01 N N V~ M 01 01 d' ~n ~O Q1 01
M~ d' d' V~I~MI~ONl~~I~O M O d'
~O ~n ~n t~ d- N ~ N d- M M o~ t~ dwi- N ~o ~ M N ~n
00 ~ l~ M \O M M M d' N 00 ~O ~ d' ~ ~ ~ O 01
o ~ 0 0 0 o N o ~ o ~ o ~ ~ ~ o o ~ o
M l~ O oo O N V5 ~ 01 O N oo vp oo ~n N ~ d' ~n
N N V'1 M ~O V~ M d' ~ ~ d' d' M d' d' d' d' ~ d' M l~
N
U ,~ ~ M I i - U
t~ N_
O bIJ d- ~ M _~bA
M
01 ,-, ~ d1 ~ d1 ~' ~ N Q1 ~ d1 d'
O O pp O U O \p "~ ~ O ~ O ~ r"
0o a1 O O d- d.
fs.i .,~ ~O w ~, W .~ M ~,, W ,.0 w ..~ O
p1 bA I~ G-~ N P.~ bD ~--W Pa bA P-~ bA ~-~
~~,' , f-err' . ~ , r-~', , ~~,'
O ~ O ~ .-r O ~ N N
O ~O ~C ~O U H O ~O O n O O
~ Ex-,
W o o, '+~ W o o~ '+~ ~ W o ~ ~ ~ ~ W fil W ,-~ ~ ~ W ,~o N ~ ~
'~ t~ ~ o '~ Wit- '~ v ~ r~ ~ d- -~ E-'
~.~a ° ~ ~a °~~ ~w ~ ~~~~ ~ ~ ~~ ~w
--. a-. ~ ~ ~ a~z''-, ;x~ ~ ~ ~ aw-. :x~ ~ . ~ ~ ~ H cW ~ .nw.~ ;~
P~ d' W N W ~ d' W N
c~ ~ 00 cd ~ ,.-~ c~ c~ ~ o0 cd ~, o0 c~
r~i N ~ r~ ~ ~ ~i N ~ ~ ~ ~ ~ r~' ~ ~
~n v» ~ t~ ~ 00
V7 M V7 M M V7 M
in N ~ N N ~n N
N 01 .~ O
M O ~O O ~O l_0 O
O M N
~-~ ~ d- l~ N d- ~O
d>
'"~W ,~-~ N
"' 'n
W ,5-
H H a H
x x x x ~ x x
387
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M M N CO O~ <f' O ~ ~ ~O M M CO ~ l~ V7 00 M ~!1 ~ 01 lp d' N O\ M
~n V1 N V1 V~ O~ ~ d- ~ O ~n d' ~ ~ ~D .~ M d' 01 O ~ 01 O d' M 00
M M ~O t~ d- ~ M N N N N N d' N M N ~~ o0 N d' t~ d'
N 01 O N 01 V7 d1 t~ M l~ M ~ N 01 ~O M (~ ~ t/7 M ~n d1 N ~ N O
I~ ~n M d- l~ ~ N v1 ~ ~O M N ~O ~ ~ N m oo O~ o0
M d- M t~ N ~-~ N ~-~ M ~~ N N d- ~ N v0 ~~
p o ~ 0 0 0 0 ~ 0 0 0 ~ o ~ 0 0 0 ~ o ~ ~ 0 0 0 ,N-,, o
d' N M d' oo ~1 l~ oo d- t~ N N v1 ~n l~ d' ~ a1 ,-, a1 ~n ~ d'
a1 0~ ~ M d- M ~n d- N d- W h M d~ d~ M ~ d- N ~n d- M ~ m o0
Ga d- mn
_ U '° w ,-.
M
N ,~ 00
N .S~ ~ bQ ~
bA O o0 01
~O ~ ~ ~ ~ ~ ~ ~ ~ 00
o U o ~ o ~ .-~ o
N N O l~ O O N O lN0 Ov
W N ~ bA O Q., ~ by ono P~.~ ø' O P-~ ~ bn 0~1
O .~ ~ ~ O ,~~', ° O O
..-°-~ '~'° 5~., ~" v~ ,-V,
O ~ ~ ~ .~ O ~" ~ O O
~' , '~.-I' c~ , ~ _~'' can
'i'~~oNO° °~O
.U W~°d-x ~ W~ ~.~~ Wwd°oMO W~°oo
bn v~ .~-~ ~ ~' \ ~ N G~.i N N N O
s~, vW' Pa .~, ~ W n P-~
W N d. W ~ W d' W , d..
-N
01 O oo ~ N 01 M
M d' V~ d' d' V~ d'
N N v~ N N ~n N
d1 0o N
N ~ 00 a1 N O ~n
0o M 01 N ~O N N
N ~ d- O l~ O \O
~O ,-~ lp N 01 O\
\O N ~ O
d1 ~ ~ D\ ~ dl
N ~ N ,--~ o°~O oho
N N
H
x x x
388
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~ ~n M v~ M N N N M ~-a M M ~ 01 ~O ~n 01 d- ~O N d' N
(~ d' 00 00 M M M M l~ ~ I~ [~ 00 N ~O .-i ~ l0 l~ N M l~
O\ M ~ 01 M ~D ~O l~ ~O N N M d' ~--~ d' M M d' O~
in ~n a1 ~O v~ ~n v~ N N ~-~ d- O d' 01 l~ N o0 c~l ~ oo M
~ ~I- ~n N ~O O M O~ V1 o0 c0 ~O O ~n
\O ~O M O M N ~--W~ ~O ~ ~~ N M d'
H r-1 ~ rW -i r-1
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
00
0o N ~n ~ ~ ~O O N ~ O .-W ~ O O O O
0o M W- dwt l~ ~ a1 l0 O o0 d- N ~n O ~n d° a1 O d' N O
N O~ r-, .-i \O M ,-i ~ ,--i N
Pa M '~
N
b-A ' ~b-A ~ ~b_A ~
N_
U lip
00~'~ O~'-'~~"~OO~d-~O~ O
O O N Vj O O v'i O ~n O O M O O
°w °w ~ ~ °w ~ °o ~ °o °w r-
°~ ~ ° r-°~ ,.~ r.°~
P-i P-i bA M P.~ bA 01 bA 01 P-~ G-a bA ~O ~ bA P-i 'CS
. S~'..,' . ..-,~'''' . .S.'i':,' . .S"i.-i' . .S.'~,-;'
00 r.,0 ~ X00 ~O'~~ O
~, ~ bA ~ Qr ~ .~r ~ ~ ~ ø, ~ N ~ M ~'
.V-~ .-.-V.,i E~ ~ .~ ~ ~ ~~ , i ~'~ ~ ~ aj .'~ ~ N O
n .O .O $\"' O ~ .O P-~ ct3 a., cd .O .O O c~ .O ''-' O .O
~ W o W o M :~ o W o o°°o x o°°o x W o W o ~ x W o
~ ~ W o ~n
'd T3 N ~ 'tf ~p a ~ a ~ "d p~ a "d V~ U ~ "d O
O O Q~ O .~ .'..'' O ~n O V7 O O O l0 O v O ~--~ ~,' O O
yn ~ v~ O O ~ v~ r, v~ ,~ v~ v~ v~ ,-, v~ v~ O ~ ~ v~ O
o ~ ~ ~ ~ U o ~ ~ ~ w ~ w ~ ~ ~ ~ ~ w ~
w~ w
~, ~ aw.~ ;~ ~ ~ ~ x aw-. ~ ~ x ~ :~ a1 ~ s~, ~ a~ ;~ ~
W W ''' W '"' '"'' ~ W N W N W N
x~x~~ x~~ ~ x~x~~ N~ x~~
o Wit- ~n ~ ~ t~ oo cs
N N N ~ N N N
N
tn Do ~ ,-~ d' ~O ~W o
\O l~ M N O ~ O cn
due'. N oho due' ~ due.
d-
M M
r~ ~' C7 L~ W x
x x ~ ~ x x x
389
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d- I~ M ~n ~O N N O oo M N m0 dw n O
--
O o0 .~ N ~O M M ~n N oo O~ I~ d' ~n
~
N
~O ~--w0 ~ t~ d' I~ ~ I~ N O N M N M
M
M l~ ~O M N ~ V1 O ~n ~ -~ ~
M
O l~ ~ O 00 d' 00 M ~ d' ,~ ~ 00 GO
~
N d- ~ d' .-, ,-, ,~ c0 ~
M
d-
0 o p~ o d- o o N o 0 0 ,-, o pp o
\ \ \ 0
~ ~ ~
l~ O O 0o N O N O O 0o O O
D1
~ l~ ~ O N a1 01 0 a1 01 d' 01 ~ a1
M
N
N
N ~ M N N N ~ N
~ ~ ~ I ~
I
'- ~
,..D ,.O ,~ ~ ~ N ,.O ,.D
' ' N N N
,..fl "C "O bl7 bA by b4 "CS
~ LO ~ ~
N N ,~ .-r O ,--a -.~ O
w O O
~O N
O a1 ,.-~t~ ,~ ,~ O ,-~ ,--i O ,~ O O
- -
~
O ~ O ~ ~ O ~ 0 ~O O ~ O
N N ~D \O l ~O
~ d> O .-v O ~ d- O d' d' O ~t O d'
~ V~ V~ V7 ~ ~
~ ~ ~ ~ ~ ~ er ' ~ ..,
bA 0 Q-, bA P-i bA bA f~ bA bA p by
1 ~ ~ ~ ~ ~ ., ~
N
O N ~ d ~ d ~ ~ ~' ~ ~ ~ ~ O
3.a ,~ ' ~ ' N ~ N N ~ N ~ +.~
O Ts +~ -~ ~- +~
, N a> N
a~
~ ~ ~, ~ c~3 ~ ~ O
cd cd cct ''
~ ~u ~ . ' cOn ' .S-',y-' .~'.,~,' +- ~.,''-N ~
~ 4j N dj v cn ~n r~
' .
~~ ,-.~
,
-
,
U N
.
O c~ cd ~ N ~ ~ "d ~ ~ '~ x 'd O
: ~ , ~ .~~ r~ x ~ ~
O
~ ~~' , ~''~'. ~ 0 ~ 0 ~ N
- ~ y 1 1
p~ ~
~
~ ., O 0. O O. n ~ n ~ O
v~ .~-~ +.~ N N N ~n N
.-, f.., ~..,~n ~ v~
, ~..,
p
cn , ~ ,--~,~ .~ ~O l00 ~Q3 ~N d
N U v~ ~ .~ ~ ,-~ ~ O p O v~ O
N i~ ~ ,s-~'' ~,' v~ v~ v~
~
o'~ ~ w a~n~~; ~ ~~ ~'' ~ ~' w ~ w w w f~
~~ ~~ ~ ~ ~ ~ ~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ W ~ ;~ :~ ~
s~ - a~ a~ a~ a.. a~
~
d ~.., d- ~ d- d L~ d d r~ d p~ d-
- - - - -
_ _ _ _ _
'~~
.
x~ ~ x.~ ~ ~ x~ ~ ~ xN ~ xN ~
O N -~ M N d' M tn d-
W O ~n ~ ~W o ~W o v~
N ~n N ~n N ~n N ~n N
M 'Gf V7 01
I~ oo l~ d1 d- N ~ M l~
M V1 00 01 M 01 00
V'7 d" M O O d1 d1 01 00
O d' O M ~n t~ d' l~ d'
.--Wn ,--iV) ~ V~ M
dl ~ ~ ~ ~ ~ D1 d1
~ W n N
'-
.a
390
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ~O ~n v~ ~ ~n N ~n v~ M ~n M ~ I~ 00 N
O~ ~ M d- ~ d- N ~n oo ~n a1 O O N d' ~n
N N N ~ ~ ~--~ ~ N ~ N M N ~n N M N
M O oo O 01 a1 d- d1 ~--i l~ ~n N N ~ M
N ~1 ~O '~f' l~ ~ V~ 01 M M 00 01 O 01
0o d- oo M N ~-~ ~-~ N ~-~ d- ~ M
o ~ ~ ~ o o ~ o M ~ o \ 0 00 N t~
~n ~ ~D ~n M t~ ~ °~ N M V~ ~ ~O l~
d- O d' ~ M M M ~1 M 00 M d' l~ d' ~ M
d' d'
01
O
~O ~O ~ ~ O O ~ O O O
O O O M M O~ - M M M
r, ~n d- ~. d. V~ ,-, ,-, N ,--~ ,-, ,
p ~ O O O ~ O O
ww°°w.~ wf~ ~Nf~f~w
SZ, A-, P1 P-~ ~, P-~ A-, bA ~ ~ A-, P-,
Q3 N O
w w w w
c~ bA v~ by cn bD v~ by v~
U ~ .~ . ~ ~ t-. t.. ~ t-~ s~
Sue" ~'', .fir ~''.
+~ O r, N ,., O 'r N " N
U
a~ ø., 3 ~ ~ ~ ~~ i ~ i ~ ° i ~ i
~' ~, U ~ ~ ~ ~ V Pi ~ P~ ~ ~ ~ P-~ ~ P1 ~ P-,
. "'' ,~ c~ ~ ~ r..~ ~bA ~' ~bA ~,' '-~ bA ~' by ~,''
M ~~ M O
v ~ ~ ~ ~ ~,'~t ~ ~,'~t °o ~ ~,'at ~,'at
.S-', ~ ,.~ l~ ' a3 ~ ' w ~ ~ l~ ~ ~ , ~ O f-~-~ . ~ O ~ ° w . ~ O ~ .
~ O
'x'' ~ ~ N ~ a-. w ~ ~s N ~ a., 'a ~ a1 ~a w ~ x a.~ ~ -~s a.~ ~ ~ a..~
rw ~- r~ ~ d- ~ r~
x~xNx~~ x~ x~ ~ x~ ~x~ x
Two ~o ~ ~ 00 0 0, o
~n ~o ~m vo ~o ~o ~o t
N ~n N N ~n ~n N v~ in v~
l~ N
01 tn ~O o0 ~O oo t~ O N m
O O~ t~ d- N l~ ~n .-~ N l~
tn .-r ~ 00 01 00 l~ N ~ ~h
o ~p oo d- ~n ~n M M dwo
~n v~ N N N ~ l~ l~ N
.-a 01 00 01 wn ~ l~ 01 t~
a>
N
a a U ~ °w~ ~ x x
c7 a
o ,°x
x x x x x x x x
391
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d- M !~ ~ -W ~ c0 ,-~ 01 I~
O O
N
00 01 lp d' ~ O V1 l0 O M
M
~O
N M co ~n ~O M ~ d-
N oo
~O
M \O V1 -i M ~ 00 d'
CO d'
l~
~n ~n oo ,-w o m M N oo ~ 00
.-~
M
N N N O d- ~O M N M
~n
p ~ 0 0 .~ o o ~ ~ o p
0
d' ~ ~
~D N ~ ~ N O N 0 d' N
N 1 ~ 1
"C3 N
M
O O ~ O p O O p~p-0 0
M M ~ M d-~ M M ~~'~M M
r-a O ~ ~-.~ O
O O ''" O tn O O ~O O O
~j ~
d-
O O O O ,....,O O ,_, O O
,-r ~
' ~ ~
~
Pa bJ~ W ~ bA
M
O n
_ _
~
i.~, ,~.~., ,tai O S-y i-~a O ,s.~.,~ bA
~ ~ ~ ~ ~ ~
~ d E-i ~ ~ x ~ ~ ' ~ ~
+~ ' ' a ~
~ d ~
' +~
,- , . ,- ~ ' +-
- ~ - ~ . N '.~
~ - N
N
N ~ N ~ ~ ~ ~ N ~
~
bA .--a .-r .--i
o~ o~ U o~ a ~ o~ ~~ o~ o~
~
~ o
o ~ o r O .-fl u~ ~ o .~ a~ ~ o ~ o
o o o o
o~' o'~ ~ o'" ~ o~' o~' ~ o~ o'~
U
U ~ U .si ~ ~ .~i M ~" ,s,' ~ .~i .Li
U U U U U U
bA
~
~ ~, a ~,'~ Wai
. ~
o ~
f-
~ w E~ w .~ .~ w .~ w .~ ~ w..~ w .~
~ o .~ ~ o ~ o o o o
~~ o c~ ~ ~ ~ ~
a a '
~
~ ~~ a~ a.~~s~~ ~,~ a~ a a~~ a~~
a a~ a a a
a~
r~ d- r~ d- ~ rx
xa xa ~ x~ ~ xa xa ~ x~ xa
N M ~n d- TW O oo I~ o0
V> ~n N V~ ~n ~n N ~n ~n
d- N
01 O 01 l~ ~i" l~ l~ \O l~
00 d' 00 M 00 00 l~ d'
\O d1 N V7 l~ ~ -~ N 01
d\ ~O -~ O N M N l~ t~
\O ~ N l~ ~n ~ ~ \O d'
a1 ~ d1 ~ ~ d1
p l~ M
d' O d' p O O
O O
_ _
392
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O two 0o m w0 ~O ~n N M d- O
O O~ ~O O d' l~ M ~n O~ N ~ t~ 01
M M N M M C~1 ~ M N N
~O ~ 01 l~ N ~~ N ~n d' ~ ~O N ~t
~n d- N Wit' N d1 ~ V7 \O \O d' ~O
d' N ~-1 M N ~ M ~~ N M
00 O1 N M ° N .-~ lp o 0 0
M N M N o ~ ~: ~ ~ ~ ~ N
~~O'Mt~MO OMV7MM
M ~ 00
O
b4 ~ '~ ,9
-, :~~ t~ bJ~
0 0 0 0 ,~- O O O N O
-_ _M _M M_ M_ O -_ _M _M _M N M_
pMp tPj O O O O p p O O O pNp O
d' N O O O O ~ O O O O ,-, ~ O
w w w w .~o w w w
en o w a~ a., a.a cw ~ a., w a.. '' en ~ aw.~
°n
O ~ ~ ~~.'' ~ ~ ~ ~ ~ N O ~ ~ ~ ~ ~ N
"~ r-7yn 'd v~ "C3 w 'l7 v~ "d v~ W n "W n "LS .,~ v~
M v~ ~ ~ U ~ a~ ~ a~ ~ ~ U ~ a~ ~ U ~ ~ a~
O ~ O ~ O ~ O ~ M '~ O ~ O ~ O ~ ~ O
~ U .~.' U .~' U ~-,'' U 01 ~ ~,' U ~"' U .~' U O .-~' U
a-' ~'
.... ,~ .,~ M
w ~ o <C ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ o.a~ ~ ~ ~
~~x~~~a~.~~=~aw.,~-°aw..~~~°~ ~..~~aw-
,'a~°~~~cs°aw..~~-c°s0
w w w W ~ W w W ~ W
x~ x~ ~ ~~ x~
~n ~n ~mn N v~ Vmn N m
N
.~ O ,-~ p o0 Q1 V7
~-~ M d- N dw0 O~ N M
l~ l~ M .-~ d' 00 01 t~ Q1
d' t~ O .-~ ~ .--~ M ~D O
M d1 ~O l~ ~ Q~ N ~O .-W~
O\ ~ ~ ~ ~ ~ ~ dl
d- ,~ ~ N N M ''-' ,-.
~ Pa
a a
x x x x ~x x x x x x
393
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
l~ d' ~O l~ l~ I~ ~ O M l~ 00 M N -W~
~O O 00
00 \O O V7 .-i M 01 M M I~ 00 V'1
~ V~ V~ V~ l~
N
M N N ~O d- o0 00 N ~ M ~ ~O
l~ ~ ~ oo
.-.
\O N l~ d' v~ 01 ~O l~ d- oo v0 V~
d- ~O l~ N a1
N
d' l~ O ~O l~ 01 ~ O oo N M l~
O N O ~
M
O~ d- N l~ l~ N M ~ N l~
l~ ~O ~
0 0 0 0 0 0 0 0
0 0 0
V7 00
M V7 \O V1 d' ~ M d' M tn
~D d' 00 d' t!~
M
a
z
O O O N
~ o O O O p
M O M
O ~ O ~ O O O O p
a
w w w r- w r- w ~ i
'' ~ ~
P-~ P~ P-W 00 p~ p.., p., P-~ b4
M
O
b1~ V7 V1 V7 V1
~ b~ bl~ ~
i.-~ -~ i. 7- S. O
+~-~ ~ i -~ a -~
. . O O
~
' ' '.O -
~ O W + +
N ~ N ~ - N
N
, ~ ~ N ~ N
o ~ o ~ H o ~ o ~ o '~ o
~
u~
o ~ o O ~ o ~ o r o ~ i O
~ o
,~', ~ .s-i'"~ ,.=i ,~".r ~'' -~' U M
U ~ U U U U V
. ,
CA ~ bA ~ by bA by b4
~' ~ ~ ~ ~ ~
V .~ ~ ~ V tN V ~ ~ V ~ V V ~ ~
~ .~ .C~ .c~ CCt N
.
~ ~ ~ U w '~
~ y w ~ w ~
w
Ts~rs - -~~s~us -.~~ -.~- u,~
a a - d-c a d
-. -, P a a
-~
W W W ~ W W W W
N
00 l~ oo .-~ O ,~ N d- tn
N ~ ~
N ~ ~ ~ N N
~
a1 a1 ~ a ~ d1
1
M O _ p
~O N ~ d
-
O O N ~ ~
N
01 Im n .-~ a1 d' ~ ~O .--
od-o d d- ~ ~O oo t~ O
o ' ~ z "' ~ w U
o
W ~ !~ ~
p U x U
.., ~ ~ ~ ~ a
x x x a
x x x x x x x x x
394
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d1 M tn V1 l~ N l0 M l~ N M
O l~ M N ~n ~t ~ d' M
M oo .~ N ,~ .-~ N N ~O N
N ~ M OJ ~ M ~ O O O
01 ~ M ~n N N l~ t~ O a1
N ,-~ ,~ ,---~ ~ .-~ ,~ ~p r-,
N
l~ ~ a1 d' l~ M M ~n 01 01
p I' O I~ M .-i ~ M ~ M
01 p M M lp M M M
N ,-
a
W
0
O p O O O O O O O O O
M ~ M M M M M M M M M
W
w .~ w w w w w w w w w
a-. ~., a1 ~ w a.~ a~ a~ a~ as a~
en W ~ en ~ on ~ en ~ aA ~ du ~ ~ bn ~ en
~ ~ an
~.
~s
a~~ ~ a~., a~~ a~~ a~~ U ~ a~ a~~ a~ a~
~ ~
d U +,:-~ .~,-d +,:-~ +,rd +,:d .~., .~-~~ +, ~
,--~ Ts :~ ~a
~ ~ c~~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~~
_ '~ ~ _ 'Q O ~ O '~ O '~ O '~ _ O '~ O '~ O
O a O O '9
'9
O ~ ~ O ~ O ~ O ~ O ~ O ~ O O ~ ~
~ ~
O O
4"U ~ ~ ~ ~i ~" ~i ~i ~i ~' ~i
~
.- U U . U . U .-U . . U ..
U U U
bA ~ bA ~ bA bD bU bA b4 ~ bA~~bD
~~~ ~--~ .--i,-, ~ ~ ~ ~ .-i ,-n ~ ,-i ,-i
~~----~~.--i ~ tti .-~ ,--i .-, ...-~~ cd . ~
.-i .-~ C~cd
H cti ,r .-, ~
> ~ cC cat cCi
c~ 7 y
, , ~ , , ~ , ~ , ~ , , ~ ~,~~,
, ~ , ., , , , , ~
~ ~ ~
~d."'1 ~ Ow c~t w c~ ~ ~O ~O c~t ~ c~ cd w
w~aTS a~ . a~~ a ~~ a . w . a~~a~ a ~ 'w~~ .~~
~ A...-~ro r '.i~a-a ~a~ a .~ a a
w ~ w w w w w w w w w
x x x x x x x x
~ ~ ~ ~ ~ ~ ~ ~
M ~O d w n ~O ~ 00 01 O .~ N
d1 00 01 Q1 01 01 01 01 O O O
V~ N v~ ~ v~ ~n ~n ~n ~ ~ ~O
O M -~ M ~ d- N 0l l~ N
V7 O o0 0o d- oo M N oo N ~O
O l~ ~t M l~ 00 01 M O O O
l~ -~ t~ N ~ oo a1 co O N
l~ N ~ 01 00 t~ v W n d- N M
a1 ~ a\
d> a1
W
U f~ f.~ ~ oo o 0
w
395
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O M M m o~ o~ oo M ~n d- I~
M M t~ O M V~ O ~n l~ ~~ N ~O O
N O~ oo d- CO O~ N O N ~ N v0
I~ N N O o0 v~ d- O t~ l~ N ~ N
O ~O O~ O ~ ~ N ~ O M M
N ~O M 01 N O oo ~ N
'"' d- ~o t~ \° \° \ \ ~n M
M N ,-mt 4')
M ~ N dN- t~ d' 0~1 O ~ O ~ d'
N
O (Ya
M U
N N
O ~ O O O O
M_ ~p - M_ M_ M_ M_ ~ OM O
O ~ ,-.i O O O O ~ O O
O N d- O O O O ~ O O
P~ ~ b!7 N P~ 0.. P-~ P~ ~ ~, G~ P-~ by
i
d
w ~ w w w ~ w
<n b1~ +~ O v~ by v~ bA cn b0 ' cn b4 ~n by :~
N ~ r--, .f,0, ~ O ~ ~ ~ .N ~ ~ ~ ~ +O
~, 'C7 ~d ~r3 "d "d
~~bA'~ p"~ p ~~' p~ p~ 't"'' _N p"~ p'~ ~'-,
O O +~ O O
o ~ ~ ~ ~ ~ o ~ o ~'~ o ~ o ~ ~ i , o ~ o
M ~ O ~ U ..~' U O ~'-, U ~~' U
P-~ ~ ~ ~~' ~ ~ ~ ~ f~ ~ "~ ~ P-y ~ ~ O
~' O
c~d ~ ~ N O N ~ ~ ~ ~ ~~ ~ ~ ~ a3 ~,~ ~ ~ ~'~ ~ ~'~ V'i
U ~-~' (~ ~ U ~ U Q~, ~ 'd U U ~ ~ U Q~, U
o w ~ o ~ ~ "~ p~ w ~ o w ~ ~ o w ~ o w ~ o ,~ ~ ~ w ~ o w ~ o °
~a w~~ ~..~U w~t~u a1 a~~~a w~s-d w~a~ r~.,~,,.~ a~~~ a~~d~d w
x.~ ~ x~ xN x~ x~ ~ x.~
M vo d- I~ ~W D t~ oo N
O o~ O O~ O O O O O
~O N ~O N ~O ~O ~O ~O M
a\
dN' O ~ dN' 01 .~-~ N
M O O ~n ~ N O t~ ~n
01 ~--i ~O W o0 l~ M N
dl
r, d-
w
OC GC ~ N H ~ H O H
x x x x x x x x x
396
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~t O lW O M ~ M O d' O l~ N .~
I- O
'~'I~ M M O 01 \O \p N O l~ d1 M
N O
d' ~h M N M 01 N ,-~ ~ M N v7
. ~ l~
M O l~ 01 M O~ ~n M 01 ~ 00 O \O
N \O
N N ~--roo N V1 ~ ~n d- O M O~
l~
~O d' ~ N ~ M l~ ~ N
d'
M ~ N ~ O ~' ~ M- ~ ~~ N M
~ d 0
1
M ~ d' O d- ~ 01 o0 ~ o0
~ p
a1
N
N O l~
- O ~ O O O O ~ l~ l~ ~ l~ 01
'-'M ''~ -
'-
d- M M M N O - N N ,-~ N ~
;
O O O O O O O O
O ~ ~ N ~
N' ~
~ .~d-w w w w .~O w w .~~.~,w w
a~ omn p~ ~, p~ P-, bn P-. a., bwo P., P~
~
.~ s
;
bn 'a ~ on ~ bn ~ bu '~ -d ~ . ~ 0
o o o 0
' ' " ~ ~ ~ U U N~ U ~-
N
~ ~ N~r NS, N.$ ~ x ' ' x ~ ..
O ~ ~ ,
~
.--~ ,--i ,--i ~ ~, ~, ~ 'S ~.,
~., .fir "
~'
~~ ~ ~ O ~ O ~ O
O O ~ O N O ~
O ~, D, ~
.ti a ~i .~ ~ U ~ M O O r'.'
U U U tn
O
P- ~ p~ a, p., N p U U ~ U p..,
~ ~ ~ ~ ~ ~a ~, ~a
r, ,,
0
w ~ ~ ~ ~ . ~
.~ r? f. f- w .~ w ~ f- w ~ w f-
o ~ .~ ~ .~ o ~ ~ ~ ~ ~ ~
o o ~ ~
~ a~ w w -o a~ a~ a, .~ a~ w ~ a~ a~
~a ~ ~s zs ~a s~, ,~ ,.o ~ .~
~ ~ ~a ~ ~
w ~ w w w w ~ w ~ ~ w w
~
x ~ x ~ x ~ x ~ x ~ x x ~ '~-Zix
-~ N ~ ~ -~ cal
O~ O d' ~ N l~ M d- a1 v1 O
O .--~ O ,-~ .-~ O .-~ ,~ O
\O ~ M l0 \O M ~O ~D M ~O M
d' t~ ~ l0 l~ M ~t O M N M
-~ M N V'1 O M 01 O (~ 00 V7
O \O V1 lfl VW ~ 00 ~ M 01
d' ~ ~O M M d' M N
~n M ~ .-, ~ ,~ t~ N ~ v~ N
O1 a1 a1 al ~ ~ ~ a1
00 ~o m ~n
~
o ~ ~ x ~ ~ ~ w r..
~
~ x
x x x x x x x x x x
397
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
00 ~ M ~O ~O ~O N oo O o0 01 .-~ ~ 01 O~ ~ N (~
d- ~O ~ u~ ~O ~O ~n ~p M \O ~ ~n O ,--~ d- d' oo O
N 'O ~O M ~n ~ ~ ~ d- ~n N ~ N ~n o0 01 O M
00 M ~ d- 01 01 ~O l~ ,-WO I~ dwn O ,mn N l~
d' d' N ~ M V~ ~ 01 00 O ~ d' d' M V~ ~O d'
M ~ ~ 00 O
M c ~ ~D c \ ~ c \ ''" \ c ~ o o ~ N
N oo ~ ~n o0 0o d- O N M ~ O 01 O
M d- d' l~ d' O M M M 00 \O ~ 01 l~
M "' U ~ U U
~M
0
i ~ '~ ~ N a, a1 0~,
0 o N ,-; o ~ ~ a '._' '~° °' ,_., ~ °' ,=~ o
a, oo O ~o ~t o N '"' o ~ o O ~ r.; o
w° w .~-~°w M~ O I~~O MM O MM O
f1, P-~ bA M P~., ~ bA N ~ ~ bA N Pw-ii ~ bA ~ P~-~ ~ bA ~
O U O O O a
N ~ ~ O ~ ~ ~ N N
i Cd ~ V~7 ~ r~ O
.,"'.., O .-~ O P-i ~ ,-, O ~ H ~ ra '~ ~p N
~ o.t ~ o ~.°~ ~ ~.~ ~~ o
~O N ~ ~ a1 ~ bA ~ ~ ~ ~ P.r ~ ~ p.., M . ~ ~ ~ ~ . ~ ~ R~ ~ P-c
~ 4-i M 4-i ~ .~ _O .~ .,~ ~~~ t_~ v~ _l~ v~
p~~N p O w0 U ~'.~ ~ ~~ 0~..~~ O.-,
V w a ~ V w O ~ ~ ~ O O ~i ~ ~ ~ w ~ ~ ~ ~ ~ ~ ~ O
w r3.,~~~w~s~;°o w~~~~Uw ~~, w ~~, w~~
P-i 4-i ~ Pi 4-m. s., .s-~'' ~.' Q-, 4-m ;.fl ~ as ~ 'Z3 '~'' P-~ a "C3 .~,' P-
a ~. ~
w w ~ w ~ w ~ w ~ w ~ w
r~,N r~,N~ xN ~ ~.~'~ ~ r~N..~fl ~N~ r~i
N M d- ~n ~p t~
M M M M M M M
NO ~ O ~!1 ~ 00
N d' ~n O
d>
N
N ~ N
r~
O W L~7 U w
x x ~ ~ ~ x
398
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O~ .~ V7 I~ M M l0 (~ 00 .~ 01 00 Q1 l~ \O M d' N M d'
N ~ N oo N ~ d- M 01 O O M o0 ~O o0 0o N vW~ ~n
N ~ M d- N N N ~ ~ N M d' M M ~n ~O
~ lp M 00 l~ N ~--a ~~ M M 00 M d1 O l~ ~ ~ V~ M
M M ~ d' d1 \O ~ N N M N ~n M N d- ~ a~ ~ ~n
MNd' ~N d'N ~~M
0 0 0 ~ ~ ~ o ~ o ~' ~ ~ ~ o N o ~ ~ o
.-i O ~n M ~ ~ N ~ o0 ~ oo ~n oo M ~ o0 O ~ ~ N
d' d- M V~ N d- O~ (~1 0o N d- V~ ~p v7 N d- ~O N ~p ~O
M
-
U ~ U
0
_ _ ~ _ ~n _ oho ~ ~n
0
- O U l~
00 ~ O O ~-r~ ''~ O (w '-; O M p O ~ '_"; O O
O O o1 l~ O M .-~ O o0 N O ~ M O O
~n O O d- (~ O V 1 r, O r, \_p O O
bfj ,~ PS-~ P~-~ ' bA due" P-~ ' by O P-i ~ bA ~ P-i ' bA 01 p-WbA
_ N
_ ~ N
'~ ~ ~ ~ 0
~ , N N ' U _N ~ ~'-'
U ~ ~ 5-i O
4-a ~ O ...'t"'r . ~ t+-~
O
N O ~ ~ ~ ~ 'i'.' ~ d- N ~ ~ .~ O ~ ~ '-~ N ~ v~ '~
°U ~~~o~o
bA s1 N O N ~ ,~-yU O _cs~ _D, v~ ~ c~ M
N°° ~ ~ ~ O~ ,~~~ a ~~ ~~ o ~w ~~
w w ~ w ~ ~ w ~ W U w .~ ~ .~ w ~ i ~ ~ w
7.a ~ ~ ~ ~ ~I ~ 4-~ ~-1 a ~ a ' ~-I ~ 4-~ N ~ cC3 U a a
d_- p~~.,d_-~d_-~d_- P~d_-
-;
..~fl r~i N r~i N ~ ~ N ~ r~ c~l W-~' N ~ x N ~ r-
IN IN IN IN IN
M M !!M M M M M
01 ~ d- M oo N N
00 O ~ 00 N M M
dl
N N N N N M V7
r-, N N
a1 a1 a1 a\ a1 a1 a1
a1
~ ~ ~ ~ ~ a
x w
U ~ ~ H ~ W
x x x x x x
399
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N oo ~n v~ ~n OWE O ~O ~O O v1 01 ~ l~ oo O~
O M ~ ~ 00 01 d' O d' M ~ 00 01 V'1 ~ O
N d' d' d' M ~ N oo ~ t~ N N d- M M
M I~ oo M N ~ ~O ~n N O N M ~ N N N
N ~ N ~O ~ \O N CO d- ~ d' ~--~ N
N M oo ~O ~n ~ N N
o ~ ~ o o N o 0 0 0 0
M 01 O N t~ 00 N ~ ~O O O 01 l~ 00 O 01
l~ ~ O 01 d Wp d' M M M d" M N i~ N
d'
U
a1
0
M ~ d- ~.,~ ~ O ~ '~ Q \O 00 ~ ~--i
r., O O pp [w O pp ,.1 O .-~ O O .-i O
N O O O ~n N O ,~ .-~ O O O O O O
~ bA N ~., P-~ ~ op ~ p.., ~ tw O P-~ P-~ ~., P.~ P-~ P-~
'r
'-' U O
N
~r O~MO~wOw,'~rnN ~OU~..,'~ '~''
a, ø'' ~ O N ~ N ~ ~ '~ ~+~~' cOn ~ '~ ~ 'd c~ . ~ "O
ate, ~ ~ ~ ~ ~ ~ ~ ° rx ~ ~ ~ ° c7
~;~C~7~~ ~ ~~~~ ~ v~ ~ ~ ~ ~ ~~~cW7~
r~ ~- ~-! d- . w ~' ~ w a~ r~
r-' W W ~ W ~ W W W W W W
x N ~ N ~ x N , ~ x N x N i1-i N x N x N x
~n ~ l~ 00 01 O ~ N M
N N N N N M M M M
M M M M M M M M M
Q1
0o M N O O N d' l~
M d' ~ V1 N ~ ~ O M
v7 01 01 .-~ 01 ~ N O d1
N N ~O o0 00 O N l~ 01
a1 a1 a1 ~n d' ~m vo ~o
d' ~ ~ M d' d' 01 O M
a
H ~ x a ~ ~ w w v
x x x x x x x
400
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O Wit- r r O M r M .--. O O
M M .-~ O r O O~ \O d' O O
d' d' r ~ ~ ~ M M 00 t!'7 V7
01 O v7 00 N d' ~--r M O \O M
M r M d' ~ d' ~ M r r
N N N ~ ~ ~ N ~ r N
0o a N ~ V1 00 \O r
N d- N O N o~ N n ~ oho
r
U
0 0
M_ M_
r r M
o'n,a~', ~Uor,U~a"',~o'n,°°
~n ~n ~n ~n v~ ~n r ~n "'
°o °o °0 0 0 °o °o o °°
M
P.t 1~ A-r bA p.a bA P-~ P-~ R.~
T-W-i t~ i.~ ~,
O O O O O O
0
o ~ o ~ ~ ~ o o ~ ~ 0 0 0 ~ o ~ ~ o
~t ~a ~t ~ ~ ~ o ~ ~ ~ o ~ ~ ~ ~t -d ~t ~ ~cs ~
N~ N~ "o ,~~'~'~ ,~~~N~ N~ '~ N
p1 U .~ O 01
o ~' ~ o ~' ~ o ~'L' ~ o° o .~ ~ o° o ,~ ~ o ~ ~~- o ~ ~ ~ ~ ~ o
~ o
W W N W N ~r W< ~ W
N xN ~N xN ~ r~N ~ rain ~N rain v-~'N
d' ~ ~O o0 r 00 01 O
M M c<1 ~ M M M d'
M M M \O M M M M
N ~t M V1 ~ ~O v~
M r ~ 01 ~ M ~O
M dwn d- a1 0o N 01
~n d- N r N r ~n O
O M r ~n oo ~n o0
r r r a, r o0 00 0,
M r
o ~ ~ ~ ~ z W o
x x ~ ~ ~ x
x x ~ x
401
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O~ ~~ d- ~O N O d- oo t~ ~o N ~o M M ~o a1 O~ O ~O O O
00 l~ d' ~O ~--~ ~ al N ~O d' N N ~ t~ N ~n ~ ~O ~D
v~ ~O ~O o~ O O M d' d- ~-~ ~ ~O d- ~~ M M ~ N N N
~O 01 a1 00 01 O O O M oo N ~n a1 O~ N I~ ~O O O ~n
\O V7 ~ (~ l0 O d' 00 V1 V7 ~ t!~ 01 ~ M N M CO 00 ~
d- d- N ~ 01 O ~ ~~ ~~ N ~n N ~ d'
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
~ \ \ \ \ ~ o \ \ \ \ \ \ ~ \ \ ~
d' M CO M O O oo ,-, V'1 00 ~ O \O N ~ O 01 00 00 M
t~ M o0 00 0o m ~o ~ ~n M vo N M ~n d- N ~n d- d
U U
00 ~ a1 ~n
V7 ~ ~!1 V1 pip V7 ~ - V7 M
- 01 ,., - O\ 01 r..., - d1 p~ ~; 01 ~ -
''; ~ ~ '"'~ ~ In d- r"' U7 ~ ~ V~
O 00' O O ~ O lp ~ 01 00 ~ V7 M
O M ,.-~ O O M ~ O N ~O O ~ v~
00o p., ' bA N P-~ P-i ~ bD O a., ~ bA O P-i ~ bA ~
O ~ O O O ~ O
yf~ y~ ~., y~ p-,~ .~~1 ~
o~ ~~'a~ o~ o~ ~~ o~ ~.-' o~ ~n
TScd ~~~ ~c~ ~d a3 a~ . ~cd ~.~ '"dc~ ,~
.-, v o o ~ ~ o ~.,
o ~' o u, 'o ~ ~ o ~'' ~ o ~ o ~ o ~ °o '~ a~ o ~ o
0 0 ~
~~,~aw.~~ ~w.~a~.~aw ~.~W~ o o~,~a ~ o
~a~~C7~ ~ ~ ~a~~C7a~~L7~~ a~~C7~-~ ~a~~C7 ~
r~ d- ~ ~ d- r~ d- ~ d-
W ~ W W ~ W ~ W
r.~iN ~ ~N r~N ..~fl r~N ~ ~,N
N M d'
d- d' d' d' d'
M M M M M
N a1 d' ~O O~
a1 d- ~n tn
N dwt d- d
d> a> dl a> d>
N
O ~ Ew-~ w U
402
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
Q~ O ~n OWE ~ .-~ N o0 01 H N N oo Omn \O ~-~ H ~n v» O
l~ .-~ O1 l~ N ~n ~n oo N l~ N O N N d- d- a1 t~ t~ ~t O o0 00
-~ .-, ,-. ~ H t~ l~ l~ H O d' l~ 00 tn ~ d' d- ~ 00 ~ l0
N .~ N .-i .-~ ~--i N H .~ H r--w H
~ .wp d' a1 ~ d' N N t~ ~O ~n M O oo d- tmn N d' H l~ M
O N M ~-~ l~ ~ I~ ~O ~O Q1 (~ a1 00 l~ O O O M M (~ d' O N
.-, H co N (~ d- d- tn o0 00 ,-mn oo m ~n N N ~n O
H ri r-i r-1 v-I v-i r1 r1 r-1 r1 v--1 r-1
0 0 0 ~ ~ 0 0 0 0 ~ o ~ o ~ 0 0 0 ~ o o ~
O M V'~ O ~ o0 .-~ N O d' a1 O V7 ~O l~ O l0 O H l~ ~ d\
d' M d' d' N o0 01 00 M M N ~n N C~I ~n ~n M ~ d' M d" 01 M
d- ~ N
U
t~ N
00 ~O d-
in ~ ~ ,~ mn ~ 00
O~ ,-., - 01 ~ '-' 01 ~p N
W j- ~ ~ H ~ ~ O '_"'~ O~
O O ~O p 00 00 O d' a1 O
r-°~ ~o °w ~~°w .'~o°w
bn o a-, bn ~n A... bn o w
O O V ~~,~ O
. ~ ~1
~, v~ F,
-°o ~ ~ ra ~
0
U
O
O ~r O v~ ~ O Ur ,~ .~ ~ O ~ ,-, ~' ø, .
~,aw ~ ,~aa o r..aw o~ ~.~,
~ ~ c7 ~ ~ ~ ~ L7 ~ u, ~ ~ C7
~_r ~ d- ~ d_-
H
N ~ r~ N ~ r~' N ~ ~ N
M IM IM IM
00 ~1' O~ 01
l~ l~ O d'
00 00 OO 00
H N N d'
a1 a\ a\ a1
O
H
w
403
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
o vo vD N o 0 00 0 ~ ~~ ~ ~n
00 .~ ,~ ~ ~n O t~ M O~ N N N
\O M t!7 ~D ~ I~ M l0 00 00 00 M
0o N t~ M N ~n d' ~-~ ~ a1 ~O ~n
O 01 l~ N ~n O d- 00 O I~
N N d' M N ~D
~ m o N o M o ~t d- \ ~O
0o I~ oo ~p l~ O M O M N oo l~
O1 N l~ p~ N O '~f' O ~ ~ l~
U
r=: U
M ,~ P~
a1
~~.o
0o d- ,--~ 00
M ~ ~!1 pNp .--i .~ ~ - 00 ~ ~ 00
d1 01 ~ ~n ~ O '"' N d1 pp ~ N
00 '"' ~ U ,~ oo ri ~ ~ ~ '-'' a1
0 0 ~ N ~ ~ ~ ~ o o ~ ~ o
O O M [w O ~ O ~[- N O O M ,--., O
by P.., ~L, ~ by o0 ~ N ~ ~ bA d' W P~-i ~ bA ~'
U
0 0 0 ~ o ~0 0 0
u.. . ~ ~ . ~ ~ ,-, Wit- ~ ~ err- ~ ~ . ~ ~ ~ o
c~C.,i ~ C~ ~ ~ v~ ~ M ~ ~ M ~ c~ ~ V 5-W7
cd ~ O w O w ,~~", -.~ ~ ,~._, ~ ,..~~ O ,-O O ~ .~,' bA ..., O :'d
~ V ~ '~3 cd "a cat '-~ ,-, ,-O ~ ,--, ...o ~ 1--~ O ~, "d cd
oz
fz, o ,~ ~ U M ~, L7 M s~ ~C ~ ~ ~., o
M ~ M ~-~ ,~ O
f~ fs.~ o, ~ ~, ~ ~ ~ u, o ~' o .~"~''
~~ °a~ °aw~~ ~a ov~~a ova ~ ~~~a~ ~ ~~ ~
~ ~ ~ ~ C7 ~ ~ c~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ° ~ ~ ~ L'7 ~ ~, r~ ~ o
~4 r~
N W '-' W N W '"' W W '"'' W
~, ri ~ ,~., ri ~
rx' N ~ N ,.~~ r-~ N ~ ~-x N ~ r~ N ~ N ~ x' N
m c~ m can c~i
o a, o o a~ ~n
M l~ 01 O N -~ O
N 01 ~ N M 01 M
N 01 M M ~ \O
Lm uo ~o Lo vo t~
a1 a1 d1 a1 a>
O 01 N O 001 l~
~ a ~ ~, z
x x x ~ ~ x x
x
404
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
O 00 00 00 M O~ M 01 O d' l0 V7 Q\ M
v7 N ~O M oo l~ N O ~n d' V1 l~ O~ ~
01 M M V~ d' t~ N d° M N M ~ I~
O v~ ~ ~ N cal ~-~ ~O l~ d- ~O M o0 O
~O ~n M O 01 01 O 00 ~n O a1 N M O
M N d' CV ~ M ~Y
0 0 ~? ~-, O\ ~ ~ ,~ lp v0 V7 d' N
01 O ~ ~ M d' ~ M ~ ~ M d' 01 M
N ~ ,-,
al
- l~
,~ O O
bA N O
N
V7 N N N N ,~ 00 O M \O l0 ~D o0
01 0~ 00 00 ~ ~ oo M M N N N ~O
mn v~ v~ ~ oo ~n o0 a1 a1 rn ~n
V7 O O .~ ,.-i .--i ~ O O ,~ .~ ,-m--i O
O O O O ~ O O O O O O O
r~.~ w r~ w ,~ M w w w w w w w
bn ~ a~ a~ a~ a~ an ~ a~ a~ a~ ~, a~ w a~
0
~t o
O cd
~cc3 c~3 cd ~~~', ~ '~ O~'O~,'OT~'
O O O ~~~' ~.'~,-," ~ ~~ocOnO~o'L3
TS "C3 'Ci ~ ~ ~ ~ N E-., C~ V c~i V c~ V
o H E~ E-~ ~ ~ ~ U r~ ~ ~' ~ C7 L7
.. ~ ~ ~ ~ .
w
a... ~. c7 a1 w w ~. ~ ~o a, a~ ~, ~ a~ w w w a.~
r~ r~ r~ ~ ~ ~ ~ ~ r~ ~ r~
'-' W W W W N W W W W W W W
x N x (V x N ~-x N ~ ~ N x N x N x N x N x N x N
l~ o0 ~ O ~ N M d- ~ ~O t~
tn v~ ~n wo ~o ~o vo ~o vo ~o
M M M M M M M M M M M
O1 N ~-~ ~ d- d' ~O ~ .-~ O
V~ 00 l~ O ~ O l~ O V'W1
M d' O O O~ N ~n d' ~n ~n O
l~ M a1 O o0 N N V1 ~
t~ ,--r oo LO ~n a1 M N ~f- co en
a1 ~ ~ ~ ~ ~ a1
N dW~ ~ ''-' ~ N o0 O
~C N N ~' N (:~ ~ d°. N M t
N Z
~ a.~ ~ H W
x x x x x x x x x x
405
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N M ~O d- N t~ ~O O~ O v»n d~ 00 01 l~ oo a> ~ 00 M d- d- O
l~ O O N ~O o0 M ~-~ 01 O 00 d~ V~ M ~n ~n (~ ~ d- M N N 01
~n ~n v~ oo ~ l~ ~ N ~O d' N d~ d' ~ ,--~ M oo M .--~ 01 ~O
I~ O O 00 l~ ~ O d' M ~ a1 ~ N ~ ~ ~n ~ ~D ~n O O M ~t~
O M M ~D N V7 .-i 01 M N ~ M M I~ ~ V~ \O M OO \O ~O
N l~ O~ O~ ~t M N M ~ ~-i l~ N l~ N O o0 d'
M o o ~ o M ~ o o ~ o ~ 0 0 0 0 0 0 ~ ~ o
M d' M l~ M d~ ~ O O l~ 00 ~ l~ ~ ~ 00 ~ 01 ~
M M ~ ~~ M M ~!1 M M ~ a1 !~ 01 N M N M ~ V7 V7
G4 U
U U U
O N l~ m 01
l0 \O p~p - ~ o l0 ~ - 00 ~ \O
N N ,-.., '-' N co - N M '"' ~O ~~ - N op '"'
~ ~ ~O O~ ~ ~ O ~_ N oho ~
w w .'~' ~ w '~' d; w '~' ~ w .,~ o w
i~ P-.i bA M P-i bA d- P~ bA ~ P, bD N p-i b0 00
by '-'
~', v
4-~ 4-a O 4-.a 'v~ 4--i '~ ~ ~ ~ "C~ E-,
O O O O ~ ~ O ~ p O O ,~ ~ O ~, O O ,.~ W
~ "d N ~ '~ zS ~ '. ~ p ~ ~~ ~ v
cd U cd U ,_, ~ cCi U _ .~O c~ U ø, V ,~ ~ ,~ CCi U
'U ~ C'7 ~ ~p N ,-~ C7 yn ,-, r, U'' O ~ ~ ~ ~ O U
M ~ W
O ~ O M Z ~ ~ O O ~~ ~ ~ O c~ ~~ ~ ~ O ~ 'N
O O .~ <n .-..,
O Cat O ~ ~ O
w w ~ ~ ~ ~ ~ ~, ~ ~ ' ~ si, aw-,, ~ ~u aw.~ ~
~i A-i a ~ a ~ ~ ~ ~ ~ "1 +'
r~a~d_- w~w_ ~d_- r~d_- r~d_-
~ ~;
i-~'N ~N~ xN~ r~N..~fl x'N ~ r~ic~l.~
0o O~ O .-~ N M
M M M M M M
d~ oo N dwO N
d~ M ~n ~ d~ N
M 00 l~ .-1 tn O
M M 00
l~ ~ N N M
a1 d1 a1 d1 a1
.-, d_- ~p ~ O
N E-~ ' 00 ~ 00
~/
O ~4' ~' oHo
x x ~ x
x
406
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N M l~ ~n ,-.-~ ,~ a1 a1 ,--y0 d~ ~ ~ ~ a1 l~
M t~ d' l~ lp a1 I~ N '~ M O 00 00 01 01 lp
M M ~ M M ~-~ ~ M 00 ~ 00 M
N O~ c0 ~O O O O l~ M M v~ N N N o0 00
O ~O ~ O t~ ~n v7 ,~ M O O O d-
N ~ ~n N ~ N ~ d' M M
'-' ~ ~ ~ 00 Q1 61 N O~
M Wit' O O N oo D ~' 00 00 ~O oo d' oo ,-i o0
O tI~ V7 [w M d- pp d' N M d' d' ~ N M M
O
N
~ 00 ~ O 00 l~ ~ I~ O O O V~
N op - ~O d' .-~ oo N oo N N N
01 ~ ~ ~ ~ ~O ~O l~ ~ l~ ~O ~O ~ ~O
O U O O O O O O O O O
O N d- O ""~ O O O O O O O O O
P~ ~ ~, P-~ ~ P-~ G-~ P-~ P~ G~ W P~
N p ~' .~ .~ .S~
cd c~3 cCi
.,'~-r 0 ~ bpA -~, ~' O ~'-, '~ '~ '~ O
000 O ~.-. O~ N~.~ ~ w ~~ P-~ ~ O
N ~ p ~ ~f''., ~ p ~ ~ _~
O ~ ~'~ N ~ Z ~ O ~ O O O
N ~ ~ V~ ~ r~ O .-~ ~ O ~ ~ "O ~ vi ~
N ~ ~ ~ ø'' O
° U ~+' ~ ~ m o
~°~r.~ Wqw~~'w~~H°wwwwwww
a-. ~ ~ .~ aw ~ '. a~ . ~ a~ ~ 4-, c'7 ~ a~ a., a-~ a~ a~ a.~ a~
r~ ~ a~' ~ ~ ~ ~ c~
W W W W W W W W
N ~' ~iN ~ ~iN ~iN ~N i-LiN rxN r-~(~l r~.iN r~N~'
d- O ~O l~ 00 O~ O ~-~ N M d'
t~ N l~ l~ t~ l~ 00 00 00 00 00
M ~O M M M M M M M M M
~!5 O l0 I~ 00 ~ M V'7 a1 O
l~ N l~ l~ ~--~ O d\ ~ d' O l~
00 M 00 d1 d' ~f1 M ~O M O
l~ d' l~ O M ~n O V~ ~O M M
tn ~O N V~ l~ ~-~ I~ 00 00 O O
a> 01 ~n v~ ~n ~G ~O ~O ~O l~ l~
W f~ N x x O N ~ N ate, w
O ~ ~ U ~ ~ ~ ~ O
x x ~ ~ ~ ~ ~ ~ x
407
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~ lp 01 O ~D M 00 I~ d' M ~ 01 CO ~
d' ~O v~ V~ M V> M N O M N ~ ~ 00
I~
d'
d' d' N (~ N M ~O M M ~O ~ ~ N ~
N
O M M O V~ M M M M ~ ~ M d'
V7 01 V1 lp ~ M \O O 00 -~ .--i(~ \O O
\O
00
N N d- ~ M .-1 m M
M l~ l~ ~O M V1 l~ a1 Q1 ~O N M l
~ ~'
~ l~ o0 ~O o0 a1 O O ~O N d' a1
v~ ~O N M V~ l~ M oo N d' N ~
\p
O~
U
~D ~ l~ ~ N l~ !~ O O N O ~O O
M M oo N l~ 00 00 ~ ~ N N M N M
~'
w n m o vo ~ ~ ~ ~ w o ~n ' N
O O O O O O O O O O O O O ono
O O O O O O O O O O O O O
w w w w w w w w w w w w w
a~ a~ a.~ a1 a, w a~ a~ a~ a~ a, a~ w bn
O
o ~~, ~ ~ y o .~.,o H
. ~ ~ ,~ .~ ~ ~ ~ ~ ~ ~d ~ zs
.~ .~ o .~ .~ .~
w ~~ o o '~ '~
w w
~ ~,
~ ~ c7 ~ O
~ ~ i
b4~ ~ x ~ ~ p ~ 0 ~ ~ .
~ ~
/~ A-i ,--ip-Ia-1
~
~ ~ ~
+'Q~, ~ ~ Q~ Q~ Q~, Q N Q W
N N ~' ~'~' O
V V
, , , ,
~.i ~ ~ ~ ~ ~ d'
N ~ r~ x x ~i ~i ~ r~' N-1 r~ x., t~ ~
N N N N N CV N N N N N N N
V7 ~ l~ oo Q~ O .-~ N M d- ~n ~ l~
a1 Q1 al O1 a\ ~ ~ a\
M M M M M M M M M M M M M
a1 ~n ~O oo ~O M oo r. ,-~ d- N d-
O l~ d- d- N ~O I~ oo ~n ~O O N l~
M 01 ~n V7 O O o0 N M ~ l0
--~ 01 01 v0 d' ~ l~ O d' I~ <t 01 ~O
~O l~ t~ oo d- t~ l~ o0 00 0o a1 01 O
Q
a1 ~ ~ ~ ~n t
a ~ ~ o as ' x ~ o ~ ~ ~ x
x ~ x
~ w ~ te W w U O
x x ~ x a x x a x x
., x
x
408
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
a1 01 v0 <i- v0 M ~n r, I~ ~O m l~ N .-, O N m d' O~ ~O O~ O l~ t~
I~ ~O '~Y' M ~-~ O M N V~ ~O l~ d' O ~-~ ~ ~t d' 01 00 ~n V~ M \O
M d- M ~n ~n d- ~~ N N N d' ~n ~n 01 ~n oo ~W O ~O M t~
00 l~ M t~ ~ ~ O M N l~ N ~n ~ ~n oo d- ~O ~n M O ~ O d' ~t
d' ~-~ ~ 01 o0 l~ l~ ~t N ~ a1 01 V1 ~ r, l~ I~ o0 I~ ~n .-~
N d- M d- d- O N 01 00 ~n oo ~n N M N ~O
0 0 0 0 0 0 ~ o ~ o o N o M o ~ 0 0 0 ~ ~ o
v7 0 N ~ ~ ~-1 d' ,~ N O I~ ~ M ~f O N O O l~ ~ l~ ~n V~ M
d1 O l~ 00 00 00 ~ d1 l~ O ~ ~ 01 ~ I~ l0 O o0 l~ ~ M ~ N M
m U U
~O N
O
N N N
O 01 ~ O M o0 O ~ ,-, ~ ~ 00
O N ~ O M 01 O M M O M M
f~ .,-_, M w ..-, lp ~T~ '....., d- f~ . ~ ~p
by ~n (1, tiA l~ t~ by ~n P1 bA o0
n
y y .~ V ~~ _3 ~ '~ O v~
0 0 ~+-~ o a~
o ~
~d O M ~3 O ~ bA o
W ~ W .U bA ~' W U .~
N -N ~f'
c~ ~ ~ ~ ~H ~ ~ -N d1
O ~ O ~ ~ ~ O~ ~ ~ O ~ ~ O N
v~ o0 ,9 ~ lp ø' ~ ~ ~' 4~ ~ M
n ~ M+~ M.~~ .~~vlW
U
~ f~ ~ ~ fi.~ ø'' ~ ,n
0
v pw.., ~ ~ ~ 4a fs~., P~-~ ~ ~~' ~ ~ v ~, ~ ~U W ~
W ~t W ~ W ~ W d-
x'N..~O rxN ~ xN,~ W N .~O
00 Q1 O
d1 41 O O
M M d' d'
t~ ~n N ~t
M d- ~n
D\
O O O O
N
z M
w a w
x x x x
409
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~O ~ d' o0 l~ ~n M M d' ~ l~ l~ M l~ O l~
O .~ O O d1 ~O M
l~
00 0o O N ~ ~ ~ O~ I~ O oo o0 0o O d- 00
O~ N N d' N 00 00
N
M M ~O ~O N N V~ v~ d' ~1 M M ~t N 00 ~O
M d- N ~ ~n l~ d'
~
01 ~O cY oo cal N v~ ~n N ~ d' M O~ r., M
d- ,-~ O~ ~ oo ~O co d'
O~
~ d N ~ ~ N N oo M N oo N O~ M O o0
~o ~ 0~ M
N
M d- ~ ~ N N d d' N ~ I~ ~ ~n
-~ ~ M
0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 M 0
0
p N op d- N oo O O ~ ~n O O ~ N l~
,--~ O l~ M N
M
M ~n ~ ~n d' ~ awn ~ t~ d- d' ~p vp W o
~o ~ M m M d-
M
U U
U
-~ t~ 0 00
o o~o ,~ o ,~ o~o ~_ ~_ ,-. ~ ,-, o
O ~ O ~p ~ ~p ~ ~ N '-' ~ due.. ,-,
T' '-' '-, ~O
d' o ~ O M O N O V7 ~ O ~O N
d' O 01 ~
f~ ~ f~ .~ f~ ~ fz-~~ W ~ N f~ ~ O
M N ~ ~
bA P-i bA P-i bA P-i bA P-a bA d' ~ bA M
N ~O 01 d'
_ .~-i ~ ~ ~', ~i
.~-i
~ . v~ c~ Cd
cCi '
~ O
,
N 'd N T03 a ~d p '~ 'O~ .
.
~
_ -,, ~ N ~ ~
~
r
cn W O W c~, W ~'
~
~
O O p O ~ l~ O O O ~ ~
.~ ~ p
,_ -, ~ i
, x ~ c~,
O ~ d. '_', O M v?
~
O ~ M
~
~4~ ~ f~o ~ ~lo ~ w0
~ ~ ~ ~ ~ ~ ~ ~ .
U ~ '~
, E
W d W d W d W d W ~ W d
- ' ' ' -
~ ~ ~ ~ ~
-; ~
~
~ ~ ~ ~N W x ~ , ~ ~i
~
N N , r - N , N
N t
N ~ d- ~ ~O l~
0 ~ 0 0 0 0
d d d d d
' ' ' - '
V~ \O l~ ~ M lf1
00 CO o0 01 O O
O ~ O
O O p
d> ~ d1 ~ d\
M
N ,~ V1 00 V~ M
U
U
w ~ ~
r. r.
x x ~ ~
~
x
410
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
OW ~ t~ O~ M d- ~O oo ~n V7 OO ~ O M M ~ N O
00 ~ oo ~ l~ O N O ~ d1 O O O l~ d' M O ~ l~
N ~ N M ~O l~ oo M ~O ~O Wn ~ ~ t~ N N
O1 00 V7 ,--~ O N N o~ M ~ l~ M M o0 d' O 10 00
M O~ N ~ O oo Ov N oo M oo v~ M d- ~ N
,~ ,--~ ,-i ,--i V1 l~ M N oo
0 0 0 o N o 0 0 ~ N o o pp o o ~.,~ o ~ o
l~ ~n ~O N oo N O d" ~ oo ~O
M d- M d- d' 00 00 ~ d- d~ cWn ''-' oho ~ can
W
M
_N _N
N V~ ~p ~O
-, ~ r, ~ N O Q O o O O
N d. ~ N
O M O O ~ M I~ O O ~ O O .-.N-i O
w .~ ~ w w .~ d- w .~ N w .~ N w
p-i bl7 l~ P-i P-~ bA 01 ~ bA M ~ b0 M p..i
C~ c~
o ~ ~ o ~ o ~ o
a~ o o a~ ~ .° ~ x ,-°o ~ x ~ o
_ _
Q.,, ~cc3 w ,~ ~ M ~ ~ M ~ b0
Uo ~~-°N'~UoCW7 ~~ ~ ?o C~7 ~o ~~W v
~~'~ U ~ ~ ~ ~~ ~ U M ~ U M p ~ O
w ~ ~ ~ ~ w ~r-~ o c~ ~ o N r,~ o N ~f~
o u"~,~ ~ o
w o ~ ~,.~~w ow .~ w ,~ ° ~w .~ ° ~w ~ °'~
P-~ .~" ~ cd t~, ~ ai ,~ awn c~ ,-~ P-, v~ S~, vW., v~ t?, w ai ~ P~ '.
W ~ W W ~ ~ ~ W ~ W N
rx N ~ ~ N t~i N ~ r.~ N ~ x N . ~ x N
0o a\ O ~ N M
O O
d' d' d' d' d' d
01 O 00 01 V7
00 00 lfl V 7 V7 M
M M d' V7 V1 l!7
,_,
d1 dl ~ ~ d\
~h
d' 0~0 ~ d. 00 00
w W
H ~ ~ ~ W
x
411
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N ~ O N ~n ~n ~ ~n N ~ d' M v~ N M °1 ~n
0o N 01 01 01 O ,~ t~ ~ t~ l~ ~O oo a1 N l~ V~
lwn t~ N N ~O ~ N ~D ~ l~ l~ ~n d' ~ v~ d-
~O l~ N O M l~ M N M ~ M CO ~ N ~-~ O
O N O ~ ~n 01 M O d' O~ oo O M ~n d' O1
O N l~ ~ N N ~O ~O N
N
o ~ ~ o ~ ~ o ~ o o ~ ~ ~ o 0
01 ~O ~n d' ~ 00 M O O ~ ~p l~ Vy~ d- ,--~ O
M M ~ 00 d' M M ~ O~ d' M O ~ V7 l0
U U U ~n
o, d- d-
O O ONOp~Op O N~N~ N
,-
p~'p ,"'' \D pip '~ ~O ~ O
O _ o '-' ~ O O ~ O d1 M O O N O
w ~ w M r., O N ~ f-pz, "~' O o d' a1 O
G~ bl~ ~ ' bA o~0 Pa bl~ ~ ~ ' bA V~'~ Pi ' bA ~
~ "'d id v~ ~ N I ~ v~ ~ ~
b~A r~ ° ~ P-~ ''~' bl1 ~ '"o ~O "o .,--~ ~ s".~ ~ .i-.~ ~ c~3
U~,~r ~,~~U ~ ~'~,N~~,-i O~ ° ,~ Q
'S"" bJ7 ~ '-' ,L,'' ~ ~ O ~ ~ Q U .~-W'°., ~ ~~" cn ~~ ~ ,-C~
~ ~'~tw U ~ k ~~7 ~'.' ~C7 UZ~~ ~,° x ° ~ °
~ z3 ~ ~ . ~ ~. ~ 'd ~ ~, r, .~ ,~ P-~ o yo ,-, v~ ep r~
~Ou'~'i~~.~~Ou'S O° O_° ~ ~~ 4-~
ø, V ~ ~ ~ ~ w ø, U ~ ~ U O W ~., ~ ~ ,~ ~ ~1 p .1~,
~~~~lw~~ ~~a~-~ ~~aw., ~yC?~.,.~ai~ ~ aw., 'N ~ aw-.
N W ~ ~ ~ W d' W d'
cd ~ ,--~ cd ~ .-~ cd ~ ,--~ cd ~ .-~ cd
~i N ~ x N ~ ~i N ~ r~ N ~ t~i N
d_' ~_W _O _l~ o_o O_~
~t d' d' d' d- d'
M lp 00 ~ l~ 00
~n l~ d' O m 00
d' N to o0 0o O
N N N N M
a1 a1 a\ d\ a\ D1
O
O ~U ~O
w
x x x x x x
412
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
wtwo M o v~ ~ ~ t~ M oo ~n ~ ~ o~ ~n
[~ \O l0 O M ~ 01 M M 01 d' V7 rr 01 N M
M d- oo ~O oo l~ t~ N N M M ~ ~ d- ~n ~n
I~ 00 V7 O O Cfi l~ ~ .~ V1 d- l0 M M M 01 N
V7 t~ N ~ 00 .-y~ 00 00 lfl O O
M CO ~ [~ M
O O O O O O O O O O O O
O oo N d" l~ ~ ~ ~i ,--~ O O a> l~ ~O M
d' V1 V7 M ~ 01 d1 M M M ~ d' V7 l
N
-
r, _U _U _U
N 'fl '~
_N _N _N
d' M ~O d- o0
O OpNp- ~~-O
N N ,d- '""' 0o ~ r"' N ~p '"'
d- d1 O ~ O O~p ~ O pip ~ O ONO ~ O
O - O O O O
.~ d- w ,~~' w ~ ~ w ~ M w ~ N w
bJ7 O p-, "d P-~ bA oo ~1., bD °~ P-~ bA d- A.,
U ~~ ~ O ~~ N v7 ~~ r-,
~A v~ Cc3
i ~ ~, o o ~, o a~ °' ~ o
x ,~ o ~ bn o . ~ '~ ,-, ~ 'r~ w °
C7 ~ ono C'7 0 ~ °°~, ~ -o° '~ ~ ° ~ '~,
° C~7
o ,~ ~ o ~ ø, ° E.~ N ° ~ ~ ~ ,~° rxr.~ o
..~~ ~ ~W~ ~Px-, 0:~~~ ox W
o a; ~ ~ "3 '~ ~ o '~ ~ ~ ~l .N ~ ~ tin .~ 'v
U ~ ~+,.~ ,s~~ ozW ~<C ~ o +,
W ~'? W ~ W ~ W ~ W
N ~ x N ~ x N ~ x N ~ x N ~ r~ N
O ~ N M d-
N N N N N
d- d' d~ d' d'
O ~ V7 vW p
d- ~n N O d
.-r v~ l~ l~ N
d" ~1 O N
M M M d' d'
d1 D1
N ~ M_
w w
x x x x x
413
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
N M 01 M 00 O V7 V7 .-~ 00 01 00 l~ M 00 d' 00 dW~ lfl d1 N
l~ N l~ d' O~ l~ ~n N . 01 N ~t ~ N l~ N N ~n M ~ M ~ o0
d' d- N M ~n oo G1 N d' N N M N N O~ N oo N ~ ~n o0
N o0 01 N ~O N 01 O M ~ M ~ ~-~ O M M O ~ ~D 01 ~ d'
~n d- ~ ~ M I~ ~ ~O O 01 O~ O O M ~ N d' a1 00 ~O
N ~~ I~ d' d' ~--~ O O .-~ .~ l~ O l~ O a1
o N o ~ 0 0 o M ~ 0 0 0 0 0 0 0 0 0 0 0 ~ o
O O M \O V1 01 V7 d' lp 00 ..-i ~ l0 O l~ o0 \O O O ~ M M
~n d' M ~ d' ~O M N 01 01 ~t M N M M N N M N N o d
U
M
N "~ N
N r,
d'
O _
U N ~ '"' ~ -_ N ~ N
oo°°oo~,o ic~ioU o
o ~,-, ~ O ~- ~ o ~ o
~~n ~
a~'
~ o ~ . ~, ~ ' ~'
0 0~
o ~ ~ ~ ~ o'oo ~ E~-~ ~ ~ o ,o.~ p o 0
M ~ en ,.~ c/~ M ~ ,~ C7 ~, o~ ~ yo ~,
0
f~ ed N
~ a~ ~ w ~ ~ ,.~ w ~' ~ ~ P~ ~ ~ ,~ ~ per..,
'r by i~ a p-1 a ~ +r ~.., S~ W r a
R~' d- f~
N N
cat ~--~ ,--i c~ ~ .-, c~ ~ ,--r cd ,--~ cct
~N ~ r~N ~ r~(~~.~ xN ~
W o t~ 00
N N N N
d~ d' d' d'
a1 ~
d- M O N
0o O OWn
N M d-
~fi d' ~' d'
a1 a1 a1 a1
Wn
H
U
H ~ a
414
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
d' M ~ l~ d' 00 00 tn O O d' ~ N \O d' M 01 I~ l~
O d' N l~ M O 01 \O M O N l~ 00 01 M ~ d1 O d'
~O ~O a1 d' l~ d- oo ~D M M O N ~ ~n ~O ~O ~O N
M M ~O 01 M M N M N ~ M l~ ~ M M d'
N N ~-W~ ~ 00 00 M ~n ~O ~ d' ~O N ~ M
~ ~O M M ~O ~n N N 01 N ~O M d- lp ~
o ~_ ~ ~ ~ o o ~ o o ~ o ~ ~ M o 0
O 01 01 d' pip pip ~O a1 ~-' t~ l~ M l~ O ~ ~ ~ 00 d"
d- d- oo ~h M N M m N d'
l~ M
O M U
M
O
_ ,~ _p _bA
O
d' ~ oo ~ O pNp - ~O l~ N I~
CO O ~ ~ N d- ~"~ M 0O ~ 00
_N ~O M ~ ~O l~ pp ~ l~ ,-,
O ~ O ~ d- O ~ M O O M ~ O
by [~ P-~ ' bA o0 P.i P-i ' b4 ~ P-i
O .~~r :.., ' CC3 ~ ~ O +,
~' ~ 4-a O N O
O ~ ~ O . ~ O ~ ,~ O ,.'~' bA ~' ~ ~,., ~, p ~i
.OS'',
o ,~ ~ ~ .,~ 'ai .~-~ ~r ~ ~ ~ aW
U ~ V v~ ~ N ~ ~ -a-~ Q1 O ~ ~ O
T3 ~ ..-~ .., cd N U ~ ~ O t-~ ° N N bA
o ~ o o ~ a~ ~ z ~ ° ~ .°; ~-' s~ H M ~n
~, ~-' vi ~' '.~ ~ ~, ,-~ rd 'i-' C/~ ~ v~ v~ ~ w ~ ~ p..,
r~ L'7 ~ ° a~ a~ ~ ~, ° ~' W
ct3 cd V U ~ o ~ ~ w 3~~- ~ ° ~ ~ p
Q, ~ ~ v~ ~ ~ ~,' 4~ ~ ~ b~D 'TJ a ~ U ø, ~ U W ~ ~ ~ t~-
N W ~ rx ~ W W ~ W
~ ~ ,-; ~ '-.i ~ ,-V a ~ ,--.
xN .~O rxN ~ r~N~ ~N~iN~ ~,N
a1 O ~ N M ~h
N M M M M M
~t 'd' ~t d' d' d'
O 00 O V~ d' 00
M M l~ ~O V1 O
00 d' d- N N M
\O N N M ~O
dw mW vp
a1 01 a1 a1 a> a1
O
a
U
415
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
~n oo r, N a1 -~ M v~ l~ a1 N ~n o0
p~ ~D oo oo
d' d
l~ l~ 01 01 00 M N l~ M ~ 01 l~ t~ ~O
M 01 l~ l0
O
01 01 m M N ~ ~D n d' M ~t M M d'
~O ~ O~ I~
.-m
N
O ~ O~ oo O I~ l~ N O O~ O~ oo d- N
N ~O N ~O
M
d' ~ d' ~ M M ~ O M l~ 00 V'7
O1 M \O M
~O M ~ N d' O~ N l~
~n v~ O ~
N
.-a ,-,
N
o o ~ ~ ~ ~ o N ~ ~ o ~ o
o ~ o
01 M O~ d' d1 ~n O Q1 N O t~ r, N
00 O \O D1
M
d' d' ~ M M M ~ d1 ~ O d-
M ~D M Q1
M
Pa N N M O
U ~ ~I ~ ~
I
~ ~
A ~ ~ ~
bp bA bA bA
N N
w
~ N N~ ~
O d N ~ ~ ~ ~ 0
' 1
.~
, 01 O~ d' V~
N ~O -, 00 ~., 00 ~ 00 ~, ,~ 00
O N O O O O O O
i
p ~ tP~ ~ p ~
p ~ r; p pp d-
' ~ w ~- d- O ~,- O
' ~' vo ,~
w . w w o ~ ~ ~
~ N , ~
-~
bIW t i~ P-a bA P-~ bA P-a bA P-~ bA P-~
l~ ~ N d
'~ ~ O
.
r,
"O .~r '~' ~' bA ~i bU ~,' -~~ U U~ ~
' n O .~,
0 ~ '~ ~ ~ ~
~r V1
~
M O ~ p ~ ~ O ~ O ,~,"' CC3 ~', r'~,
~ "~1 ~ "c~ . "~ M ~ ~,' '-'
~ ""r
0 V x c x, o~o~x, r~,~~ [-~'a~
O N'n
~J O x ~ P-~ 00 A'' pp Gi, ~
~ ~ O
~ V
N O N M .~ ~"' d' N
N r' ,~ ~ ~ .~ O ~
,~., ~ ,--~ ~ O <n
O N N ~
N
o ~ ~ w ~ wx ~ w o' ~ o~ w ~
~ o ~
~'
W M ~ , , ~ ,
~ ~ 7 x ~
~
a~ s~, a.~ a~ ~ a~ oo a., ~ a1 w
.~ 0, ,
~
w
~' ~ x ~i ~ ~i ~ x ~ ~ ~ ~
i- N N r N r r
N N N i
N
W ~O t~ o0 a\ O
dM' ~ dM' dM'
N h ue N
d o a1 d N O c
o ' n
M M ~ d1 ~ M M
d\
N l~ ~O ~p pp
~ ~ ~ ~ W
" ~ W
'
O U
x x x
416
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
M
01
M
d'
r-1
M
dl
d>
N
O
O
w
~r
O
O v~
cd
N
0
a~ .~ c~
~ '-.;
~i N
M
N
O
N
d1
w
U
x
417
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
[60] Table 2 further characterizes certain encoded polypeptides of the
invention, by
providing the results of comparisons to protein and protein family databases.
The first
column provides a unique clone identifier, "Clone ID NO:", corresponding to a
cDNA clone
disclosed in Table 1A. The second column provides the unique contig
identifier, "Contig
ID:" which allows correlation with the information in Table 1A. The third
column provides
the sequence identifier, "SEQ ID NO:", for the contig polynucleotide
sequences. The fourth
column provides the analysis method by which the homology/identity disclosed
in the Table
was determined. The fifth column provides a description of the PFAM/NR hit
identified by
each analysis. 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 column five. Comparisons were made
between
polypeptides encoded by polynucleotides of the invention and a non-redundant
protein
database (herein referred to as "NR"), or a database of protein families
(herein referred to as
"PFAM"), as described below.
[61] The NR database, which comprises the NBRF PIR database, the NCBI GenPept
database, and the SIB SwissProt and TrEMBL databases, was made non-redundant
using the
computer program nrdb2 (Warren Gish, Washington University in Saint Louis).
Each of the
polynucleotides shown in Table 1A, column 3 (e.g., SEQ ID NO:X or the 'Query'
sequence)
was used to search against the NR database. The computer program BLASTX was
used to
compare a 6-frame translation of the Query sequence to the NR database (for
information
about the BLASTX algorithm please see Altshul et al., J. Mol. Biol. 215:403-
410 (1990);
and Gish and States, Nat. Genet. 3:266-272 (1993). A description of the
sequence that is most
similar to the Query sequence (the highest scoring 'Subject') is shown in
column five of
Table 2 and the database accession number for that sequence is provided in
column six. The
highest scoring 'Subject' is reported in Table 2 if (a) the estimated
probability that the match
occurred by chance alone is less than 1.0e-07, and (b) the match was not to a
known
repetitive element. BLASTX returns alignments of short polypeptide segments of
the Query
and Subject sequences which share a high degree of similarity; these segments
are known as
High-Scoring Segment Pairs or HSPs. Table 2 reports the degree of similarity
between the
Query and the Subject for each HSP as a percent identity in Column 7. The
percent identity is
determined by dividing the number of exact matches between the two aligned
sequences in
the HSP, dividing by the number of Query amino acids in the HSP and
multiplying by 100.
418
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
The polynucleotides of SEQ ID NO:X which encode the polypeptide sequence that
generates
an HSP are delineated by columns 8 and 9 of Table 2.
[62] The PFAM database, PFAM version 2.1, (Sonnhammer et al., Nucl. Acids
Res.,
26:320-322, 1998)) consists of a series of multiple sequence alignments; one
alignment for
each protein family. Each multiple sequence alignment is converted into a
probability model
called a Hidden Markov Model, or HMM, that represents the position-specific
variation
among the sequences that make up the multiple sequence alignment (see, e.g.,
Durbin et al.,
Biological sequence analysis: probabilistic fnodels of proteins and nucleic
acids, Cambridge
University Press, 1998 for the theory of HMMs). The program HMMER version 1.8
(Sean
Eddy, Washington University in Saint Louis) was used to compare the predicted
protein
sequence for each Query sequence (SEQ ID NO:Y in Table 1A) to each of the HMMs
derived from PFAM version 2.1. A HMM derived from PFAM version 2.1 was said to
be a
significant match to a polypeptide of the invention if the score returned by
HMMER 1.8 was
greater than 0.8 times the HMMER 1.8 score obtained with the most distantly
related known
member of that protein family. The description of the PFAM family which shares
a
significant match with a polypeptide of the invention is listed in coltunn 5
of Table 2, and
the database accession number of the PFAM hit is provided in column 6. Column
7 provides
the score returned by HMMER version 1.8 for the alignment. Columns 8 and 9
delineate the
polynucleotides of SEQ ID NO:X which encode the polypeptide sequence which
show a
significant match to a PFAM protein family.
[63] As mentioned, columns 8 and 9 in Table 2, "NT From" and "NT To",
delineate the
polynucleotides of "SEQ ID NO:X" that encode a polypeptide having a
significant match to
the PFAM/NR database as disclosed in the fifth column. In one embodiment, the
invention
provides a protein comprising, or alternatively consisting of, a polypeptide
encoded by the
polynucleotides of SEQ ID NO:X delineated in columns 8 and 9 of Table 2. Also
provided
are polynucleotides encoding such proteins, and the complementary strand
thereto.
[64] The nucleotide sequence SEQ ID NO:X and the translated SEQ ID NO:Y are
sufficiently accurate and otherwise suitable for a variety of uses well known
in the art and
described further below. For instance, the nucleotide sequences of SEQ ID NO:X
are useful
for designing nucleic acid hybridization probes that will detect nucleic acid
sequences
contained in SEQ ID NO:X or the cDNA contained in Clone ID NO:Z. These probes
will
also hybridize to nucleic acid molecules in biological samples, thereby
enabling immediate
applications in chromosome mapping, linkage analysis, tissue identification
and/or typing,
419
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
and a variety of forensic and diagnostic methods of the invention. Similarly,
polypeptides
identified from SEQ ID NO:Y may be used to generate antibodies which bind
specifically to
these polypeptides, or fragments thereof, and/or to the polypeptides encoded
by the cDNA
clones identified in, for example, Table 1A.
[65] 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).
[66] 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 a predicted translated amino acid
sequence
identified as SEQ ID NO:Y, but also a sample of plasmid DNA containing cDNA
Clone ID
NO:Z (deposited with the ATCC on October 5, 2000, and receiving ATCC
designation
numbers PTA 2574 and PTA 2575; deposited with the ATCC on January 5, 2001, and
having
depositor reference numbers TS-l, TS-2, AC-1, and AC-2; and/or as set forth,
for example,
in Table 1A, 6 and 7). The nucleotide sequence of each deposited clone can
readily be
determined by sequencing the deposited clone in accordance with known methods.
Further,
techniques known in the art can be used to verify the nucleotide sequences of
SEQ ID NO:X.
[67] The predicted amino acid sequence can then be verified from such
deposits.
Moreover, the amino acid sequence of the protein encoded by a particular clone
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.
RACE PYOtocol Fov Recovery of Full-Length Genes
[68] Partial cDNA clones can be made full-length by utilizing the rapid
amplification of
cDNA ends (RACE) procedure described in Frohman, M.A., et al., Proc. Nat'l.
Aced. Sci.
USA, 85:8998-9002 (1988). A cDNA clone missing either the 5' or 3' end can be
reconstructed to include the absent base pairs extending to the translational
start or stop
codon, respectively. In some cases, cDNAs are missing the start codon of
translation,
420
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
therefor. The following briefly describes a modification of this original 5'
RACE procedure.
Poly A+ or total RNA is reverse transcribed with Superscript II (Gibco/BRL)
and an
antisense or complementary primer specific to the cDNA sequence. The primer is
removed
from the reaction with a Microcon Concentrator (Amicon). The first-strand cDNA
is then
tailed with dATP and terminal deoxynucleotide transferase (GibcoBRL). Thus, an
anchor
sequence is produced which is needed for PCR amplification. The second strand
is
synthesized from the dA-tail in PCR buffer, Taq DNA polymerase (Perkin-Elmer
Cetus), an
oligo-dT primer containing three adjacent restriction sites (Xhol, SaII and
CIaI) at the. 5' end
and a primer containing just these restriction sites. This double-stranded
cDNA is PCR
amplified for 40 cycles with the same primers as well as a nested cDNA-
specific antisense
primer. The PCR products are size-separated on an ethidium bromide-agarose gel
and the
region of gel containing cDNA products the predicted size of missing protein-
coding DNA is
removed, cDNA is purified from the agarose with the Magic PCR Prep kit
(Promega),
restriction digested with XhoI or SaII, and ligated to a plasmid such as
pBluescript SKII
(Stratagene) at XhoI and EcoRV sites. This DNA is transformed into bacteria
and the
plasmid clones sequenced to identify the correct protein-coding inserts.
Correct 5' ends are
confirmed by comparing this sequence with the putatively identified homologue
and overlap
with the partial cDNA clone. Similar methods known in the art and/or
commercial kits are
used to amplify and recover 3' ends.
[69] Several quality-controlled kits are commercially available for purchase.
Similar
reagents and methods to those above are supplied in kit form from GibcoBRL for
both 5' and
3' RACE for recovery of full length genes. A second kit is available from
Clontech which is
a modification of a related technique, SLIC (single-stranded ligation to
single-stranded
cDNA), developed by Dumas .et al.; Nucleic Acids Res., 19:5227-32 (1991). The
major
differences in procedure are that the RNA is alkaline hydrolyzed after reverse
transcription
and RNA ligase is used to join a restriction site-containing anchor primer to
the first-strand
cDNA. This obviates the necessity for the dA-tailing reaction which results in
a polyT
stretch that is difficult to sequence past.
(70] An alternative to generating 5' or 3' cDNA from RNA is to use cDNA
library
double-stranded DNA. An asymmetric PCR-amplified antisense cDNA strand is
synthesized
with an antisense cDNA-specific primer and a plasmid-anchored primer. These
primers are
removed and a symmetric PCR reaction is performed with a nested cDNA-specific
antisense
primer and the plasmid-anchored primer.
421
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
RNA Ligase Protocol For Generating The 5' or 3' End Sequences To Obtain Full
Length
Genes
[71] Once a gene of interest is identified, several methods are available for
the
identification of the 5' or 3' portions of the gene which may not be present
in the original
cDNA plasmid. These methods include, but are not limited to, filter probing,
clone
enrichment using specific probes and protocols similar and identical to 5' and
3' RACE.
While the full length gene may be present in the library and can be identified
by probing, a
useful method for generating the 5' or 3' end is to use the existing sequence
information from
the original cDNA to generate the missing information. A method similar to. 5'
RACE is
available for generating the missing 5' end of a desired full-length gene.
(This method was
published by Fromont-Racine et al., Nucleic Acids Res., 21(7):1683-1684
(1993)). Briefly, a
specific RNA oligonucleotide is ligated to the 5' ends of a population of RNA
presumably
containing full-length gene RNA transcript and a primer set containing a
primer specific to
the Iigated RNA oligonucleotide and a primer specific to a known sequence of
the gene of
interest, is used to PCR amplify the 5' portion of the desired full length
gene which may then
be sequenced and used to generate the full length gene. This method starts
with total RNA
isolated from the desired source, poly A RNA may be used but is not a
prerequisite for this
procedure. The RNA preparation may then be treated with phosphatase if
necessary to
eliminate 5' phosphate groups on degraded or damaged RNA which may, interfere
with the
later RNA Iigase step, The phosphatase if used is then inactivated and the RNA
is treated
with tobacco acid pyrophosphatase in order to remove the cap structure present
at the 5' ends
of messenger RNAs. This reaction leaves a 5' phosphate group at the 5' end of
the cap
cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA
ligase.
This modified RNA preparation can then be used as a template for first strand
cDNA
synthesis using a gene specific oligonucleatide. The first strand synthesis
reaction can then
be used as a template for PCR amplification of the desired 5' end using a
primer specific to
the ligated RNA oligonucleotide and a primer specific to the known sequence of
the gene of
interest. The resultant product is then sequenced and analyzed to confirm that
the 5' end
sequence belongs to the relevant gene.
[72] The present invention also relates to vectors or plasmids which include
such DNA
sequences, as well as the use of the DNA sequences. The material deposited
with the ATCC
(deposited with the ATCC on October 5, 2000, and receiving ATCC designation
numbers
422
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
PTA 2574 and PTA 2575; deposited with the ATCC on January 5, 2001, and
receiving
ATCC designation numbers TS-l, TS-2, AC-1, and AC-2; and/or as set forth, for
example, in
Table 1A, Table 6, or Table 7) is a mixture of cDNA clones derived from a
variety of human
tissue and cloned in either a plasmid vector or a phage vector, as described,
for example, in
Table 7. These deposits are referred to as "the deposits" herein. The tissues
from which
some of the clones were derived are listed in Table 7, and the vector in which
the
corresponding cDNA is contained is also indicated in Table 7. The deposited
material
includes cDNA clones corresponding to SEQ ID NO:X described, for example, in
Table 1A
(Clone ID NO:Z). A clone which is isolatable from the ATCC Deposits by use of
a sequence
listed as SEQ ID NO:X, may include the entire coding region of a human gene or
in other
cases such clone may include a substantial portion of the coding region of a
human gene.
Furthermore, although the sequence listing may in some instances list only a
portion of the
DNA sequence in a clone included in the ATCC Deposits, it is well within the
ability of one
skilled in the art to sequence the DNA included in a clone contained in the
ATCC Deposits
by use of a sequence (or portion thereof) described in, for example Tables
lAor 2 by
procedures hereinafter further described, and others apparent to those skilled
in the art.
[73] Also provided in Table 7 is the name of the vector which contains the
cDNA
clone. Each vector is routinely used in the art. The following additional
information is
provided for convenience.
[74] 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 (Alting-
Mees, M. A. et al., Sty°ategies 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 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.
[75] 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
423
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
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., BiolTechfzology 9: (1991).
[76] The present invention also relates to the genes corresponding to SEQ ID
NO:X,
SEQ ID NO:Y, and/or the deposited clone (Clone ID NO:Z). The corresponding
gene can be
isolated in accordance with known methods using the sequence information
disclosed herein.
Such methods include preparing probes or primers from the disclosed sequence
and
identifying or amplifying the corresponding gene from appropriate sources of
genomic
material.
[77] 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 ID NO:X or the complement thereof, polypeptides
encoded by
genes corresponding to SEQ ID NO:X or the complement thereof, and/or the cDNA
contained in Clone ID NO:Z, 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.
[78] The polypeptides of the invention can be prepared in any suitable manner.
Such
polypeptides include isolated naturally occurring polypeptides, recombinantly
produced
polypeptides, synthetically produced polypeptides, or polypeptides produced by
a
combination of these methods. Means for preparing such polypeptides are well
understood in
the art.
[79] The polypeptides may be in the form of the secreted protein, including
the mature
form, or may be a part of a larger protein, such as a fusion protein (see
below). It is often
advantageous to include an additional amino acid sequence which contains
secretory or
leader sequences, pro-sequences, sequences which aid in purification, such as
multiple
histidine residues, or an additional sequence for stability during recombinant
production.
424
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
[80] The polypeptides of the present invention are preferably provided in an
isolated
form, and preferably are substantially purified. A recombinantly produced
version of a
polypeptide, including the secreted polypeptide, can be substantially purified
using
techniques described herein or otherwise known in the art, such as, for
example, by the one-
step method described in Smith and Johnson, Gene 67:31-40 (1988). Polypeptides
of the
invention also can be purified from natural, synthetic or recombinant sources
using.
techniques described herein or otherwise known in the art, such as, for
example, antibodies of
the invention raised against the polypeptides of the present invention in
methods which are
well known in the art.
[81] The present invention provides a polynucleotide comprising, or
alternatively
consisting of, the nucleic acid sequence of SEQ ID NO:X, and/or the cDNA
sequence
contained in Clone ID 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 ID NO:X or a complement thereof, a polypeptide encoded by the
cDNA
contained in Clone ID NO:Z, and/or the polypeptide sequence encoded by a
nucleotide
sequence in SEQ ID NO:B as defined in column 6 of Table 1B. Polynucleotides
encoding a
polypeptide comprising, or alternatively consisting of the polypeptide
sequence of SEQ ID
NO:Y, a polypeptide encoded by SEQ ID NO:X, a polypeptide encoded by the cDNA
contained in Clone ID NO:Z, and/or a polypeptide sequence encoded by a
nucleotide
sequence in SEQ ID NO:B as defined in column 6 of Table 1B 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 ID NO:X, a
nucleic acid sequence encoding a polypeptide encoded by the complement of the
nucleic acid
sequence of SEQ ID NO:X, and/or the cDNA contained in Clone ID NO:Z.
[82] Moreover, representative examples of polynucleotides of the invention
comprise,
or alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more of
the sequences delineated in Table 1B column 6, or any combination thereof.
Additional,
representative examples of polynucleotides of the invention comprise, or
alternatively consist
of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the
complementary
strands) of the sequences delineated in Table 1B column 6, or any combination
thereof. In
further embodiments, the above-described polynucleotides of the invention
comprise, or
alternatively consist of, sequences delineated in Table 1B, column 6, and have
a nucleic acid
sequence which is different from that of the BAC fragment having the sequence
disclosed in
425
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
SEQ ID NO:B (see Table 1B, column 5). In additional embodiments, the above-
described
polynucleotides of the invention comprise, or alternatively consist of,
sequences delineated in
Table 1B, column 6, and have a nucleic acid sequence which is different from
that published
for the BAC'clone identified as BAC ID NO:A (see Table 1B, column 4). In
additional
embodiments, the above-described polynucleotides of the invention comprise, or
alternatively consist of, sequences delineated in Table 1B, colunm 6, and have
a nucleic acid
sequence which is different from that contained in the BAC clone identified as
BAC ID
NO:A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides,
other
polynucleotides that encode these polypeptides, and antibodies that bind these
polypeptides
are also encompassed by the invention. Additionally, fragments and variants of
the above-
described polynucleotides and polypeptides are also encompassed by the
invention.
[83] Further, representative examples of polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more of the
sequences delineated in column 6 of Table 1B which correspond to the same
Clone ID NO:Z
(see Table 1B, column 1), or any combination thereof. Additional,
representative examples
of polynucleotides of the invention comprise, or alternatively consist of,
one, two, three, four,
five, six, seven, eight, nine, ten, or more of the complementary strands) of
the sequences
delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z
(see Table
1B, column 1), or any combination thereof. In further embodiments, the above-
described
polynucleotides of the invention comprise, or alternatively consist of,
sequences delineated in
column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B,
column
I) and have a nucleic acid sequence which is different from that of the BAC
fragment having
the sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional
embodiments, the above-described polynucleotides of the invention comprise, or
alternatively consist of, sequences delineated in column 6 of Table 1B which
correspond to
the same Clone ID NO:Z (see Table 1B, column 1) and have a nucleic acid
sequence which is
different from that published for the BAC clone identified as BAC ID NO:A (see
Table 1B,
column 4). In additional embodiments, the above-described polynucleotides of
the invention
comprise, or alternatively consist of, sequences delineated in column 6 of
Table 1B which
correspond to the same Clone ID NO:Z (see Table 1B, column 1) and have a
nucleic acid
sequence which is different from that contained in the BAC clone identified as
BAC ID
NO:A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides,
other
polynucleotides that encode these polypeptides, and antibodies that bind these
polypeptides
426
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
are also encompassed by the invention. Additionally, fragments and variants of
the above-
described polynucleotides and polypeptides are also encompassed by the
invention.
[84j Further, representative examples of polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more of the
sequences delineated in column 6 of Table 1B which correspond to the same
contig sequence
identifer SEQ ID NO:X (see Table 1B, column 2), or any combination thereof.
Additional,
representative examples of polynucleotides of the invention comprise, or
alternatively consist
of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the
complementary
strands) of the sequences delineated in column 6 of Table 1B which correspond
to the same
contig sequence identifer SEQ ID NO:X (see Table 1B, column 2), or any
combination
thereof. In further embodiments, the above-described polynucleotides of the
invention
comprise, or alternatively consist of, sequences delineated in column 6 of
Table 1B which
correspond to the same contig sequence identifer SEQ ID NO:X (see Table 1B,
column 2)
and have a nucleic acid sequence which is different from that of the BAC
fragment having
the sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional
embodiments, the above-described polynucleotides of the invention comprise, or
alternatively consist of, sequences delineated in column 6 of Table 1B which
correspond to
the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2) and
have a
nucleic acid sequence which is different from that published for the BAC clone
identified as
BAC ID NO:A (see Table IB, column 4). In additional embodiments, the above-
described
polynucleotides of the invention comprise, or alternatively consist of,
sequences delineated in
column 6 of Table 1B which correspond to the same contig sequence identifer
SEQ ID NO:X
(see Table 1B, column 2) and have a nucleic acid sequence which is different
from that
contained in the BAC clone identified as BAC ID NO:A (See Table 1B, column 4).
Polypeptides encoded by these polynucleotides, other polynucleotides that
encode these
polypeptides, and antibodies that bind these polypeptides are also encompassed
by the
invention. Additionally, fragments and variants of the above-described
polynucleotides and
polypeptides are also encompassed by the invention.
[85] Moreover, representative examples of polynucleotides of the invention
comprise,
or alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more of
the sequences delineated in the same row of Table 1B column 6, or any
combination thereof.
Additional, representative examples of polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more of the
427
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
complementary strands) of the sequences delineated in the same row of Table 1B
column 6,
or any combination thereof. In preferred embodiments, the polynucleotides of
the invention
comprise, or alternatively consist of, one, two, three, four, five, six,
seven, eight, nine, ten, or
more of the complementary strands) of the sequences delineated in the same row
of Table
1B column 6, wherein sequentially delineated sequences in the table (i.e.
corresponding to
those exons located closest to each other) are directly contiguous in a 5' to
3' orientation. In
further embodiments, above-described polynucleotides of the invention
comprise, or
alternatively consist of, sequences delineated in the same row of Table 1B,
column 6, and
have a nucleic acid sequence which is different from that of the BAC fragment
having the
sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional
embodiments,
the above-described polynucleotides of the invention comprise, or
alternatively consist of,
sequences delineated in the same row of Table 1B, column 6, and have a nucleic
acid
sequence which is different from that published for the BAC clone identified
as BAC ID
NO:A (see Table 1B, column 4). In additional embodiments, the above-described
polynucleotides of the invention comprise, or alternatively consist of,
sequences delineated in
the same row of Table 1B, column 6, and have a nucleic acid sequence which is
different
from that contained in the BAC clone identified as BAC ID NO:A (see Table 1B,
column 4).
Polypeptides encoded by these polynucleotides, other polynucleotides that
encode these
polypeptides, and antibodies that bind these polypeptides are also encompassed
by the
invention.
[86] In additional specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more of the
sequences delineated in column 6 of Table 1B, and the polynucleotide sequence
of SEQ ID
NO:X (e.g., as defined in Table 1B, column 2) or fragments or variants
thereof. Polypeptides
encoded by these polynucleotides, other polynucleotides that encode these
polypeptides, and
antibodies that bind these polypeptides are also encompassed by the invention.
[87] In additional specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more of the
sequences delineated in column 6 of Table 1B which correspond to the same
Clone ID NO:Z
(see Table 1B, column 1), and the polynucleotide sequence of SEQ ID NO:X
(e.g., as defined
in Table 1A or 1B) or fragments or variants thereof. In preferred embodiments,
the
delineated sequences) and polynucleotide sequence of SEQ ID NO:X correspond to
the
same Clone ID NO:Z. Polypeptides encoded by these polynucleotides, other
polynucleotides
428
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
that encode these polypeptides, and antibodies that bind these polypeptides
are also
encompassed by the invention.
[88] In further specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more of the
sequences delineated in the same row of column 6 of Table 1B, and the
polynucleotide
sequence of SEQ ID NO:X (e.g., as defined in Table 1A or 1B) or fragments or
variants
thereof. In preferred embodiments, the delineated sequences) and
polynucleotide sequence
of SEQ ID NO:X correspond to the same row of column 6 of Table 1B.
Polypeptides
encoded by these polynucleotides, other polynucleotides that encode these
polypeptides, and
antibodies that bind these polypeptides are also encompassed by the invention.
[89] In additional specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of a polynucleotide sequence in which the 3' 10
polynucleotides of one
of the sequences delineated in column 6 of Table 1B and the 5' 10
polynucleotides of the
sequence of SEQ ID NO:X are directly contiguous. Nucleic acids which hybridize
to the
complement of these 20 contiguous polynucleotides under stringent
hybridization conditions
or alternatively, under lower stringency conditions, are also encompassed by
the invention.
Polypeptides encoded by these polynucleotides and/or nucleic acids, other
polynucleotides
and/or nucleic acids that encode these polypeptides, and antibodies that bind
these
polypeptides are also encompassed by the invention. Additionally, fragments
and variants of
the above-described polynucleotides, nucleic acids, and polypeptides are also
encompassed
by the invention.
[90] In additional specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides of one
of the sequences delineated in column 6 of Table 1B and the 5' 10
polynucleotides of a
fragment or variant of the sequence of SEQ ID NO:X are directly contiguous
Nucleic acids
which hybridize to the complement of these 20 contiguous polynucleotides under
stringent
hybridization conditions or alternatively, under Iower stringency conditions,
are also
encompassed by the invention. Polypeptides encoded by these polynucleotides
and/or
nucleic acids, other polynucleotides and/or nucleic acids encoding these
polypeptides, and
antibodies that bind these polypeptides are also encompassed by the invention.
Additionally,
fragments and variants of the above-described polynucleotides, nucleic acids,
and
polypeptides are also encompassed by the invention.
429
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
[91] In specific embodiments, polynucleotides of the invention ~ comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides of the .
sequence of SEQ ID NO:X and the 5' 10 polynucleotides of the sequence of one
of the
sequences delineated in column 6 of Table IB are directly contiguous. Nucleic
acids which
hybridize to the complement of these.20 contiguous polynucleotides under
stringent
hybridization conditions or alternatively, under lower stringency conditions,
are also
encompassed by the invention. Polypeptides encoded by these polynucleotides
and/or
nucleic acids, other polynucleotides and/or nucleic acids encoding these
polypeptides, and
antibodies that bind these polypeptides are also encompassed by the invention.
Additionally,
fragments and variants of the above-described polynucleotides, nucleic acids,
and
polypeptides are also encompassed by the invention.
[92] In specific embodiments, polynucleotides of the invention comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides of a
fragment or variant of the sequence of SEQ .ID NO:X and the 5' 10'
polynucleotides of the
sequence of one of the sequences delineated in column 6 of Table 1B are
directly contiguous.
Nucleic acids which hybridize to the complement of these 20 contiguous
polynucleotides
under stringent hybridization conditions or alternatively, under lower
stringency conditions,
are also encompassed by the invention. Polypeptides encoded by these
polynucleotides
and/or nucleic acids, other polynucleotides and/or nucleic acids encoding
these polypeptides,
and antibodies that bind these polypeptides are also encompassed by the
invention.
Additionally, fragments and variants of the above-described polynucleotides,
nucleic acids,
and polypeptides, are also encompassed by the invention.
[93] In further specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides of one
of the sequences delineated in column 6 of Table 1B and the 5' 10
polynucleotides of another
sequence in column 6 are directly contiguous. Nucleic acids which hybridize to
the
complement of these 20 contiguous polynucleotides under stringent
hybridization conditions
or alternatively, under lower stringency conditions, are also encompassed by
the invention.
Polypeptides encoded by these polynucleotides and/or nucleic acids, other
polynucleotides
and/or nucleic acids encoding these polypeptides, and antibodies that bind
these polypeptides
are also encompassed by the invention. Additionally, fragments and variants of
the above-
described polynucleotides, nucleic acids, and polypeptides are also
encompassed by the
invention.
430
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
[94] In specific embodiments, polynucleotides of the invention comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides of one
of the sequences delineated in column 6 of Table 1B and the 5' 10
polynucleotides of another
sequence in column 6 corresponding to the same Clone ID NO:Z (see Table 1B,
column 1)
are directly contiguous. Nucleic acids which hybridize to the complement of
these 20 lower
stringency conditions, are also encompassed by the invention. Polypeptides
encoded by these
polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic
acids encoding
these polypeptides, and antibodies that bind these polypeptides are also
encompassed by the
invention. Additionally, fragments and variants of the above-described
polynucleotides,
nucleic acids, and polypeptides are also encompassed by the invention.
[95] In specific embodiments, polynucleotides of the invention comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides of one
sequence in column 6 corresponding to the same contig sequence identifer SEQ
ID NO:X
(see Table 1B, column 2) are directly contiguous. Nucleic acids which
hybridize to the
complement of these 20 contiguous polynucleotides under stringent
hybridization conditions
or alternatively, under lower stringency conditions, axe also encompassed by
the invention.
Polypeptides encoded by these polynucleotides and/or nucleic acids, other
polynucleotides
and/or nucleic acids encoding these polypeptides, and antibodies that bind
these polypeptides
are also encompassed by the invention. Additionally, fragments and variants of
the above-
described polynucleotides, nucleic acids, and polypeptides are also
encompassed by the
invention.
[96] In specific embodiments, polynucleotides of the invention comprise, or
alternatively consist of a polynucleotide sequence in which the 3' 10
polynucleotides of one
of the sequences delineated in column 6 of Table IB and the 5' 10
polynucleotides of another
sequence in column 6 corresponding to the same row are directly contiguous. In
preferred
embodiments, the 3' 10 polynucleotides of one of the sequences delineated in
column 6 of
Table 1B is directly contiguous with the 5' IO polynucleotides of the next
sequential exon
delineated in Table 1B, column 6. Nucleic acids which hybridize to the
complement of these
20 contiguous polynucleotides under stringent hybridization conditions or
alternatively,
under lower stringency conditions, are also encompassed by the invention.
Polypeptides
encoded by these polynucleotides and/or nucleic acids, other polynucleotides
and/or nucleic
acids encoding these polypeptides, and antibodies that bind these polypeptides
are also
431
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
encompassed by the invention. Additionally, fragments and variants of the
above-described
polynucleotides, nucleic acids, and polypeptides are also encompassed by the
invention.
(97] Many polynucleotide sequences, such as EST sequences, are publicly
available
and accessible through sequence databases and may have been publicly available
prior to
conception of the present invention. Preferably, such related polynucleotides
are specifically
excluded from the scope of the present invention. Accordingly, for each contig
sequence
(SEQ ID NO:X) listed in the fourth column of Table 1A, preferably excluded are
one or more
polynucleotides comprising a nucleotide sequence described by the general
formula of a-b,
where a is any integer between 1 and the final nucleotide minus 15 of SEQ ID
NO:X, b is an
integer of 15 to the final nucleotide of SEQ ID 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. More specifically, preferably excluded are one or more
polynucleotides
comprising a nucleotide sequence described by the general formula of a-b,
where a and b are
integers as defined in columns 4 and 5, respectively, of Table 3. In specific
embodiments, the
polynucleotides of the invention do not consist of at least one, two, three,
four, five, ten, or
more of the specific polynucleotide sequences referenced by the Genbank
Accession No. as
disclosed in column 6 of Table 3 (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). In no way is this
listing meant to
encompass all of the sequences which may be excluded by the general formula,
it is just a
representative example. All references available through these accessions are
hereby
incorporated by reference in their entirety.
432
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
TABLE 3
SEQ
ID EST Disclaimer
lone NO: ontig Range
ID X ID: of a ccession #'s
NO: Z Range
of b
HDPTE21 11 11658611 - 4732 15 -
4746
H6EDR51 12 11978941 - 2300 15 -
2314
HAPRA41 13 11540541 - 1264 15 -
1278
HBXBI07 14 11719581 - 339 15 -
353
HBXCM38 15 9100861 - 2160 15 - AI752485, AI804792, AI439106,
2174 AI971133,
AI991958, AI752484, AI432296,
AI478420,
AW082819, AI912373, 889026,
AA894797,
AI55416I, AI752414, HI3307,
AI249I65,
861527, N62403, 889727, N47856,
AI689339, AI368569, 861583,
AI984780,
AA219502, H44175, AI802627,
AI752415,
T32963, AW295386, AA985168,
H06745,
840750, M79099, AA203312,
800511,
A91842, A91846, A91844, and
A91848.
HCE3E50 16 12275861 - 3775 15 -
3789
HCE D04 17 11508681 - 625 15 -
639
HDPHI92 18 9099001 - 2933 15 - AC068341.
2947
HDPLT89 19 9624031 - 2437 15 -
2451
HDPSU48 20 12282841 - 2902 15 -
2916
HDPWE80 21 9099161 - 932 15 -
946
HD FY84 22 10921371 - 3253 15 -
3267
NEON 23 9307051 = 897 15 -
19 911
HFCBB56 24 9100731 - 553 15 - AA339423, and AC068296.
567
HFKKZ94 25 11630701 - 1318 15 -
1332
HHBGJ53 26 11876681 - 388 15 -
402
HHFJF24 27 12126241 - 2787 15 -
2801
HHFMM10 28 11788011 - 1857 15 -
1871
HHPBA42 29 9019211 - 899 15 -
913
HHPSP89 30 12170521 - 2277 15 -
2291
HKABX13 31 11671821 - 970 15 -
984
HLTHG77 32 11624091 - 392 I5 -
406
HLWBZ09 33 11797141 - 1940 15 -
1954
HLWEH54 34 12277131 - 4510 15 -
4524
HLYAA41 35 11880291 - 797 15 -
811
HLYDV62 36 11540651 - 805 15 -
819
HMCFB47 37 11514981 - 796 15 -
810
HMSOI20 38 11788171 - 2431 15 -
2445
HOENH55 39 11634601 - 612 15 -
626
HPIAI01 40 10781781 - 926 15 -
940
HPJCT50 41 12017731 - 1983 15 -
1997
HPMFE91 42 11647401 - 1867 15 -
1881
HRAED51 43 10905221 - 645 15 -
659
HSMBA19 44 11979251 - 2252 15 -
2266
HSYCY88 45 9147751 - 1128 15 -
1142
HTEDW26 46 9097491 - 1158 15 -
1172
HTEKD92 47 10905241 - 1447 15 -
1461
HTLDT05 48 12271271 - 2672 15 -
2686
HTPDS90 49 11979261 - 1920 15 -
1934
HTPHM71 50 11946981 - 2017 15 -
2031
HUUAR12 51 11947021 - 1704 15 -
1718
HWAGP22 52 11501951 - 1716 15 -
1730
433
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HWBCE37 53 906968 1 - 418 15~-
432
HWLFB60 54 12234991 - 286715 -
2881
HDPGS 55 10757251 - 447 15 -
16 461
HDQDV69 56 937850 1 - 837 15 - AA887783, AW392670, U46341,
851 AL119457,
AL119341, AW372827, U46346,
AW384394,
AW363220, AL119484, AL119497,
AL119355, AL119319, AL119324,
AL119443, 299396, U46350,
U46351,
AL119363, AL119391, AL119444,
AL134902, U46347, U46349,
AL119483,
AL119396, AL134528, AL119418,
AL119335, AL119496, AL119439,
AL042433, AL119522, AL042965,
AL134524, AL119399, AL134920,
AL037205, AL119401, U46345,
AL134536,
AI142132, AL119464, AL042450,
AL042614,
AL043029, AL134525, AL134538,
AI142131,
AL042551, AL042984, AL042975,
AL042544, AL043019, AL042970,
AI142134,
AL042542, AL043003, AL119488,
AF169035,
AF085233, AB026436, AR054110,
A81671,
AR066494, AR060234, and AR069079.
HE6BK63 57 11538791 - 755 15 -
769
HFKDR14 58 974255 1 - 172115 - AI761729, AW162515, AW104395,
1735
AW298361, AI073443, N40162,
AI832126,
AI827518, AW297353, 852045,
AI342317,
871958, AF128625, AF021936,
and
AB032950.
HFPER82 59 11522491 - 619 15 -
633
HAAA058 60 10910881 - 130915 -
1323
HADFK69 61 10919371 - 160315 -
1617
HDPM062 62 11523291 - 112315 -
1137
HDPM085 63 12282821 - 247915 -
2493
HDPUY72 64 12282851 - 304015 -
3054
HDTJF87 65 11546401 - 826 15 -
840
HE8TB94 66 11787941 - 191315 -
1927
HE8UB55 67 12281131 - 333215 -
3346
HEBGA65 68 11786331 - 180315 -
1817
HEGBB59 69 11979071 - 246515 -
2479
HELHC48 70 956003 1 - 803 15 -
817
HEO H90 71 12126461 - 260915 -
2623
HFKHA18 72 11522421 - 105515 -
1069
HFKMA10 73 964258 1 - 960 15 -
974
HHBFM91 74 10921161 - 901 15 -
915
HIBBF63 75 912715 1 - 950 15 - AC012171, AC012171, AC012171,
964
AC009065, AC009065, AC009065,
AC005346, AC005346, and AC005346.
HMCEI38 76 11344101 - 613 15 -
627
HMWJD68 77 11547901 - 135015 -
1364
HOEOL58 78 10780901 - 778 15 -
792
HRACA51 79 11628561 - 107515 -
1089
HSHAV32 80 11803881 - 258915 -
2603
HTPDE66 81 971281 1 - 479 15 -
493
HTPDV73 82 997659 1 - 411 15 -
425
HTPHE33 83 11638711 - 171415 -
1728
HUFDN58 84 12246091 - 240415 -
2418
HUVFX92 85 12253291 - 428 15 -
442
434
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HWAEG71 86 11823211 - 147115 -
1485
HWAHD49 87 12280641 - 136515 -
1379
HWLGG31 88 11788251 - 200715 -
2021
HWLKF25 89 10890521 - 109715 -
1111
H2CBH45 90 963811 1 - 470 15 - AA307462, AA036880, AL133047,
484 D89677,
AC068243, and AC068243.
HAGDN53 91 10921611 - 170215 -
1716
HAMFM39 92 971347 1 - 459315 - AI951619, AI814592, AI745391,
4607 AI922346,
AA426190, AW105735, AW297557,
AI829867, AI971865, AA227834,
AW028756,
AA151872, AA757072, AI202419,
AW 176248, AW295401, AI659079,
AAI49658, AA425I59, AI765117,
AI870033,
AW194075, AA233413, AW102818,
861588,
AA365664, AA365663, AA601170,
861532,
AA357346, AA551861, AI66023I,
AI467782,
299396, AW392670, AL119324,
AL119319,
U46350, U46351, AL119457,
AL119484,
AL119391, U46347, AW372827,
AL119522,
AL119439, AL119335, AW384394,
AL119483, AW363220, AL119363,
AL119497, U46349, AL119355,
AL119444,
AL119443, U46341, AL134518,
AL134525,
AL119341, AL037205, AL119401,
U46346,
AL119396, AL134538, AL134531,
AL134528, AL119418, AL119496,
AL119399, U46345, AL134524,
AL042544,
AL042614, AL042984, AL042542,
AL043019, AL042450, AL134542,
AL043003, AL042965, AL042975,
AL043029, AL042551, AL119464,
I05430,
I05393, A10617, AR028792,
AR028791,
AR028793, I25027, AR054109,
I44515,
I26928, I26930, I26927, I25041,
I44516,
A01324, AR035224, AR009151,
I85513,
AR009152, A01323, AR027099,
AR034783,
A94046, A94054, I63120, AR067733,
AR064322, AR064323, AR064320,
AR064321, A32110, A94048,
A94061,
A49045, AR038321, A83642,
AR019094,
A83643, A70359, A92666, AR038307,
A92668, A92667, I49890, A92665,
A92081,
A92080, A92077, A92078, A92079,
AR018924, AR018923, A48774,
A48775,
AR000006, AR015960, AR015961,
AR000007, A91752, A91751,
AR051652,
A85308, AR068508, AR068510,
AR068509,
I91969, A91754, I58322, I58323,
AR003585,
A63067, A51047, A63064, A63072,
AR031375, AR068507, A60213,
AR068506,
AR062871, A44171, AR068550,
A23373,
AR068551, A49700, A60207,
A60208,
A29109, A32111, I58669, A58521,
AR031374, I07209, I07249,
A63954,
AR051651, AR019097, AR019098,
AR019096, AR029417, I77227,
AR020199,
AR020200, AR001287, AR020198,
AR020197, I89986, AR051957,
AR029418,
AR067734, AR067731, AR067732,
Y14971,
435
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
A93444, A46342, A46343, AB026436,
I09121, AR032878, AR060234,
AR066494,
A81671, AR054110, and AR069079.
HBGQT03 93 9081731 - 1196 15 - AW193981, AA576536, AW439879,
1210
AA218860, AA587394, AI735027,
AW206358, AI075695, AI749755,
AI073515,
AI283940, AI828816, AW328242,
AA452508,
AI741698, F25077, AA454093,
AI280249,
AI826261, AI567379, AA350150,
AI251129,
F26225, AI354257, AA171893,
AW129660,
AI357160, F26293, F36700,
H24638,
AI270014, AI952189, AA834233,
AI689497,
AI688448, F17480, 238509,
T11668, N93072,
AW362737, T11669, AW273866,
N93071,
AW328241, AF130979, AC024045,
AC024045, and AC024045.
HBGSJ13 94 11507901 - 808 15 -
822
HBIBQ89 95 9097821 - 851 15 - AA399613, F11248, 242117,
865 AA082253,
F05395, T35421, and AB007925.
HCECM90 96 9450881 - 1379 15 - AA463356, AA453500, AA322899,
1393
AA340682, H24259, AA603868,
AA330182,
819782, and AB023227.
HCEPH71 97 5227391 - 432 15 - AA326209, AA383931, AL365319,
446 and
' AL390715.
HCFMT57 98 11752041 - 2197 15 -
2211
HCOMM05 99 11731461 - 1625 15 -
1639
HCOOZl 100 9653061 - 689 15 - AI350354, AI904299, AI902503,
l 703 D61534,
T78554, AW 183962, AI218626,
AW304978,
W74167, AI081779, AL022238,
AL137499,
AL022238, AL022238, and AL022238.
HCWFF88 101 5065771 - 304 15 - AL157951, AL157951, AL157951,
318 and
AC025670.
HDMAVOl 102 11946961 - 1796 15 -
1810
HDPDA47 103 9291931 - 1036 15 - AW402583, AL049683, and AL023653.
1050
HDPFF24 104 9092321 - 447 15 - AI929099, AI566117, AI928828,
461 N88094~
AA365879, AA281290, H67457,
N87549,
AW450464, AA295368, AA527887,
AI033615, AA354369, AA086081,
and
AA903373.
HDPP035 105 9662481 - 1890 15 - AI640500, AW439548, AI823872,
~ 1904
AW297416, AA831672, AI815031,
AA994323, AA741162, AA471280,
AI223999, AW339548, AW235171,
AI635436, AA035703, AA747998,
AI371399,
N67227, AA361754, AA063573,
AI536057,
AI357169, 833401, C01451,
833402,
AA825399, AF165138, and AF130247.
HDPSR74 106 9113961 - 709 15 -
723
HDTKQ14 107 8869361 - 541 15 - AL023653, AL049683, AL359542,
555
AL359542, and AL359542.
HE6GF02 108 11508971 - 790 15 -
804
HE8PK12 I09 9098841 - 707 15 - AA296029, AL117472, U58883,
721 AF136380,
AF136381, AF078667, and AF078666.
HE9SE62 110 9114761 - 915 15 - AW021430, AI765247, AI822051,
929 AI822104,
AA010459, N70537, AL133567,
and
AB018312.
HEOPL36 111 11956821 - 2095 15 -
2109
HFBDJ13 112 9112641 - 476 15 - M86084, and AF030131.
490
436
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HFTDF15 113 6570201 - 367 15 - AL365277, AL365277, AL365277,
381
AC024511, AC024511, and AC024511.
HHE ' 114 9328511 - 873 15 - AA355773, and AA355926.
V39 887
HHFCK09 115 9653041 - 2789 15 - AI218626, AI076006, AW 162820,
2803 AI797880,
AI922744, AI872391, AI559566,
AL045117,
AW161046, AW162613, AI565503,
AW183962, AI857802, AA460810,
AI$84907,
AI371131, AW248493, AI081779,
AA460372,
AA679085, N27884, AA581796,
AA074070,
AA971563, AI292006, AI922373,
W76538,
N93245, AI609183, AW172513,
AI904299,
AI682939, AA075764, AI885613,
AA747871,
AA449042, AA928020, AW401847,
AA449757, AW268637, AW073851,
AW304978, AI683858, AA568598,
W74167,
AI367698, AW19I998, N62781,
AW016535,
AI902503, AA347639, AA297591,
AA379280, AA568887, AA649970,
AW264577, AI221886, H20460,
AW387087,
AW000860, AI275195, AA341002,
T32918,
AW162711, W25103, AI699657,
842681,
AW243790, AA768740, T78554,
AI279653,
AI560482, AI696251, AI951374,
245830,
AA147203, AI499410, 843259,
AI350354,
AA732831, AW079129, AA375228,
F08622,
AI475009, 856337, AA379846,
817163,
AW380349, AA783050, AW247402,
N47545,
835508, 851077, AI474934,
N79729,
D61534, 241466, AI678630,
AA339343,
AW367003, AA160401, 241592,
AW079321,
N47546, AI252528, 858857,
T16943, H55297,
AL022238, AL137499, and AJ236700.
HISDS62 116 9359321 - 506 15 - W27339, AA126I05, AA306119,
520 W27700,
AB007884, and AJ250425.
HLQDT35 117 8397771 - 516 15 - AA706241, AA707183, AA152440,
530 N99172,
AA131985, AA358765, AA253107,
810421,
_ N56752, AA290907, 808557,
AA485099,
AI091625, AA134742, AL137699,
AC010998,
AC010998, AC010998, AC013357,
AC013357, and AC013357.
HLWFN63 118 9084371 - 3089 15 - AA707313, AI880426, AI684827,
3103 AI744551,
AI307796, AA101249, AI284152,
AA007399,
N98643, AI375268, N66095,
871685,
802817, AA085724, AI221876,
AI061056,
AW207571, AA111956, AI460369,
AI333887,
AA594062, 818624, 862793,
W22434,
AW007868, AA776586, T70023,
871720,
H70803, AA323135, AA101290,
AA029721,
AA320669, AI193496, 807828,
AA007478,
AI915644, AI932703, T69946,
862792,
AA029660, AI859215, AA205667,
AI625446,
AI273982, AB018333, AC006599,
AL033378,
AL033378, AC006599, and AC006599.
HMEFT66 119 8561491 - 337 15 -
351
HMSCD15 120 9181331 - 1223 15 - AA828277, AI707568, AI333720,
1237 W33154,
AI880870, AA848014, AA864599,
N50622,
AW087770, AW270419, AA761244,
AA262754, AA779760, AI880826,
AW407353, W37119, AA206843,
242584,
437
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
AA206842, AB011126, AL158207,
AL158207, and AC027008.
HMSH064 121 746582 1 - 398 15 -
412
HMTAW83 122 911385 1 - 487 15 - AI908321, AA831896, AR058970,
501 AR058968,
A68194, and AR058969.
HMVAM09 123 963814 1 - 100915 - AI685410, AI969804, AA621392,
1023 AA358533,
AW135812, AI376856, and AI276887.
HNSAA28 124 946988 1 - 154415 - AA713959, AI564093, AA768779,
1558
AA825697, AA808021, AA808149,
AI401490, AW 181992, AW444640,
AI018I59, AF146277, and AF077003.
HOGE 125 12262071 - 419615 -
43 4210
HOUDH19 126 11509181 - 515 15 -
529
HOUFT36 127 911293 1 - 832 15 - AI806483, AI147946, AA256164,
846 AW236751,
AA057615, AW362445, AA542823,
AF162130, AC005084, and AF161181.
HPMFL08 128 959569 1 - 452 15 - AA555286, AA640814, AI281916,
466
AW073979, AI378363, 870468,
AW242350,
AW013856, AA644290, AW449140,
293016,
AC012384, AL035541, AC005228,
AC003662, AC009300, and 293016.
HRSMD49 129 723025 1 - 443 15 - AA136820.
457
HSDII69 130 917180 1 - 161215 - AA203346, AA203330, AA489694,
1626
AI912487, AW024848, AA133454,
AA640288, AA658936, 224863,
AA665267,
AA878769, AI024792, AI383978,
AW022618,
T31809, AA318980, T86474,
AA669824,
AA115749, AW296909, AA552781,
AI459513, AI332862, AI332863,
and T86475.
HSDSB06 131 949151 1 - 226415 - AW009631, AI765056, AA877550,
2278
AA102362, AA625117, AA447454,
AA446651, AA724535, AI220147,
AA430607, AA019158, AI198643,
AW389353, AA516463, AW197881,
AA045561, AA186967, H86071,
H67029
AW378928, H12433, AA768085,
866487;
AA478635, N55248, AA359925,
833870,
AA385529, AA054621, AA961423,
AW002948, AI802284, AA377365,
D31590,
AW275740, AI766068, C01179,
AL133047,
D89677, and AF003234.
HSFAM09 132 11509651 - 531 15 -
545
HSSAX53 133 507509 1 - 348 15 -
362
HSVAW49 134 11509601 - 970 15 -
984
HTEAG49 135 954614 1 - 128915 - AW452652, AI039005, AA780077,
1303
AW316890, AI337290, AA463229,
AA463230, AI423317, AI468158,
AA382497,
N66986, AF041822, AL390796,
AL390796,
AL357045, and AL357045.
HTLBH67 136 751985 1 - 432 15 - W 19592, AC005368, AC008439,
446 AC022420,
AC022420, AC022420, AC005368,
AC005368, AC008781, and AC008781.
HTLJC71 137 922923 1 - 173815 - AL039539, AL045443, AI336919,
1752 AA406128,
AA405229, AL042307, AA431504,
AA311249, AW086440, AA813520,
AI240644, AA897733, AW268487,
AA782009, AW172455, AI301209,
AI014598,
AA969918, AL041043, AA431178,
438
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
AL039540, AA973051, AI221826,
AL133030,
AC009516, AP000552, AP000556,
AP000557,
AL117509, AC023490, AC023490,
AC009516, AC009516, AC009516,
AC018752, AC018751, AC018751,
AC007957, and AC007957.
HTPAD46 138 5033131 - 343 15 - AA386091, AA386130, AL133510,
357 and
AC010932.
HTTKP07 139 9113901 - 562 15 - AI640500, AA035703, AF130247,
576 and
AF165138.
HUCOW 140 9333571 - 843 15 - W52616, AA102287, 860274,
17 857 AA307147,
H17000, H15631, C03464, and
AA192581.
HWHGF52 141 7261021 - 441 15 - AA223889, and AB002360.
455
HWHHB69 142 12126121 - 2914 15 -
2928
HWLFH94 143 11513871 - 1251 15 -
1265
HWMBM1 144 9096831 - 858 15 - AI339104, AA861042, AA134985,
3 872 AA868144, AA134946, AI626100,
AA922724, AA535447, AA056635,
AA308766, D25742, AA916634,
AA551763,
AA873574, AW192836, AR044148,
AL158847, and AL158847.
HWWDN3 145 9113571 - 1233 15 - AI671062, AI023330, AW243448,
4 1247 AI990947,
AW081367, AW391909, AA448391,
AI984688, AA448394, AI283270,
AI344135,
AW014216, AA127530, AA335984,
AA377148, 242084, 812430,
AA400585,
AC019214, and AC019214.
HCEML27 146 9970511 - 894 15 -
908
HELHJ69 147 11289241 - 630 15 -
644
HFKL,A09148 11788001 - 2072 15 -
2086
HSBBF79 149 9657641 - 1361 15 -
1375
HSLKA77 150 12042691 - 4086 15 -
4100
HAGDR21 151 10904331 - 1414 15 -
1428
HHFNH27 152 10252771 - 1952 15 -
1966
HTLIT05 153 12176251 - 844 15 -
858
HAPNV33 154 11513741 - 793 15 -
807
HBTAE84 155 11288001 - 489 15 -
503
HDPVY89 156 8270261 - 684 15 - AC026283, and AC026283.
698
HGLDB21 157 10109201 - 1670 15 -
1684
HMIAN37 158 9478811 - 677 15 -
691
HODAK55 159 I l 1 - 713 15 -
10333 727
HSLEI59 160 11288011 - 758 15 -
772
HS FH29 161 12170611 - 1907 15 -
1921
HTLEA35 162 11072301 - 674 15 -
688
HUVGG63 163 12047161 - 2211 15 -
2225
HAGAX57 164 11508651 - 1237 15 -
1251
HAMGXlS 165 11779321 - 750 15 -
764
HAUBV06 166 11060411 - 2203 15 -
2217
HBWCM62 167 11852731 - 465 15 -
479
HCWFA35 168 11056721 - 611 15 -
625
HDACA35 169 11072361 - 983 15 -
997
HD GM08 170 11514691 - 896 15 -
910
HELGB06 171 11487411 - 433 15 -
447
HEOPR74 172 12268221 - 1245 15 -
1259
HIBEK35 173 7314801 - 402 15 -
416
HJMAR88 174 11049371 - 683 15 -
697
HMWGU56 175 12264701 - 1016 15 -
1030
439
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HOUDS09 176 11640101 - 163115 -
1645
HTEGM38 177 675087 1 - 350 15 -
364
HTEKY82 178 11524951 - 486 15 -
500
HTLCY54 179 11935501 - 104915 -
1063
HFOXK14 180 603245 1 - 616 15 - AL096870, and AL096870.
630
HHFF069 181 837703 1 - 901 15 -
915
HHFLU06 182 857884 1 - 316 15 - AL096870 and AL096870.
330
HAGBA56 183 732597 1 - 653 15 - AA812064, AA430303, AA430200,
667
AI803142, AI425013, AA954361,
AB020641,
U62391, AF033655, AC006036,
AC000057,
and AC002458.
HAGGF84 184 911312 1 - 421 15 - AL135568, AJ252239, AF071569,
435 U73504,
D14906, J05072, X63615, AC004056,
and
AC004168.
HAHGD33 185 921782 1 - 105115 - AW378448, AW378426, AA064738,
1065 243369,
AA984486, D31100, W79308,
T35774,
T08259, W52734, W73106, AI904952,
810018, AA348984, T80752,
AA639598,
857404, T81225, AW408302,
T81300,
813945, T47464, W79389, 243504,
AA404490, AA196613, W01185,
H14918,
H45144, and AF113249.
HAHIY08 186 962113 1 - 265 15 - AA100160, AA307684, AA244505,
279 857782,
AA864846, AR044133, and AR044123.
HBIOZ10 187 973131 1 - 490 15 - AC010761, and AC010761.
504
HBKDI30 188 729048 1 - 625 15 - AA197072, 802824, J05194,
639 J03886, and
AL160175.
HBXBW40 189 706115 1 - 462 15 - AL023754, AL049688, and D86557.
476
HCEHE35 190 909937 1 - 378 15 - AB019692.
392
HCEPW85 191 911374 1 - 302 15 - N83965, AA326737, and H14153.
316
HCFAT25 192 932068 1 - 579 15 - AI287912, AL134532, AF096300,
593 AB014587,
AC005035, AL137755, and U88984.
HCFCF47 193 11397311 - 980 15 -
994
HDAAV61 194 810305 1 - 329 15 - AI762433, AI191825, AA159268,
343 AA083866,
AW105372, AA157878, AI140935,
AI922109,
AA158846, AA488548, AI187149,
AA442140, AA837990, AI494201,
AL048644,
AI366974, AI537837, AA425228,
AW410089,
AL038605, AI821259, AW084097,
AW083168, AI624304, AI918554,
AA508692,
AI918634, AI307494, AI349622,
AI738867,
AI310571, AI802372, AI918408,
AW021662,
AI348897, AI366959, AW058233,
AI345397,
AL038564, AW089275, AI340511,
AA857847, AI446405, AI799305,
AW022494,
AW020288, AI28I867, AI312210,
AI307569,
AI270295, N71180, AI702301,
N75771,
AL036652, AW021373, AL036856,
AI312428, AI866820, AW059713,
AI889147,
N27632, AI336513, AW022102,
AA019646,
AI348895, AI313320, AI336495,
AI310920,
AI307503, AW079736, AW082532,
AW089572, AI345143, AI309391,
AI955906,
AI309431, AI336662, AI868204,
AI310575,
AI349276, AI307507, N22406,
AA420722,
AI336565, AI683559, AL040694,
AI311440,
AI334893, AI349186, AI340533,
AW088560,
AI690472, AI521005, AI537515,
AI493601,
440
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
AI348847, AW083572, AW020397,
AA493923, AI521799, AA835966,
AI334895,
AI309380, AW068845, AA814721,
AI343091,
AI401697, AA176980, AI815232,
AW020419,
AI340627, AW087838, AA555145,
AI366968,
AI348969, AI625464, AI307210,
AW022636,
AI348854, AI584130, AI679959,
AI313352,
AA789133, AW268072, AI336585,
AI349787,
AI349266, AI334452, N99092,
AI312271,
AI345114, AI344938, AI305745,
AI345224,
AW 168503, AA127565, AI312146,
AI590423,
AI312339, AI340537, AI500659,
AI345258,
AW054972, AA848053, AI307459,
AI559863,
AI349971, AI348879, W33163,
AW193134,
H89138, AW090539, AI348777,
AI311604,
AI343030, AI311892, AI680377,
AI349805,
AI887775, AI582871, AI349814,
AI310930,
AI500706, AI335426, AW263804,
AI312333,
AW268261, AI349957, AI345370,
AI114703,
AI370392, AI500662, AA460184,
AI783861,
AW150487, AI310945, AI336634,
AI889168,
AI440263, AI307735, AI345471,
AI963690,
AI312431, AI468959, T99953,
AI345005,
AI613343, AI571699, AW162189,
AI312353,
AI271234, AI623736, AI888956,
AI560545,
AI934000, AI343131, AI540606,
AI334884,
AI307543, AI567582, AI345251,
AI349269,
AW071412, AI254226, AW020592,
AI307734, AI859644, AI307708,
AI804505,
AW058279, AI582912, AW172723,
N29277,
AI312325, AW071395, AI345156,
AI242736,
AI340659, AW071377, AI311159,
AI866573,
AI672130, AA579232, AI343140,
AI452556,
AI612885, AI340644, AI636788,
AA837508,
AI440091, AI572396, AA494167,
AI702065,
AI334930, AI309443, AI862066,
AI345562,
AI702527, 841605, AI307520,
AW020693,
AI371228, AI345026, AI679174,
AI805688,
AC007136, Y11092, AL137565,
AF125532,
AF003737, E01314, J05032,
I48978,
AF111851, L30117, X65873,
AL133014,
AL137560, X93495, A08913,
AR038854,
I89947, A08912, A08910, I89931,
A08909,
577771, AL050015, I89934,
AF162270,
I49625, A08908, 576508, D83989,
A18777,
A08907, AF113676, A27171,
AL137641,
U75932, AF067728, AB007812,
L13297,
AL050146, X63574, AF017437,
D89079,
U57715, AL133098, AF120268,
AL133010,
E12579, AF061943, I00734,
561953, X79812,
E00617, E00717, E00778, U72620,
A08911,
AF114818, AL122045, AL080074,
AL137658,
E15324, AL080140, AL050108,
AF113013,
M30514, AF078844, AF113690,
E02253,
272491, AF106697, M27260,
AF151109,
AF205861, AJ010277, A52563,
AL137548,
AF055917, AR011880, E15569,
AF095901,
AF042090, AL110159, I89944,
L31397,
AR034830, I96214, AL110197,
AF125948,
441
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
AL137558, U49434, AL080129,
AF012536,
AF143957, U42031, AL117440,
A08915,
AL080060, AF113019, S36676,
Y10080,
U00763, AF153205, AF094480,
AF017790,
AF026124, AF017152, AF058921,
X06146,
AL133077, AF158248, AL137656,
A12297,
A08916, AF008439, AC004093,
AL137539,
Y10655, 575997, AF113694,
AJ001838,
X76228, Y10823, Y11254, A83556,
AF00030I, AR059883, X54971,
AL049466,
AF016271, AL050393, AL049452,
E12580,
X53587, X57961, AP000081,
AR068466,
AF026816, I48979, AL110171,
AL080086,
X63410, AR020905, AF091084,
AB016226,
AL133067, AF126247, AF113677,
AF175903,
A07588, AF118094, AL049464,
AF097996,
L40363, U90884, U53505, AF176651,
AL137459, U55017, AJ238278,
AL117460,
U95114, L31396, X99717, AL122093,
U42766, AL137521, AL137479,
X96540,
AL110280, X72889, A58524,
X00861,
A58523, AC002467, AC006371,
I29004,
AL080124, AB019565, AL133104,
AL133637, AFl 10329, AL049938,
AL137557,
AL133558, X62580, X70685,
AR029490,
AL049314, AF106827, AL133081,
I42402,
I46765, AL137648, AF031147,
E01812,
AF079763, AL117585, U68233,
I92592,
E07108, A07647, AF036268,
568736,
AL117394, U72621, AL133565,
AL133031,
AL133606, AJ006417, AF061573,
X98834,
AL122123, AL031346, AC004227,
Y08769,
I22272, AL137463, AF169154,
L19437,
AR059958, AL122098, AF061795,
AF151685,
U57352, X66975, AF139986,
AL050092,
AF137367, X98066, AL122049,
AF113689,
563521, AF118064, AB026995,
AF118070,
AL050277, AF113699, U58996,
AF159615,
AL137711, AL080162, AF125949,
U62966,
AL137547, X67813, AC007136,
AC007136,
and AC007136.
HDPKD75 195 8108241 - 524 15 - AA923698, AL040000, AF191838,
538
AR016417, AF191839, and AF145705.
HDPNC96 196 9345201 - 720 15 - AA256100, and AB023182.
734
HDPSR15 197 9696661 - 1218 15 - AW195239, AW149418, AW005579,
1232
AI378013, AA147800, AI436586,
AI392913,
AW337924, AI377235, AI26493I,
AI203549,
AW 104319, AI094031, AA461376,
H59980,
AW166255, AA508841, AI360737,
AA463275, AA417605, AI682196,
H59937,
AI208175, N30324, AA460078,
AW001677,
AA514325, N50317, AA741518,
AI091790,
T11446, AA360254, AI208678,
AA214523,
D20738, 861563, T12550, T11445,
AA428834, AI276889, AB026289,
and
AR044150.
HDQDX20 198 9190271 - 1280 15 - AI905612, N75655, N94726,
1294 AA297704,
H53438, AW339945, AW405560,
AA719945,
AI682436, AA971968, AW085268,
H67340,
442
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
AI419590, AI863597, 884229,
AA996342,
H69541, D45315, AI002247,
AI138274,
AI648605, W03933, AA348656,
AI610448,
AI769304, AA362755, AI708290,
D45320,
AW270686, AF169035, AF085233,
and
AF 113007.
HDQHB 199 12260891 - 2263 15 -
19 2277
HDTBY88 200 9344721 - 495 15 - AA868305, AI700890, AA789239,
509 AI803004,
AI694352, AA043382, F08474,
821498,
AF112183,AF112184, andAC005354.
HE2KZ07 201 9099481 - 1167 15 - AI141657, AW410635, AI377644,
1181 AI373441,
AI435842, AI813994, AI222162,
AI816276,
AA134062, AA11552I, AA027340,
AI198968, AI936995, AA432023,
AI417110,
AA019881, AA431770, T33003,
AI804202,
AW296590, AA894568, AA888588,
AI816392, AW 157195, AA774185,
AI312197,
AA770240, AI005469, T15996,
AI589559,
T83662, AI802351, AA164900,
AI637808,
AW294821, AI612103, AI452706,
896447,
AI214546, AA083117, AI219844,
AI312448,
AA978205, H98210, AI423512,
AA115526,
N74543, AI823785, H19250,
T16797,
AI803155, AW051574, 241102,
AI300274,
AA970855, T30646, T78862,
T81921,
842142, 838428, 805531, T99321,
H16697,
808035, AA114950, H52123,
AA114923,
841504, 808085, F18392, D79266,
842920,
AI028740, AAl 14993, F34433,
F25527,
AA130289, C02151, AL118820,
AI696123,
H10371, AA954386, T34819,
AA135800,
AI219437, T81018, AA135799,
AI372829,
AI056831, H68913, AW051694,
AI986390,
W28788, H10372, U95740, D86556,
AB004267, AB023027, and AF181984.
HE8UY74 202 9609141 - 553 15 - N23547, H06088, 224919, 894366,
567
AA010516, AA004981, AA304780,
AL356968, and AL356968.
HE9N066 203 9743531 - 976 15 - AI732997, AA865818, AA977633,
990 269734,
AB035267, AB020741, and 268339.
HEMBT61 204 9399571 - 449 15 - N86549, AW369713, and AB002301.
463
HETLF29 205 9097621 - 404 15 - AA960957, AI001155, and AC004664.
418
HFIUE75 206 9097581 - 1104 15 - AA745592, AA780791, AI680317,
1118
AA205127, 806019, AW074511,
T76970,
AW408392, T86065, T77135,
AI709216,
805922, T85884, AA730855,
and 877022.
HFHIT06 207 9340191 - 286 15 - AC026976, AC068353, AC068353,
300
AF284563, AF284563, and AC026976.
HHEGG20 208 8944091 - 808 15 - AF084205.
822
HHEHC53 209 9217831 - 896 15 - AW408302, AW410815, AW 161181,
910
AA160313, AA226860, AA044358,
AI632654, AA232389, 243369,
AA249020,
T35774, AA852244, AA064738,
AA295773,
D31100, 813945, AA205277,
T47464,
T08259, AI904952, AF113249,
AC009427,
AC009427, and AC009427.
HHERQ79 210 9440571 - 497 15 - AW340333, AI806295, AW268810,
511
AA827664, AA829237, AA909185,
443
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
AA919008, AA604425, AW407893,
AA011359, AL134902, D63485,
AB016590,
AB016589, and AR043113.
HISAF59 211 959140 1 - 899 15 - AW401787, AI394630, AI418298,
913
AW375742, T30407, 244281,
F07299,
825015, T32685, AA974700,
F07734,
AA297059, AW239548, AA897415,
845025,
AI807678, AI343378, AW206793,
AW138409, AW163027, AI815476,
AA503315, AA047793, AW137324,
AW140018, AI936871, AI015047,
AI017077,
AI168175, AI302185, AI025217,
F03423,
846686, AI073417, 240806,
AA026054,
AW002416, AI652375, F03562,
T03397,
AI983297, H42881, T82311,
AI025310,
AI831833, 808769, AI911100,
AA471062,
AW157059, AA382959, H22172,
AI356604,
AI537006, AI825970, AW338394,
AW192088, AI559159, AA593826,
AW078709, and 261277.
HKAKM10 212 918685 1 - 596 15 - AW166113, 888730, AF071071,
610 AF170303,
AF170304, AF077658, and AF071070.
HLTHP86 213 919354 1 - 247015 - AA702160, AI457618, AI951809,
2484 AI808761,
AI911971, AI808636, AI633963,
AI092909,
AA922021, N53I71, AA809486,
AI092910,
AI253245, AA236950, AI432182,
AI093897,
AI363415, N50448, AI248799,
AA663589,
AA235935, AI239417, AA121162,
AW270053, AI889821, AW296666,
AI263508, N50504, H16878,
H09671,
AW028355, AW300355, 856761,
H84971,
AI373750, H16267, 244040,
244727,
AI025923, N58608, T95750,
T34716,
AA363673, 843831, AA687486,
891239,
AI829631, AA687431, AA852910,
H16769,
T95749, AI268135, AI686257,
856913,
240554, AA834548, AA872305,
C02338, and
AF 161420.
HMSJL96 214 934483 1 - 662 15 - 801798.
676
HMTAJ73 215 813296 1 - 651 15 - AI831613, AI924408, AI870169,
665 AW068406,
AI368905, AW168626, AI284115,
AA678670,
AA568895, H19069, AA627558,
AA857431,
AJ010119, AF074714, AF074715,
AC015698,
and AC015698.
HNTCP13 216 909770 1 - 179315 - AI479379, AW273740, AA463847,
1807 AI740675,
AI014722, AI922082, AA463334,
AW009462,
AI073540, N95224, AI190238,
AA007373,
AI798079, AA476563, AA670286,
H02882,
N92851, AA652716, AW016339,
H45475,
W25554, AA774170, H45576,
AI370125,
AI811794, AW119159, H03781,
H20952,
AA853882, AA853883, AI471060,
AW382128, AW371996, W21053,
H20991,
AA368628, AW138258, AA476448,
AA876335, AA788825, AF037447,
and
AC004486.
HNTMD79 217 934522 1 - 573 15 - AA305176, AL160291, AL160291,
587
AL365228, and AL365228.
4~i4~
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HNTMH70 218 7571841 - 674 15 - H19102, AI699883, AI383263,
688 AC005726,
and AC004807.
HNTNB14 219 9099421 - 644 15 - AA082976, 860839, AA349498,
658 F12661,
T74243, L22557, AC068701,
and AC068701.
HODFF88 220 9749111 - 1843 15 - D80164, D59502, D80193, D80195,
1857 D59275,
C15076, D80227, D58283, D80022,
D80166,"
D81030, D59859, D51799, D59619,
D80210,
D80391, D80240, D59787, D51423,
D80253,
D80043, D80269, D50979, D80212,
D80038,
D80196, D80024, D80219, D80188,
C14331,
D59467, D57483, D59927, D80378,
D80366,
C14389, D59889, D50995, D80045,
D59610,
AA305409, C14429, D80241,
D51060,
T03269, C14014, AW178893,
C75259,
AA305578, D81026, D59695,
D51022,
AW179328, D81111, AW178775,
D80134,
AW378532, AW177440, D51250,
AW352158,
D80268, F13647, AA514188,
AW369651,
D80251, D80522, D51079, D80248,
D80949,
D58253, AW178762, D80168,
D52291,
C14227, AA514186, AI905856,
AW177501,
AW177511, D80133, 221582,
AW360811,
C05695, C14298, AW352117,
D80064,
AW176467, AW375405, AW378540,
C14407,
AW377671, D51097, AW366296,
D80302,
AW360844, AW360817, AW375406,
AW378534, AW179332, AW377672,
AW179023, AW178905, D80132,
AW360834,
AA285331, D80439, AW352171,
AW377676,
AW178906, AW352170, AW177731,
D80247,
AW178907, AW179019, AW179024,
D51103,
AW 177505, AW360841, AW 179020,
AW 178909, AW 177456, AW
179329,
AW178980, AW177733, AW378528,
AW 178908, AW 178754, AW
179018,
AW179220, AI557751, AW179004,
AW178914, AW378525, AW352174,
T11417,
D80157, AW 177728, D59627,
D51759,
AW367967, AW'178774, AW178911,
AW378543, AW352163, D59503,
D80258,
D80014, C06015, AI557774,
AW178983,
AW352120, T03116, AW178781,
T48593,
D58246, C14077, D59653, AW177723,
D58101, D45260, AI525923,
AW178986,
AW367950, C03092, AA809122,
H67854,
D59551, H67866, C14975, T02974,
AW378533, AW378539, D51213,
AW177734,
AI535686, D59317, D51221,
AI525917,
C14973, AA514184, C14344,
D45273,
AI525925, AI525920, D59474,
AI525227,
D31458, C14046, AI525242,
AI525235,
T03048, AI525912, AW378542,
AI525215,
AI525237, C16955, C05763,
233452,
AI535850, AI535961, A84916,
AJ132110,
A62300, A62298, AR018138,
X67155,
Y17188, D26022, A25909, A67220,
D89785,
A78862, D34614, D88547, AF058696,
X82626, AR008278, AB028859,
AR025207,
I82448, Y12724, A82595, AB012117,
445
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
AR060385, AB002449, A85396,
AR066482,
A44171, A85477, A94995, X68127,
I19525,
A86792, X93549, AR008443,
AR016808,
U87250, I50133, I50126, I50132,
I50128,
AR066488, AR016514, AR060138,
A45456,
A26615, AR052274, I14842,
Y09669,
A43192, A43190, AR038669,
AR066487,
A30438, AF135125, D88507,
AR066490,
D50010, AR054175, I18367,
Y17187,
A63261, AR008277, AR008281,
AR008408,
AR062872, A70867, AB033121,
AR016691,
AR016690, U46128, D13509,
AR060133,
I79511, AR064240, A64136,
A68321,
U87247, AB023656, U79457,
AF123263,
' X93535, and AR008382.
HOHCE47 221 12166831 - 214715 -
2161
HPCRV84 222 945856 1 - 475 15 - AA307070, D79997, L76158,
489 and X95351.
HRACK83 223 888037 1 - 566 15 - AC005832.
580
HRADM45 224 717358 1 - 468 15 - AA418916, AA426580, AJ271722,
482 AP000260,
AP000036, AF055919, AP000099,
and
AP000098.
HRAED74 225 942527 1 - 691 15 - AC005940, L42810, 583194,
705 AF117384, and
AB023658.
HRODZ70 226 942673 1 - 572 15 - AA292911, AA167655, AA167766,
586 H97685,
AA635138, 241812, and AB007941.
HSKAC24 227 823869 1 - 498 15 - AF170301, AF170302, AF077659,
512 and
AF 144573.
HSSMT34 228 911294 1 - 540 15 - AA378627, F07835, and AL117482.
554
HT3BG12 229 921593 1 - 368 15 - AB028951, and AL122055.
382
HTEG005 230 932583 1 - 108615 - AA059465, AA059211, AA731209,
1100
AA236961, T86500, T87461,
AL024498, and
M35862.
HTEKT33 231 953308 1 - 164815 - AW292935, AW027321, AW027332,
1662
AI538521, AL040176, H29877,
H85389,
H29974, H84772, 241499, AL045794,
T24112, T24119, D80253, D80043,
AI744745,
AL039924, D80219, AW013814,
D59275,
T10477, D51250, D80240, AA016312,
D80227, H00069, D80210, D51423,
D80134,
AL043441, T02921, D59619,
D80193,
AL039156, D80391, AL039150,
AL043445,
AL038821, D59787, AL039509,
AL039564,
AL039538, AL044530, AL039108,
AL039678, D80196, AL039074,
AL038837,
AL039625, AL039648, AL039629,
AL039566, D80045, AL039659,
T23947,
AL037726, AL038531, D80168,
AL039109,
AL040992, AL039128, AL044407,
AL036973, AL043423, AL045337,
AL037051, AL045353, AL036725,
AL039386, AL039423, AL045341,
AL042909, AL039410, C14227,
D80366,
AL043422, AL038025, D59927,
T11051,
D81026, AL039085, AL036196,
C14014,
D59889, AI535783, AW451070,
D80038,
C75259, D50995, C15076, AL037639,
847228, D80022, AI535983,
AL037526,
AL037615, D80I95, D80949
D58283,
446
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
D81030, D51799, T11417, D80188,
D80378,
D80522, D59467, F13647, AW452756,
AI.036767, T03269, T23659,
AL036117,
D50979, D80212, D59502, D52291,
221582,
AA285331, D80164, C14429,
D80166,
D59859, D80269, D59695, AL036765,
AI557751, D80268, AL036924,
AA514190,
AL038851, D58253, T48598,
C14298,
D80024, AL036191, D57483,
D59610,
AL037679, AL036418, D80241,
D59627,
D81111, AI910186, C14389,
C14331, 225782,
AL037601, AL036679, D51060,
AL036238,
AW178893, AA305409, AL037047,
D51079,
AL037082, AW177440, D51022,
AW179328,
AW178775, AA305578, D80014,
AW378532,
AI557774, AW352158, AI905856,
AW377671, D51213, AW369651,
D80251,
AA514188, D51097, AL036964,
D80248,
AW178762, AW177501, AW177511,
D80064,
AW360834, 299396, AA514186,
D80133,
AW360811, AW352117, T02974,
C05695,
AL037054, H00072, C14407,
AW176467,
AW378540, AW375405, D80302,
AL036733,
AL037021, AW366296, AW360844,
AW360817, AW375406, AW378534,
AW179332, D80132, AW377672,
AW179023,
AW178905, AW179220, AL036158,
D80439,
AW352171, D59373, AW377676,
D80258,
AW178906, AW352170, AW177731,
D80247,
AW 178907, AW 179019, AW
179024,
AW378539, AW177505, C14077,
AW450376,
AW 179020, AW360841, C06015,
AW 178909,
AW 177456, AW 179329, AW
178980,
AW 177733, AW378528, AW 178908,
AW178754, AW179018, A85396,
A25909,
AR025207, X68127, A86792,
A44171,
A85477, U87250, A67220, AR062871,
A84772, AR067732, A84776,
AR017907,
I18371, A84773, A84775, AR037157,
A84774, AR062872, AR062873,
AR067731,
A20702, A58522, A43189, A43188,
A20700,
A91750, D34614, AR043602,
AR043603,
AR043601, AR036905, AJ244003,
AR018924,
A95051, AR018923, A48774,
A98767,
A48775, A38214, A95117, AR015960,
A95052, A93963, A93964, I63120,
I56772,
195540, AR000007, AR015961,
A18053,
AR031374, A63067, A51047,
A63064,
A49700, AR031375, A63072,
A23334,
A75888, I70384, A18050, AR068507,
AR068506, A601~11, A23633,
AR007512,
A23998, I03343, A58521, AR020969,
I06859,
A58524, I60241, I60242, AR054109,
E12615,
AR022240, AR035193, A58523,
A92133,
A24783, A24782, A81878, A27396,
AR027100, I28266, E14304,
A97211, A49045,
AF156294, A82653, AF156296,
E16636,
A58525, A64081, I25027, E16678,
I26929,
I44515, I26928, AB012117,
I26930, I26927,
447
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
A93016, I49890, AR038762,
AR000006,
I44516, E13740, A58526, A91753,
296142,
AR066482, Y17188, I68636,
V00745,
AJ244004, A02712, X73004,
E16590,
AR008430, I19516, D88984,
I03665, I03664,
A15078, A10361, AR036903,
AJ244005,
D28584, A35537, A02136, A04664,
Y11923,
A13393, A35536, A02135, A04663,
A11245,
A02710, I13349, A07700, A13392,
I19517,
I01992, A76773, A22413, I21869,
A70040,
AF118808, I08051, I00074,
I92483,
AR038286, E00523, A97221,
E03165,
E02221, E01614, E13364, I00079,
D26022,
A92636, Y11926, I66495, I66494,
I66498,
I66497, I66496, I66486, I66487,
AJ230933,
I19525, E06034, I00077, A51384,
AR035975,
AR035974, AR035977, AR035976,
AR035978, 570644, D14548,
I25041, I07429,
A62300, A91754, A62298, 565373,
A60957,
X58217, AF019720, X67155,
A60968,
A84916, X13220, I84554, I69350,
I84553,
A04710, AR027069, AF096793,
AJ132110,
A20701, A52326, X92518, D44443,
AF096810, 578798, A10363,
A60985,
A60990, A78862, AB007195,
A60987,
D89785, X15418, E04616, A18722,
A80951,
I08250, 569292, AF130655,
M32676,
AR018138, D88547, X93549,
X82626,
I07888, AF058696, AR008278,
AB028859,
583538, AF135125, I82448,
and I15997.
HTEMU66 232 9444191 - 107815 - 1092AL039924, AL045794, AW013814,
AL036630, T02921, AL044412,
T24119,
AL044364, T24112, AW450335,
AL039476,
D51250, D80253, D80043, AL040992,
AL039109, AL038531, AL037726,
AL039629, AL039625, AL039648,
-
AL038837, AL039074, AL039678,
AL039108, AL039538, AL039564,
AL039156, AL039659, AL039566,
AL039509, AL039521, H00069,
AL039128,
AL044407, AL036973, AL045337,
AL037051, AL045353, AL039386,
AL039423, AL045341, AL042909,
AL039410, D59787, AL039150,
AL044530,
AL038821, AL038025, D80219,
AL036725,
AL043422, D59275, AL043445,
AL039459,
AI535983, D80227, AL043586,
AL043423,
D80240, AL043441, D80210,
D51423,
T23947, AL036650, D80134,
AL036196,
D59619, D80391, AL037639,
D80193,
AW451070, AL037615, D80196,
AL036767,
C14227, AL039085, AI535783,
D80949,
AL036117, D80366, D59927,
AL037526,
AL042334, AW452756, D80168,
847228,
AL036238, AL036679, AL037601,
T11051,
D81026, AL039504, C14014,
D50995,
C75259, AL039842, AL036964,
D80045,
AL036733, AL036158, AL037027,
AL036924, AL037054, D59889,
AL036765,
448
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
T23659, AI557751, AL038851,
T23658,
AL037177, AL036998, D80022,
AL037047,
AL044413, AW293068, AL037643,
AL036227, AL036418, AL036133,
D80038,
T11417, AL037082, AL036163,
D58283,
D80195, AL036207, AL037124,
D81030,
D80188, AL037021, AL036191,
AL036167,
AL036132, AL037049, AL037679,
AL036190, AL037600, D51799,
AL036139,
D80378, F13647, D80522, T03269,
AL036152, T23656, C14429,
T48598,
D50979, D80212, AL036900,
221582,
AL037178, AA514190, AL048425,
AA285331, AW451416, D59502,
AL043613,
D58253, AL039555, AL043585,
D80166,
D59859, AL037085, D80268,
D80269,
225782, AL037569, D80024,
D52291,
614331, AL036174, AL036808,
AL036953,
D57483, 299396, D59610, AW450376,
AL044178, D80241, AL036150,
D8111 l,
AI910186, D80164, D59627,
C14389,
H00072, C15076, D59467, D51060,
AA305409, AL036268, AW178893,
D51213,
D51079, C14298, AL038043,
N47620,
D80251, AW177440, D51022,
C14407,
AL044447, AW179328, D80014,
AW178775,
AL037077, AW378532, AA305578,
D80064,
AW352158, D80248, D59695,
AI905856,
AW369651, D51097, AL043840,
AL037002,
AW178762, AA514188, AW177501,
AWI77511, AA514186, D80133,
AW360834,
AL039417, AW360811, C05695,
225783,
AI557774, AW135155, D80258,
T02974,
AW352117, AW176467, AW375405,
AW378540, AW377671, AA809122,
AW366296, A25909, A85396,
A86792,
A44171, A85477, X68127, AR062871,
A84772, A84776, A84773, A84775,
A84774,
AR037157, AR017907, AR062872,
AR062873, AR067731, AR067732,
A58522,
A91750, A20702, A43189, A43188,
A20700,
AR036905, A95051, AR038762,
A95117,
A38214, A98767, AR031374,
I56772, I95540,
AR018924, A49700, A63067,
A51047,
A63064, AR018923, A48774,
A63072,
A95052, A48775, AR068507,
AI8053,
AR068506, A93963, A93964,
A23334,
A75888, I70384, AR043602,
AR015960,
AR043603, AR043601, A5852I,
AR000007,
AR015961, A18050, A60111,
A23633,
A10361, A23998, AR007512,
AR020969,
I60241, I60242, I63120, AR054109,
I03343,
AR031375, AR022240, A58524,
A58523,
A81878, A24783, A24782, E12615,
AR035193, A92133, E14304,
A27396,
AR027100, I28266, A49045,
E16678, A82653,
E16636, I06859, A93016, I25027,
AR000006,
I26929, E13740, I44515, I26928,
I26930,
I26927, A58525, I49890, I44516,
A58526,
449
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
A91753, AJ244003, AR025207,
I18371,
E06034, AF156296, A13038,
A29289,
AR029417, AF156294, AR067733,
AR029418, AR067734, A64081,
AR028669,
AR028668, AR028667, AR028670,
AR017908, A68112, A68104,
A98467,
I62368, AR031488, I13521,
I52048, I44531,
A84746, A17115, AR028672,
A18079,
AR038066, I50882, I15353,
I66495, I66494,
I66498, I66497, I66496, I66486,
I66487,
A71440, A71435, A67220, I13349,
A07699,
E08322, I74623, A60109, AJ244004,
U87250,
I00081, A70040, AR028564,
A83643,
A98420, A98423, A98432, A98436,
A98417,
A98427, A83151, I01968, A13388,
E00974,
A02228, E00954, E00952, E00953,
E00955,
I08049, I43960, AR021440,
E03165, E02221,
E13364, A10360, E02679, E02104,
E02098,
A92666, E02001, E01718, E02003,
E02102,
E03550, A28163, E02100, E01997,
A58998,
E02291, E02292, E02293, E01999,
E02396,
E02327, E01563, E02431, E01693,
E01696,
A92668, AR005163, AR005154,
AR005157,
AR005160, I09250, AR005153,
A92667,
E01024, AR050583, AR050584,
E02430,
E01148, E12527, E01503, AR005165,
E12523, E02432, A49701, A62009,
E01216,
I77211, A95096, I70974, I31847,
I31848,
AR060673, AR060676, A95106,
A95105,
A80476, A91965, E01324, I08638,
A80474,
A94048, A94061, A80477, AR035224,
A80475, A94046, A94054, I63560,
AR031529, A49428, I63561,
I63563, E16036,
AC018903, AC068470, AL049186,
AL049186, AC006S 10, AL022167,
and
AC022305.
HTEMV09 233 909843 1 - 13471S - AI818734, AA454060, AA453640,
1361
AW268879, AI377304, AI818733,
AI818743,
AI681535, AI741915, AA948041,
AI198872,
AW341578, AI267885, AA767746,
AI677678,
AI829855, AI677729, AW 129267,
AA947425,
AA297313, AL041049, N67346,
and
AA889773.
HTEMV66 234 11510751 - 847 15 -
861
HTGAU79 235 11750711 - 213915 -
2153
HTLEJ11 236 973302 1 - 956 15 - M62294.
970
HTLIY52 237 12186911 - 136215 -
1376
HTOAK34 238 966800 1 - 127115 - AW408167, AA491322, AA505126,
1285
AI340133, AA831203, N27153,
AA053564,
AA809481, AF181985, and AF179867.
HTPGG25 239 911282 1 - 829 15 - AA018361, AI768326, AI333117,
843 AA324901,
F07835, AA378627, AL117482,
261430,
AC020705, and AC020705.
HUJAD24 240 11613191 - 172215 -
1736
HUTSF11 241 966029 1 - 416 15 - AI384010, AI288640, 220435,
430 and A74523.
HUVGZ88 242 12276281 - 292115 -
2935
HWADY66 243 10962521 - 352 15 -
366
HWAFG04 244 952878 1 - 164615 - AI302185, AI652375, AI936871,
1660 AW206793,
450
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
AI025217, AI983297, AW002416,
AI025310,
AA593826, AI559159, AI418298,
AW140018,
AI017077, D54154, T03397,
AW239548,
H42947, D57560, AW192088,
823870,
AI394630, AA503315, AA026054,
F07734,
240806, AI807678, AA297059,
C14980,
AW338394, AI073417, AW 138409,
AA088799, AI356604, C15480,
AI825970,
AI537006, AI168175, 846685,
AA974700,
AW078709, 846686, AI343378,
AA364780,
AI015047, AW137324, H42881,
AA325059,
AI831833, H22172, AA897415,
F03562,
845025, F03423, AA382960,
T82311,
AW401787, AA382959, AW373232,
AC018571, AC018571, AC015651,
AC015651, AC015651, AC046185,
and
AC046185.
HWAFS18 245 948434 1 - 946 15 - W25237, and AF156884.
960
HWAGS73 246 11502121 - 612 15 -
626
HWLEA48 247 927676 1 - 415 15 - AA130828, AF169034, 298752,
429 and
AF 169033.
HWLHS82 248 934505 1 - 415 15 - AW401390, and AC005581.
429
HWMIB81 249 955336 1 - 147915 - AW380440, AW299858, AW391525,
1493 H78769,
H78659, H53674, AA628987,
AA447173,
AW204470, AA343468, AA480342,
AF155118, AC021719, and AC016143.
HCWDV17 250 11056731 - 684 15 -
698
HELDI95 251 11033741 - 983 15 -
997
HAGF025 252 11508451 - 806 15 -
820
HAWAB54 253 11493191 - 142815 -
1442
HLIBV06 254 934887 1 - 222415 -
2238
HMALL66 255 11050971 - 495 15 -
509
HOACE12 256 858976 1 - 439 15 -
453
HOGCG69 257 924848 1 - 120915 -
1223
HAGAE09 258 11508641 - 838 15 -
852
HAGAE34 259 11218691 - 757 15 -
771
HARMH78 260 11375721 - 547 15 -
561
HBJLB53 261 12269881 - 203715 -
2051
HBJNB52 262 11287921 - 793 15 -
807
HDAB 263 12017031 - 446 15 -
83 460
HDPDC84 264 12269901 - 324315 -
3257
HDPUF40 265 12124941 - 238415 -
2398
HDPWU07 266 12282861 - 326215 -
3276
HDTJJ02 267 11063281 - 318 15 -
332
HE2GA18 268 11218721 - 276 15 -
290
HE2SY03 269 12079251 - 107015 -
1084
HELGY64 270 12282891 - 266915 -
2683
HFIYW31 271 11514761 - 127115 -
1285
HFVIP88 272 11247051 - 898 15 -
912
HGBAS76 273 I 193040I - 167715 -
1691
HHEBB62 274 11514811 - 541 15 -
555
HuF.$jJ73275 11514831 - 100715 -
1021
HHEMAl 276 11514841 - 638 15 -
l 652
HHE KO1 277 11073921 - 622 15 -
636
HHPEM84 278 915639 1 - 360 15 -
374
HHSED84 279 11508321 - 760 15 -
774
HIBCC94 280 11612921 - 126415 -
1278
451
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HKADN56 281 12202541 - 3121 15 -
3135
HKIXG58 282 11247501 - 713 15 -
727
HLICI13 283 11779631 - 1856 15 -
1870
HLTGF17 284 6624051 - 370 15 -
384
HLYDC50 285 11514941 - 860 15 -
874
HMADD49 286 12170311 - 2214 15 -
2228
HMEKE78 287 11282901 - 1811 15 -
1825
HMSHU26 288 11508331 - 1079 15 -
1093
HNEEB82 289 10765091 - 677 15 -
691
HNHIA06 290 11620861 - 710 15 -
724
HODFYl6 291 11052441 - 797 15 -
811
HP SB68 292 12210221 - 431 15 -
445
HRDBH04 293 11508761 - 1472 15 -
1486
HSICR69 294 12269651 - 1734 15 -
1748
HSIGJ94 295 1105417I - 701 15 -
715
HSYBL15 296 11042991 - 917 15 -
931
HTEKH29 297 8556601 - 2063 15 -
2077
HTGEL46 298 11515201 - 1543 15 -
1557
HTGFA05 299 I 198110I - 1736 15 -
1750
HTLDU61 300 11653191 - 1092 15 -
1106
HTOFT34 301 11524901 - 1467 15 -
1481
HTTDH46 302 11524911 - 1130 15 -
1144
HTTIO05 303 12299051 - 2571 15 -
2585
HWHGY45 304 9116211 - 191 15 - AC021102.
205
HWL R48 305 11283041 - 494 15 -
508
HWL X76 306 11522801 - 453 15 -
467
HATDD09 307 11653311 - 1282 15 -
1296
HBJGT03 308 11054841 - 768 15 -
782
HMTMF45 309 11417371 - 773 15 -
787
HHPDV86 310 522953I - 666 15 -'680AL109627, AL109627, AC025928,
and
AC025928.
HE8BT56 311 732602I - 365 15 -
379
HUJDH06 312 9076131 - 692 15 -
706
HOEJG61 313 9076141 - 660 15 -
674
HE8PN24 314 9076201 - 713 15 -
727
HGBHI37 315 909745I - 491 15 -
505
HCHOK82 316 _ 1 - 1077 15 -
909755 1091
HFPCH24 317 _ I - 474 15 -
912608 488
HTTKF86 318 _ 1 - 332 15 - 282188, 282188, and 282188.
912689 346
HCESA79 319 9127091 - 302 15 - AC012171, AC012171, ACOI2171,
316 AC009065, AC009065, AC009065,
AC005346, AC005346, and AC005346.
HDTBJ28 320 9127141 - 521 15 - AP001793, AC008052, AC008052,
535 ACOI5676, AC015676, and AP000864.
HDPBF48 321 9127831 - 945 15 -
959
HTPFY55 322 9129281 - 562 15 -
576
HMSCM47 323 9236321 - 711 15 -
725
HEO A56 324 9251321 - 413 15 - AC013449.
427
HTPC 325 9253491 - 436 15 - 299716, and 299716.
24 450
HWAEI37 326 9294811 - 403 15 - AL035461, and AL035461.
417
HDPSF03 327 9695361 - 1283 15 -
1297
HLHST63 328 5815281 - 410 15 -
424
HFAAJ44 329 4892011 - 287 15 -
301
HSLEM44 330 5066041 - 337 15 - AC078913, AC022123, and AC010357.
351
HETCL79 331 5228261 - 465 15 -
479
HFTAR20 332 6700411 - 908 15 -
922
HCUFD32 333 6993791 - 702 15 -
716
452
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
I3KAE039334 7053321 - 450 15 -
464
HLWBR95 335 7344741 - 908 15 - AC013252, and ACOI3252.
922
HPWCJ63 336 7725531 - 1407 15 -
1421
HBXCM35 337 7829111 - 578 15 -
592
HULBN83 338 8578361 - 624 15 -
638
HAGET77 339 8852651 - 1730 15 -
1744
HMSOZ55 340 9109111 - 979 15 - AC024229, and AC024229.
993
HAPOR42 341 9112921 - 1102 15 -
1116
HMVAU10 342 9114491 - 574 15 -
588
HTTFY29 343 9114541 - 707 15 -
721
HHFJY06 344 9114561 - 584 15 -
598
HPCIK72 345 9114591 - 269 15 -
283
HFIDT84 346 9198781 - 2655 15 -
2669
HMCAV88 347 9248741 - 1031 15 - AC068231, AC068231, AC068231,
1045
AL357752, AL357752, AC005476,
and
AC005476.
uK_A_IP73348 9288091 - 1441 15 -
1455
HFVHV40 349 9458491 - 668 15 - AC020911, AC020911, and AC020911.
682
HTJNI80 350 9522311 - 1017 15 -
1031
HEAAE08 35I 9599701 - 1053 15 - AC008687, and AC008687.
1067
HDPLU91 352 9631991 - 734 15 -
748
HAPRM21 353 9632001 - 857 15 - AL034374, AL034374, and AL034374.
871
HTDAB30 354 9653201 - 1248 15 -
1262
H2CBN90 3_55 9669191 - 809 15 -
823
HBTFJ47 356 9713051 - 1767 15 -
1781
HADEX52 357 9713511 - 1819 15 -
1833
HTADZ74 358 8114891 - 602 15 - AF077346, AC007278, and AC007278.
616
HAPNZ77 359 8870721 - 469 15 - AC003046, AC005859, AC076973,
483
AC003046, AC005859, AC023098,
and
AC023098.
HELDR74 360 9630011 - 1414 15 - AI741422, AW249482, AA573909,
1428
AA085764, AW272801, AI052311,
AA151131, AI700257, AA490620,
AA310938, AI683396, AI284596,
AA961817,
AA862960, AW073675, 887485,
AI828443,
AI925221, AI969547, AW001375,
N24896,
AI521481, AI925228, AI695515,
AA609182,
AA151130, AI245859, AA490809,
AA040451, AW139250, AI970384,
AI961068,
T67610, AA923298, AA513675,
AW027490,
T96070, AI624751, T67494,
AI936161,
AW196036, AA679554, AI917354,
N36317,
AA302588, AI932690, AW250249,
888163,
T72363, AI796143, W32439,
AA582049,
AI539047, W45013, and AF113795.
HDPLJ22 361 8599151 - 533 15 -
547
HPMLD11 362 8902041 - 1297 15 -
1311
HMVDZ78 363 9385741 - 236 15 - AB002313.
250
HTSFJ40 364 7224061 - 378 15 - W28953, H19139, 854508, HI0122,
392 H08285,
AA313257, 859784, F08505,
852605,
243765, F08180, AI401170,
F05493, F07194,
RI3670, R1364I, 245409, AW407594,
F07185, AW407965, AA461135,
AA371650,
AC006171, AC006171, and AL161645.
HEMBZ62 365 7425511 - 458 15 - 813025.
472
HHFGZ38 366 7855911 - 1153 15 - AA372117, AA133546, and AI468754.
1167
HDPLN70 367 8540101 - 968 15 -
982
453
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HSDJH12 368 876344 1 - 610 15 - AA428452, AAI34294, T83462,
624 AI219740,
AA010048, AI478566, AI990289,
AC021747,
AL359882, and AC046143.
HNBUTO1 369 913838 1 - 109015 - AI219740, AI478566, AI632246,
1104 AA279757,
AA977612, AA716656, AA687260,
AI801069, AA071046, AI985849,
AW370598,
AA6306I7, AW370599, AW370625,
AA134295, AW390691, AI990289,
AA134294, AA428452, AI143764,
D30955,
AW370620, AA352142, AA074442,
T83462,
AW071043, T79236, and AI744728.
HEOQN14 370 923752 1 - 103115 - AI014538, AW006457, AI479414,
1045 AI805243,
AI290929, AI129301, AI872459,
AI601146,
AI708870, AI973043, AI540074,
AI186894,
AI682389, AI654747, AA460832,
AI392777,
AA405714, AA649837, AI356090,
AI358510,
AW294364, AA954900, AA991687,
AI540589, AI953865, AA977875,
AW190678,
861326, 854477, AW009738,
AA724308,
AW297I00, 854409, AA627570,
AA504833,
AA489470, H08185, 808582,
AA778454,
AI810108, 241744, 843473,
AA765208,
AI698394, 239824, H19140,
241120, F03843,
AA701889, AA159318, AW408231,
AA404221, H84256, AW131981,
AI401170,
AA405779, AI475002, F01761,
AW 189730,
H84262, F04422, AA404687,
AA502309,
AA37I650, H29I88, AA58I ISI,
AA477301,
AA749407, AA477302, and AI144326.
HTXKL.86 371 928194 1 - 767 15 - AI810108, W28953, AA313257,
781 AI401170,
AW408231, AA371650, H19139,
854508,
H10122, 859784, H08285, F08505,
243765,
AI014538, AA504833, 852605,
F08180,
AA765208, F05493, AA461135,
F07194,
813641, AA70I889, AA159318,
245409,
AW407594, H84256, AA404221,
813670,
F07185, H84262, AA404687,
AW407965,
AI144326, AW006457, and AA581151.
HD GV77 372 937546 1 - 187615 -
1890
HE8TM80 373 955022 1 - 741 15 - 856714, AA125853, AA127005,
755 H06566,
T70821, AA307834, H53723,
and AFI910I8.
HWLEY40 374 957875 1 - 144315 - W28953, AI810108, AA159318,
1457 AA461135,
H10122, AA313257, AA701889,
AI654981,
AI401170, H19139, H08285,
AW408231,
AA371650, 854508, 859784,
AW407594,
F07194, AA504833, F08180,
F08505, 243765,
852605, F07185, H84256, AW407965,
F05493, H84262, AA404221,
813670,
AA765208, 245409, AA404687,
813641,
AI014538, AI144326, AC006171,
AC006171,
and AL161645.
HDPPD36 375 493820 1 - 546 15 -
560
HOUBZ94 376 527876 1 - 139 15 - AC005954, AC005954, and AC068475.
153
HMIAH32 377 550977 1 - 689 15 -
703
HDPTH43 378 573418 1 - 434 15 -
448
HCE3W04 379 615501 1 - 859 15 - AC025165, AC025165, AC022506,
873
AC022506, and AC022366.
HMUBZ20 380 670393 1 - 349 15 -
~ 363
454
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HDPAB51 381 6856651 - 941 15 -
955
HPJAP28 382 6863491 - 432 15 - AC004794, AC004794, and AC004794.
446
HIBEC79 383 7030001 - 325 15 - AC011458, AC011458, and AC011458.
339
HO BF64 384 7031771 - 389 15 -
403
HTEDL38 385 7616091 - 547 15 -
561
HE9HI71 386 7793751 - 668 15 -
682
HNFHS82 387 7799461 - 401 15 - AC010835.
415
HOUH089 388 7865481 - 895 15 -
909
HFPBB28 389 8445261 - 321 15 - AC016135, AC002518, AC073717,
335 and
AC018512.
HHEW 390 8760631 - 1052 15 -
61 1066
HUFGH09 391 8770781 - 635 15 -
649
HLICA79 392 8808811 - 2031 15 -
2045
HSLIHO1 393 8842511 - 1868 15 -
1882
HE90V91 394 8873641 - 774 15 -
788
HHEDS85 395 8946021 - 491 15 -
505
HNTDJ68 396 8996241 - 2389 15 -
2403
HKAH077 397 9066711 - 699 15 -
713
HTFNP84 398 9096871 - 2474 15 -
2488
HD GZ78 399 9097351 - 428 15 - AC026282.
442
HHEMD52 400 9097421 - 1605 15 -
1619
HSID 401 9098541 - 783 15 - AC003070.
38 797
HSKBF02 402 9098551 - 383 15 -
397
HIBDE74 403 7660111 - 508 15 -
522
HWMAE53 404 9098771 - 436 15 -
450
HFXCG28 405 9099611 - 596 15 -
610
HFTCU45 406 9100531 - 538 15 -
552
HFTBL33 407 9100551 - 1475 15 - AC025165, AC025165, and AC022366.
1489
HTXJA84 408 9113871 - 900 15 -
914
HKAAW89 409 9113891 - 433 15 -
447
HSXDD55 410 9114601 - 1164 15 -
1178
HUFCI64 411 9I 1 - 759 15 - AC00415I, and AC004I5I.
1558 773
HWAFT84 412 9115591 - 1342 15 - AC004151, and AC004151.
1356
HETCL18 413 9145351 - 1388 15 -
1402
HCRNK75 414 9145361 - 2256 15 -
2270
HTPFA03 4'15 9227651 - 315 15 -
329
HWADR60 416 9264871 - 1275 15 - AC023176, and AC023176.
1289
HWLFJO1 417 9280171 - 781 15 -
795
HTXNG95 418 9285771 - 1380 15 -
1394
HPCIG66 419 9308861 - 945 15 - AC024888, AC024888, and AC024888.
959
HCRPU72 420 9311401 - 931 15 - AC023151.
945
HE9RT95 421 9345561 - 804 15 - AC022420, AC022420, AC022420,
818 and
AC008439.
HFXJM13 422 9357251 - 426 15 -
440
HDPWU37 423 9407051 - 522 15 -
536
HHSDL85 424 9422461 - 760 15 -
774
HTJMD31 425 9428481 - 638 15 -
652
HWADD57 426 9430391 - 996 15 - AC011492, and AC011492.
1010
HLWAH05 427 9449041 - 1338 15 -
1352
HDPCI84 428 9455271 - 2479 15 -
2493
HBXDJ07 429 9468301 - 1470 15 - H11405, 855569, N27906, H20863,
1484 N25140,
and U27708.
HAMFD12 430 9524381 - 526 15 -
540
HFKHR40 431 9524701 - 2240 15 - AC061707, AC061707, AC061707,
2254 AC018805, and AC018805.
HDTAI08 432 9532651 - 590 15 -
604
HMKCX80 433 9562541 - 1174 15 -
1188
455
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
HCEMF69 434 9613081 - 1026 15 -
1040
HWLHF10 435 963422I - 1387 15 - ACOI0545, AC010545, and AC010545.
1401
HOEMG82 436 9638551 - 1087 15 -
1101
HFXDR37 437 9659151 - 2442 15 -
2456
HNNAS46 438 9694701 - 1493 15 -'1507
HRAAS26 439 9712191 - 645 15 -
659
HHEEL28 440 9730961 - 524 15 -
538
HCETF22 441 9733241 - 2632 15 -
2646
HCMSF55 442 9122841 - 715 15 -
729
456
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
TABLE 4
Code Description Tissue Organ ell Di easeVector
Lin
AR022a Heart a Heart
AR023a Liver a Liver
AR024a mammar land a mammary
land
AR025a Prostate a Prostate
AR026a small intestinea small intestine
AR027a Stomach a Stomach
AR028Blood B cells Blood B cells
AR029Blood B cells Blood B cells
activated activated
AR030Blood B cells Blood B cells
resting restin
AR031Blood T cells Blood T cells
activated activated
AR032Blood T cells Blood T cells
restin restin
AR033brain brain
AR034breast breast
AR035breast cancer breast cancer
AR036CeII Line CAOV3 Cell Line
CAOV3
AR037cell line PA-1 cell line
PA-1
AR038cell line transformedcell line
transformed
AR039colon colon
AR040colon (9808co65R)colon (9808co65R)
AR041colon(9809co15) colon(9809co15)
AR042colon cancer colon cancer
AR043colon cancer colon cancer
(9808co64R) (9808co64R)
AR044colon cancer colon cancer
9809co14 9809co14
AR045corn clone 5 corn clone
5
AR046corn clone 6 corn clone
6
AR047corn clone2 corn clone2
AR048corn clone3 corn clone3
AR049Corn Clone4 Corn Clone4
AR050Donor II B CellsDonor II
24hrs B Cells
24hrs
AR051Donor a B Cells Donor II
72hrs B Cells
72hrs
AR052Donor II B-CellsDonor II
24 hrs. B-Cells
24
hrs.
AR053Donor II B-CellsDonor II
72hrs B-Cells
72hrs
AR054Donor II RestingDonor II
B Cells Resting
B
Cells
AR055Heart Heart
AR056Human Lung (clonetech)Human Lung
(clonetech)
AR057Human Mammary Human Mammary
(clontech) (clontech)
457
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
AR058Human Thymus Human Thymus
(clonetech) (clonetech)
AR059Jurkat (unstimulated)Jurkat
(unstimulated)
AR060Kidney Kidney
AR061Liver Liver
AR062Liver (Clontech)Liver (Clontech)
AR063Lymphocytes chronicLymphocytes
lymphocytic leukaemiachronic lymphocytic
leukaemia
AR064Lymphocytes diffuseLymphocytes
large
B cell lymphoma diffuse large
B cell
lymphoma
AR065Lymphocytes follicularLymphocytes
I m homa follicular
1 m homa
AR066normal breast normal breast
AR067Normal Ovarian Normal Ovarian
(4004901) (4004901)
AR068Normal Ovary Normal Ovary
95086045
95086045
AR069Normal Ovary Normal Ovary
97016208
97016208
AR070Normal Ovary Normal Ovary '
98066005
98066005
AR071Ovarian Cancer Ovarian Cancer
AR072Ovarian Cancer Ovarian Cancer
(97026001) (97026001)
AR073Ovarian Cancer Ovarian Cancer
(97076029) (97076029)
AR074Ovarian Cancer Ovarian Cancer
(98046011) (98046011)
AR075Ovarian Cancer Ovarian Cancer
(98066019) (98066019)
AR076Ovarian Cancer Ovarian Cancer
(98076017) (98076017)
AR077Ovarian Cancer Ovarian Cancer
(98096001) (98096001)
AR078ovarian cancer ovarian cancer
15799
15799
AR079Ovarian Cancer Ovarian Cancer
177I7AID 177I7AID
AR080Ovarian Cancer Ovarian Cancer
400466481 400466481
AR081Ovarian Cancer Ovarian Cancer
4005315A1 4005315A1
AR082ovarian cancer ovarian cancer
94127303
94127303
AR083Ovarian Cancer Ovarian Cancer
96069304
96069304
AR084Ovarian Cancer Ovarian Cancer
97076029
97076029
AR085Ovarian Cancer Ovarian Cancer
98076045
98076045
458
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
AR086ovarian cancer ovarian
98096001 cancer
98096001
AR087Ovarian Cancer Ovarian
9905C032RC Cancer
9905C032RC
AR088Ovarian cancer Ovarian
9907 C00 cancer
3rd 9907
C00 3rd
AR089Prostate Prostate
AR090Prostate (clonetech)Prostate
. (clonetech)
AR091rostate cancer rostate
cancer
AR092prostate cancer prostate
#15176 cancer
#15176
AR093prostate cancer prostate
#15509 cancer
#15509
AR094prostate cancer prostate
#15673 cancer
#15673
AR095Small Intestine Small Intestine
(Clontech) (Clontech)
AR096S Teen S leen
AR097Thymus T cells Thymus T
activated cells
activated
AR098Thymus T cells Thymus T
resting cells
restin
AR099Tonsil Tonsil
AR100Tonsil geminal Tonsil geminal
center center centroblast
centroblast
AR101Tonsil germinal Tonsil germinal
center B center B
cell cell
AR102Tonsil lym h Tonsil lym
node h node
AR103Tonsil memory Tonsil memory
B cell B
cell
AR104Whole Brain Whole Brain
AR Xeno raft ES-2 Xeno raft
105 ES-2
AR106Xeno raft SW626 Xeno raft
SW626
H0002Human Adult HeartHuman AdultHeart Uni-ZAP
Heart XR
H0004Human Adult SpleenHuman AdultSpleen Uni-ZAP
S leen XR
H0008Whole 6 Week Uni-ZAP
Old XR
Emb o
H0009Human Fetal Brain Uni-ZAP
XR
H0011Human Fetal KidneHuman FetalKidne Uni-ZAP
Kidne XR
H0012Human Fetal KidneHuman FetalKidne Uni-ZAP
Kidne XR
H0013Human 8 Week Human 8 Embryo Uni-ZAP
Whole Week Old XR
Emb o Emb o
H0014Human Gall BladderHuman Gall Gall Bladder Uni-ZAP
Bladder XR
H0015Human Gall Bladder,Human Gall Gall Bladder Uni-ZAP
fraction II Bladder XR
H0022Jurkat Cells Jurkat T-Cell Lambda
Line ZAP II
H0023Human Fetal Lun Uni-ZAP
XR
H0024Human Fetal Lun Human FetalLun Uni-ZAP
III Luno XR
H0025Human Adult LymphHuman AdultLymph Lambda
Node L m h Node Node ZAP II
H0026Namalwa Cells Namalwa Lambda
B-CeII ZAP II
459
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
Line, EBV
immortalized
H0027Human Ovarian diseaseUni-ZAP
Cancer XR
H0028Human Old Ovar Human Old Ovary Bluescri
Ova t
H0029Human Pancreas Human PancreasPancreas Uni-ZAP
XR
H0030Human Placenta Uni-ZAP
XR
H0031Human Placenta Human PlacentaPlacenta Uni-ZAP
XR
H0032Human Prostate Human ProstateProstate Uni-ZAP
XR
H0033Human Pituita Human Pituita Uni-ZAP
XR
H0036Human Adult Human Adult Small Uni-ZAP
Small Small Int. XR
Intestine Intestine
H0037Human Adult Human Adult Small pBluescript
Small Small Int.
Intestine Intestine
H0038Human Testes Human TestesTestis Uni-ZAP
XR
H0039Human Pancreas Human PancreasPancreas diseaseUni-ZAP
Tumor Tumor XR
H0040Human Testes Human TestesTestis diseaseUni-ZAP
Tumar Tumor XR
H0041Human Fetal Human Fetal Bone Uni-ZAP
Bone Bone XR
H0042Human Adult Human Adult Lung Uni-ZAP
Pulmonary Pulmona XR
H0046Human EndometrialHuman EndometrialUterus diseaseUni-ZAP
Tumor Tumor XR
H0050Human Fetal Human Fetal Heart Uni-ZAP
Heart Heart XR
H0051Human HippocampusHuman Brain Uni-ZAP
Hippocampus XR
H0052Human CerebellumHuman CerebellumBrain Uni-ZAP
XR
H0056Human UmbilicalHuman UmbilicalUmbilical Uni-ZAP
Vein, Vein Endothelialvein XR
Endo. remake Cells
H0057Human Fetal Uni-ZAP
S leen XR
H0059Human Uterine Human UterineUterus diseaseLambda ZAP
Cancer Cancer II
H0063Human Th mus Human ThymusTh mus Uni-ZAP
XR
H0064Human Right Human Brain,Brain Uni-ZAP
Hemisphere right XR
of Brain hemis here
H0068Human Skin TumorHuman Skin Skin diseaseUni-ZAP
Tumor XR
H0069Human ActivatedActivated Blood Cell Uni-ZAP
T-Cells T-Cells Line XR
H0071Human Infant Human InfantAdrenal Uni-ZAP
Adrenal Adrenal Glandland XR
Gland
H0075Human ActivatedActivated Blood Cell Uni-ZAP
T-Cells T-Cells Line XR
(II)
H0079Human Whole Human Whole Embryo Uni-ZAP
7 Week 7 XR
Old Emb o (II) Week Old
Embr o
H0081Human Fetal Human Fetal Skin Uni-ZAP
Epithelium Skin XR
(Skin)
H0082Human Fetal Human Fetal Sk Muscle Uni-ZAP
Muscle Muscle XR
H0083HUMAN JURKAT Jurkat Cells Uni-ZAP
MEMBRANEBOUND XR
POLYSOMES
H0085Human Colon Human Colon Lambda ZAP
II
H0086Human a ithelioidE ithelioid Sk Muscle diseaseUni-ZAP
XR
460
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
sarcoma Sarcoma,
muscle
H0087Human Th mus Human Thymus Bluescri
t
H0090Human T-Cell T-Cell Lym T-Cell diseaseUni-ZAP
L m homa homa XR
H0092Human Pancreas Human PancreasPancreas diseaseUni-ZAP
Tumor XR
Tumor
H0098Human Adult Liver,Human Adult Liver Uni-ZAP
Liver XR
subtracted
HO100Human Whole Six Human Whole Embryo Uni-ZAP
Week Six XR
Old Emb o Week Old
Emb o
HO101Human 7 Weeks Human Whole Embryo Lambda ZAP
Old 7 II
Embryo, subtractedWeek Old
Emb o
H0102Human Whole 6 Human Whole Embryo pBluescript
Week Six
Old Emb o (II), Week Old
subt Emb o
HO105Human Fetal Heart,Human Fetal Heart pBluescript
Heart
subtracted
H0107Human Infant Human InfantAdrenal pBluescript
Adrenal
Gland, subtractedAdrenal Glandland
H0108Human Adult LymphHuman Adult Lymph Uni-ZAP
Node XR
Node, subtractedLym h Node
HO111Human Placenta, Human PlacentaPlacenta pBluescript
subtracted
H0112Human ParathyroidHuman ParathyroidParathyroid pBluescript
Tumor, subtractedTumor
H0118Human Adult KidneyHuman Adult Kidney Uni-ZAP
XR
Kidne
H0122Human Adult SkeletalHuman SkeletalSk Muscle Uni-ZAP
XR
Muscle Muscle
H0123Human Fetal DuraHuman Fetal Brain Uni-ZAP
Mater Dura XR
Mater
H0124Human Human Sk Muscle diseaseUni-ZAP
XR
RhabdomyosarcomaRhabdomyosarcoma
H0125Cem cells cyclohexamideCyclohexamideBlood Cell Uni-ZAP
Line XR
treated Treated Cem,
Jurkat,
Ra'i, and
Su t
H0130LNCAP untreated LNCAP Cell ProstateCell Uni-ZAP
Line Line XR
H0131LNCAP + o.3nM LNCAP Cell ProstateCell Uni-ZAP
81881 Line Line XR
H0132LNCAP + 30nM LNCAP Cell ProstateCell Uni-ZAP
81881 Line Line XR
H0134Raji Cells, cyclohexamideCyclohexamideBlood Cell Uni-ZAP
Line XR
treated Treated Cem,
Jurkat,
Raji, and
Supt
H0135Human Synovial Human SynovialSynovium Uni-ZAP
Sarcoma XR
Sarcoma
H0136Supt Celts, cyclohexamideCyclohexamideBlood Cell Uni-ZAP
Line XR
treated Treated Cem,
Jurkat,
Raji, and
Su t
H0140Activated T-Cells,Activated Blood Cell Uni-ZAP
8 hrs. T-Cells Line XR
H0144Nine Week Old 9 Wk Old Embryo Uni-ZAP
Early Early XR
Stage Human Stage Human
H01497 Week Old EarlyHuman Whole Embryo Uni-ZAP
Stage 7 XR
Human, subtractedWeek Old
Embr o
HO150Human E idid E idid mis Testis Uni-ZAP
mus XR
H0152Early Stage HumanHuman Fetal Liver Uni-ZAP
Liver, Liver XR
fract(II)
461
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
H0154Human FibrosarcomaHuman Skin Skin diseaseUni-ZAP
XR
Fibrosarcoma
H0156Human Adrenal Human AdrenalAdrenal diseaseUni-ZAP
Gland XR
Tumor Gland Tumor Gland
H0159Activated T-Cells,Activated Blood Cell Uni-ZAP
8 hrs., T-Cells Line XR
1i ation 2
H0161Activated T-Cells,Activated Blood Cell Uni-ZAP
24 hrs., T-Cells Line XR
1i ation 2
H0163Human Synovium Human S noviumS novium Uni-ZAP
XR
H0165Human Prostate Human ProstateProstate diseaseUni-ZAP
Cancer, XR
Sta a B2 Cancer, sta
a B2
H0166Human Prostate Human ProstateProstate diseaseUni-ZAP
Cancer, XR
Stage B2 fractionCancer, stage
B2
H0169Human Prostate Human ProstateProstate diseaseUni-ZAP
Cancer, XR
Sta a C fractionCancer, sta
a C
H017012 Week Old EarlyTwelve Week Embryo Uni-ZAP
Stage Old XR
Human Earl Sta
a Human
H017112 Week Old EarlyTwelve Week Embryo Uni-ZAP
Stage Old XR
Human, II Earl Sta
a Human
H0172Human Fetal Brain,Human Fetal Brain Lambda ZAP
Brain II
random primed
H0175H. Adult Spleen, pSportl
ziplox
H0177CAMAIEe CeII CAMAlEe CellBreast Cell Uni-ZAP
Line Line XR
Line
H0178Human Fetal BrainHuman Fetal Brain Uni-ZAP
Brain XR
H0179Human Neutro Human NeutroBlood Cell Uni-ZAP
hil hil Line XR
H0180Human Primary Human PrimaryBreast diseaseUni-ZAP
Breast XR
Cancer Breast Cancer
H0181Human Primary Human PrimaryBreast diseaseUni-ZAP
Breast XR
Cancer Breast Cancer
H0182Human Primary Human PrimaryBreast diseaseUni-ZAP
Breast XR
Cancer Breast Cancer
H0187Restin T-Cell T-Cells Blood Cell Lambda ZAP
Line II
H0188Human Normal Human NormalBreast Uni-ZAP
Breast XR
Breast
H0189Human Resting Human Blood Cell Uni-ZAP
Line XR
Macrophage Macrophage/Monoc
ytes
H0191Human Activated Human Blood Cell Uni-ZAP
Line XR
Macrophage (LPS),Macrophage/Monoc
thiour
tes
H0194Human Cerebellum,Human CerebellumBrain pBluescript
subtracted
H0196Human Cardiomyopathy,Human Heart Uni-ZAP
XR
subtracted Cardiom o
ath
H0197Human Fetal Liver,Human Fetal Liver Uni-ZAP
Liver XR
subtracted
H0199Human Fetal Liver,Human Fetal Liver Uni-ZAP
Liver XR
subtracted, ne
clone
H0201Human Hippocampus,Human Brain pBluescript
subtracted Hi ocam us
H0208Early Stage HumanHuman Fetal Lung pBluescript
Lung, Lung
subtracted
462
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
H0212Human Prostate,Human ProstateProstate pBluescript
subtracted
H0213Human Pituitary,Human Pituitary Uni-ZAP
XR
subtracted
H0216Supt cells, CyclohexamideBlood Cell pBluescript
cyclohexamide Line
treated, subtractedTreated Cem,
Jurkat,
Raji, and
Su t
H0217Supt cells, CyclohexamideBlood Cell pBluescript
cyclohexamide Line
treated, differentiallyTreated Cem,
Jurkat,
ex ressed Ra'i, and
Su t
H0222Activated T-Cells,Activated Blood Cell Uni-ZAP
8 hrs, T-Cells Line XR
subtracted
H023IHuman Colon, Human Colon BIuescri
subtraction t
H0233Human Fetal Human Fetal Heart pBluescript
Heart, Heart
Differential
(Adult-
s ecific)
H0234human colon Human Colon Liver pBluescript
cancer,
metastatic to Cancer, metasticized
liver,
differentially to liver
ex ressed
H0235Human colon Human Colon Liver pBluescript
cancer,
metaticized Cancer, metasticized
to liver,
subtraction to liver
H0239Human Kidney Human KidneyKidney diseaseUni-ZAP
Tumor XR
Tumor
H0241C7MCF7 cell C7MCF7 Cell Breast Cell Uni-ZAP
line, Line, Line XR
estrogen treated,estrogen
treated
subtraction
H0244Human 8 Week Human 8 WeekEmbryo Uni-ZAP
Whole Old XR
Embr o, subtractedEmb o
H0246Human Fetal Human Fetal Liver Uni-ZAP
Liver- Liver XR
Enzyme subtraction
H0247Human Membrane Human MembraneBlood Cell Uni-ZAP
Bound Line XR
Polysomes- EnzymeBound Polysomes
Subtraction
H0249HE7, subtractedHuman Whole Embryo Uni-ZAP
by 7 XR
hybridization Week Old
with E7 Embryo
cDNA
H0250Human ActivatedHuman Monocytes Uni-ZAP
XR
Monocytes
H0251Human ChondrosarcomaHuman Cartilage diseaseUni-ZAP
XR
Chondrosarcoma
H0252Human OsteosarcomaHuman Bone diseaseUni-ZAP
XR
Osteosarcoma
H0253Human adult Human Adult Testis Uni-ZAP
testis, large Testis XR
inserts
H0254Breast Lymph Breast LymphLymph Uni-ZAP
node cDNA Node Node XR
Libra
H0255breast lymph Breast LymphLymph Lambda
node CDNA Node Node ZAP II
Libra
H0257HL-60, PMA 4H HL-60 Cells,Blood Cell Uni-ZAP
PMA Line XR
stimulated
4H
H0261H. cerebellum, Human CerebellumBrain Uni-ZAP
Enzyme XR
subtracted
463
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
H0263human colon Human Colon Colon diseaseLambda ZAP
cancer II
Cancer
H0264human tonsils Human Tonsil Tonsil Uni-ZAP
XR
H0265Activated T-CeIIT-Cells Blood Celi Uni-ZAP
Line XR
( l2hs)fThiouridine
labelledEco
H0266Human MicrovascularHMEC Vein Cell Lambda ZAP
Line II
Endothelial
Cells, fract.
A
H0267Human MicrovascularHMEC Vein Cell Lambda ZAP
Line II
Endothelial
Cells, fract.
B
H0268Human UmbilicalHUVE Cells UmbilicalCell Lambda ZAP
Vein Line II
Endothelial vein
Cells, fract.
A
H0269Human UmbilicalHUVE Cells UmbilicalCell Lambda ZAP
Vein Line II
Endothelial vein
Cells, fract.
B
H0271Human Neutrophil,Human NeutrophilBlood Cell Uni-ZAP
- Line XR
Activated Activated
H0272HUMAN TONSILS, Human Tonsil Tonsil Uni-ZAP
XR
FRACTION 2
H0280K562 + PMA (36 K562 Cell cell Cell ZAP Ex ress
hrs) line line Line
H0282HBGB"s differentialHuman PrimaryBreast Uni-ZAP
XR
consolidation Breast Cancer
H0284Human OB MG63 Human Bone Cell Uni-ZAP
control Line XR
fraction I Osteoblastoma
MG63 cell
line
H0286Human OB MG63 Human Bone Cell Uni-ZAP
treated Line XR
(10 nM E2) fractionOsteoblastoma
I
MG63 cell
line
H0288Human OB HOS Human Bone Cell Uni-ZAP
control Line XR
fraction I Osteoblastoma
HOS
cell line
H0290Human O$ HOS Human Bone Cell Uni-ZAP
treated Line XR
( 1 nM E2) fractionOsteoblastoma
I HOS
cell line
H0292Human OB HOS Human Bone Cell Uni-ZAP
treated Line XR
(10 nM E2) fractionOsteoblastoma
I HOS
cell line
H0294Amniotic Cells Amniotic CellsPlacentaCell Uni-ZAP
- TNF - Line XR
induced TNF induced
H0295Amniotic Cells Amniotic CellsPlacentaCell Uni-ZAP
- Primary - Line XR
Culture Primary Culture
H0298HCBB"s differentialCAMAlEe Cell Breast Cell Uni-ZAP
Line XR
consolidation Line
H0299HCBA"s differentialCAMAlEe Cell Breast Cell Uni-ZAP
Line XR
consolidation Line
H0300CD34 positive CD34 PositiveCord ZAP Express
cells (Cord Cells Blood
Blood)
H0305CD34 positive CD34 PosifiveCord ZAP Express
cells (Cord Cells Blood
Blood)
H0306CD34 depleted CD34 DepletedCord ZAP Express
Buffy Coat Blood
(Cord Blood) Buffy Coat
(Cord
Blood)
H0309Human Chronic Synovium, Synovium diseaseUni-ZAP
Synovitis Chronic XR
Synovitisl
464
CA 02395816 2002-06-26
WO 01/54733 PCT/USO1/01312
Osteoarthritis
H0310human caudate Brain Brain Uni-ZAP
nucleus XR
H0316HUMAN STOMACH Human StomachStomach Uni-ZAP
XR
H0318HUMAN B CELL Human B CellLymph diseaseUni-ZAP
LYMPHOMA Lymphoma Node XR
H0320Human frontal Human FrontalBrain Uni-ZAP
cortex Cortex XR
H0327human corpus Human CorpusBrain Uni-ZAP
colosum Callosum XR
H0328human ovarian Ovarian CancerOvar diseaseUni-ZAP
cancer XR
H0329DermatofibrosarcomaDermatofibrosarcomSkin diseaseUni-ZAP
Protuberance a Protuberans XR
H0331Hepatocellular HepatocellularLiver diseaseLambda ZAP
Tumor Tumor II
H0333HemangiopericytomaHemangiopericytomBlood diseaseLambda ZAP
a vessel II
H0334Kidney cancer Kidney CancerKidne diseaseUni-ZAP
XR
H0339Duodenum Duodenum Uni-ZAP
XR
H0340Corpus CallosumCorpus Collosum- Uni-ZAP
93052 XR
H0341Bone Marrow Bone Marrow Bone MarrowCell Uni-ZAP
Cell Line Cell Line XR
(RS4;11) Line RS4;11
H0342Lin ual G rus Lin ual G Brain Uni-Za XR
rus
H0343stomach cancer Stomach Cancer diseaseUni-ZAP
(human) - XR
5383A (human)
H0345SKIN Skin - 4000868HSkin Uni-ZAP
XR
H0349human adult Human Adult Liver pCMVSport
liver cDNA Liver 1
libr
H0351Glioblastoma GlioblastomaBrain diseaseUni-ZAP
XR
H03524vilm"s tumor Wilm"s Tumor diseaseUni-ZAP
XR
H0355Human Liver Human Liver, pCMVSport
normal Adult 1
H0356Human Kidne Human Kidne Kidney CMVS ort
1
H0359KMH2 cell line KMH2 ZAP Ex ress
H0361Human rejected Human Rejected diseasepBluescript
kidney Kidne
H0364Human Osteoclastoma,Human diseasepBluescript
excised Osteoclastoma
H0365Osteoclastoma-normalizedHuman diseaseUni-ZAP
B Osteoclastoma XR
H0366IA~28 cell lineL428 ZAP Ex ress
H0369H. Atrophic Atrophic Uni-ZAP
Endometrium Endometrium XR
and
myometrium
H0370H. Lymph node Lymph node diseaseUni-ZAP
breast with XR
Cancer Met. Breast
Cancer
H0372Human Testes Human TestesTestis CMV S ort
1
H0373Human Heart Human Adult Heart CMV S ort
Heart 1
H0374Human Brain Human Brain CMVS ort
1
H0375Human Lun Human Lun CMVS ort
1
H0376Human Spleen Human Adult Spleen pCMVSport
S leen 1
465
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 3
~~ TTENANT LES PAGES 1 A 465
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 3
CONTAINING PAGES 1 TO 465
NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:
