AU758074B2 - Polynucleotides isolated from skin cells and methods for their use - Google Patents

Description

WO 99/55865 PCTNZ99/00051 POLYNUCLEOTIDES ISOLATED FROM SKIN CELLS AND METHODS FOR THEIR USI Technical Field of the Invention This invention relates to polynucleotides encoding polypeptides, polypeptides expressed in skin cells, and their use in therapeutic methods.

Background of the Invention The skin is the largest organ in the body and serves as a protective cover. The loss of skin, as occurs in a badly burned person, may lead to death owing to the absence of a barrier against infection by external microbial organisms, as well as loss of body temperature and body fluids.

Skin tissue is composed of several layers. The outermost layer is the epidermis which is supported by a basement membrane and overlies the dermis. Beneath the dermis is loose connective tissue and fascia which cover muscles or bony tissue. The skin is a self-renewing tissue in that cells are constantly being formed and shed. The deepest cells of the epidermis are the basal cells, which are enriched in cells capable of replication. Such replicating cells are called progenitor or stem cells. Replicating cells in turn give rise to daughter cells called 'transit amplifying cells'. These cells undergo differentiation and maturation into keratinocytes (mature, skin cells) as they move from the basal layer to the more superficial layers of the epidermis. In the process, keratinocytes become cornified and are ultimately shed from the skin surface. Other cells in the epidermis include melanocytes which synthesize melanin, the pigment responsible for protection against sunlight. The Langerhans cell also resides in the epidermis and functions as a cell which processes foreign proteins for presentation to the immune system.

The dermis contains nerves, blood and lymphatic vessels, fibrous and fatty tissue.

Within the dermis are fibroblasts, macrophages and mast cells. Both the epidermis and dermis are penetrated by sweat, or sebaceous, glands and hair follicles. Each strand of WO 99/55865 PCT/NZ99/00051 hair is derived from a hair follicle. When hair is plucked out, the hair re-grows from epithelial cells directed by the dermal papillae of the hair follicle.

When the skin surface is breached, for example in a wound, the stem cells proliferate and daughter keratinocytes migrate across the wound to reseal the tissues. The skin cells therefore possess genes activated in response to trauma. The products of these genes include several growth factors, such as epidermal growth factor, which mediate the proliferation of skin cells. The genes that are activated in the skin, and the protein products of such genes, may be developed as agents for the treatment of skin wounds.

Additional growth factors derived from skin cells may also influence growth of other cell types. As skin cancers are a disorder of the growth of skin cells, proteins derived from skin that regulate cellular growth may be developed as agents for the treatment of skin cancers. Skin derived proteins that regulate the production of melanin may be useful as agents which protect skin against unwanted effects of sunlight.

Keratinocytes are known to secrete cytokines and express various cell surface proteins. Cytokines and cell surface molecules are proteins which play an important role in the inflammatory response against infection and also in autoimmune diseases affecting the skin. Genes and their protein products that are expressed by skin cells may thus be developed into agents for the treatment of inflammatory disorders affecting the skin.

Hair is an important part of a person's individuality. Disorders of the skin may lead to hair loss. Alopecia areata is a disease characterized by the patchy loss of hair over the scalp. Total baldness is a side effect of drug treatment for cancer. The growth and development of hair are mediated by the effects of genes expressed in skin and dermal papillae. Such genes and their protein products may be usefully developed into agents for the treatment of disorders of-the hair follicle.

New treatments are required to hasten the healing of skin wounds, to prevent the loss of hair, enhance the re-growth of hair or removal of hair, and to treat autoimmune and inflammatory skin diseases more effectively and without adverse effects. More effective treatments of skin cancers are also required. There thus remains a need in the art for the identification and isolation of genes encoding proteins expressed in the skin, for use in the development of therapeutic agents for the treatment of disorders including those associated with skin.

2 WO 99/55865 PCT/NZ99/00051 Summary of the Invention The present invention provides polypeptides expressed in skin cells, together with polynucleotides encoding such polypeptides, expression vectors and host cells comprising such polynucleotides, and methods for their use.

In specific embodiments, isolated polynucleotides are provided that comprise a DNA sequence selected from the group consisting of: sequences recited in SEQ ID NO: 1-14, 45-48, 64-68, 77-89, l'8, 119, 198-231, 239-249, 254-274, 349-372 and 399- 405; complements of the sequences recited in SEQ ID NO: 1-14, 45-48, 64-68, 77-89, 118, 119, 198-231, 239-249, 254-274, 349-372 and 399-405; reverse complements of the sequences recited in SEQ ID NO: 1-14, 45-48, 64-68, 77-89, 118, 119, 198-231, 239- 249, 254-274, 349-372 and 399-405; reverse sequences of the sequences recited in SEQ ID NO: 1-14, 45-48, 64-68, 77-89, 118, 119, 198-231, 239-249, 254-274, 349-372 and 399-405; sequences having a 99% probability of being the same as a sequence of and sequences having at least 50%, 75% or 90% identity to a sequence of In further embodiments, the present invention provides isolated polypeptides comprising an amino acid sequence selected from the group consisting of: sequences provided in SEQ ID NO: 120-197, 275-348, 373-398 and 406-409; and sequences having at least 50%, 75% or 90% identity to a sequence provided in SEQ ID NO: 120- 197, 275-348, 373-398 and 406-409, together with isolated polynucleotides encoding such polypeptides. Isolated polypeptides which comprise at least a functional portion of a polypeptide comprising an amino acid sequence selected from the group consisting of: sequences provided in SEQ ID NO: 120-197, 275-348, 373-398 and 406-409; and sequences having 50%, 75% or 90% identity to a sequence of SEQ ID NO: 120-197, 275-348, 373-398 and 406-409 are also provided.

In related embodiments, the present invention provides expression vectors comprising the above polynucleotides, together with host cells transformed with such vectors.

In a further aspect, the present invention provides a method of stimulating keratinocyte growth and motility, inhibiting the growth of epithelial-derived cancer cells, 3 WO 99/55865 PCT/NZ99/00051 inhibiting angiogenesis and vascularization of tumors, or modulating the growth of blood vessels in a subject, comprising administering to the subject a composition comprising an isolated polypeptide, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: sequences provided in SEQ ID NO: 187, 196, 342, 343, 395, 397, and 398; and sequences having at least 50%, 75% or 90% identity to a sequence provided in SEQ ID NO: 187, 196, 342, 343, 395, 397, and 398.

Methods for modulating skin inflammation in a subject are also provided, the methods comprising administering to the subject a composition comprising an isolated polypeptide, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: sequences provided in SEQ ID NO: 338 and 347; and (b) sequences having at least 50%, 75% or 90% identity to a sequence provided in SEQ ID NO: 338 and 347. In an additional aspect, the present invention provides methods for stimulating the growth of epithelial cells in a subject. Such methods comprise administering to the subject a composition comprising an isolated polypeptide including an amino acid sequence selected from the group consisting of: sequences provided in SEQ ID NO: 129 and 348; and sequences having at least 50%, 75% or 90%/ identity to a sequence provided in SEQ ID NO: 129 and 348. In yet a further aspect, methods for inhibiting the binding of HIV-1 to leukocytes, for the treatment of an inflammatory disease or for the treatment of cancer in a subject are provided, the methods comprising administering to the subject a composition comprising an isolated polypeptide including an amino acid sequence selected from the group consisting of: sequences provided in SEQ ID NO: 340, 344, 345 and 346; and sequences having at least 50%, 75% or identity to a sequence provided in SEQ ID NO: 340, 344, 345 and 346.

As detailed below, the isolated polynucleotides and polypeptides of the present invention may be usefully employed in the preparation of therapeutic agents for the treatment of skin disorders.

The above-mentioned and additional features of the present invention, together with the manner of obtaining them, will be best understood by reference to the following more detailed description. All references disclosed herein are hereby incorporated herein by reference in their entirety as if each was incorporated individually.

WO 99/55865 PCTINZ99/00051 Brief Description of the Drawings Fig. 1 shows the results of a Northern analysis of the distribution of huTR1 mRNA in human tissues. Key: He, Heart; Br, Brain; P1, Placenta; Lu, Lung; Li, Liver; SM, Skeletal muscle; Ki, Kidney; Sp, Spleen; Th, Thymus; Pr, Prostate; Ov, Ovary.

Fig. 2 shows the results of a MAP kinase assay of muTRIa and huTRla.

MuTRla (500ng/ml), huTRla (100ng/ml) or LPS (3pg/ml) were added as described in the text.

Fig. 3 shows the stimulation of growth of neonatal foreskin keratinocytes by muTR1a.

Fig. 4 shows the stimulation of growth of the transformed human keratinocyte cell line HaCaT by muTRIa and huTRla.

\Fig. 5 shows the inhibition of growth of the human epidermal carcinoma cell line A431 by muTRIa and huTRla.

Fig. 6 shows the inhibition of IL-2 induced growth of concanavalin A-stimulated murine splenocytes by KS2a.

Fig. 7 shows the stimulation of growth of rat intestinal epithelial cells (IEC-18) by a combination of KS3a plus apo-transferrin.

Fig. 8 illustrates the oxidative burst effect of TR-1 (100 ng/ml), muKS1 (100 ng/ml), SDFlcI (100 ng/ml), and fMLP (10 [iM) on human PBMC.

Figure 9 shows the chemotactic effect ofmuKS1 and SDF-la on THP-1 cells.

Figure 10 shows the induction of cellular infiltrate in C3H/HeJ mice after intraperitoneal injections with muKS1 (50 pg), GV14B (50 4g) and PBS.

Figure 11 demonstrates the induction of phosphorylation of ERK1 and ERK2 in CV1/EBNA and HeLa cell lines by huTRla.

Figure 12 shows the huTR1 mRNA expression in HeLa cells after stimulation by muTR1, huTR1, huTGFa and PBS (100 ng/ml each).

Figure 13 shows activation of the SRE by muTRIa in PC-12 (Fig. 13a) and HaCaT (Fig. 13b) cells.

WO 99/55865 PCT/NZ99/00051 Figure 14 shows the inhibition of huTRIa mediated growth on HaCaT cells by an antibody to the EGF receptor.

Detailed Description of the Invention In one aspect, the present invention provides polynucleotides that were isolated from mammalian skin cells. As used herein, the term "polynucleotide" means a single or double-stranded polymer of deoxyribonucleotide or ribonucleotide bases and includes DNA and RNA molecules, both sense and anti-sense strands. The term comprehends cDNA, genomic DNA, recombinant DNA and wholly or partially synthesized nucleic acid molecules. A polynucleotide may consist of an entire gene, or a portion thereof. A gene is a DNA sequence that codes for a functional protein or RNA molecule. Operable anti-sense polynucleotides may comprise a fragment of the corresponding polynucleotide, and the definition of "polynucleotide" therefore includes all operable anti-sense fragments. Anti-sense polynucleotides and techniques involving anti-sense polynucleotides are well known in the art and are described, for example, in Robinson- Benion et al., "Anti-sense Techniques," Methods in Enzymol. 254(23):363-375, 1995; and Kawasaki et al., Artific. Organs 20 (8):836-848, 1996.

Identification of genomic DNA and heterologous species DNAs can be accomplished by standard DNA/DNA hybridization techniques, under appropriately stringent conditions, using all or part of a cDNA sequence as a probe to screen an appropriate library. Alternatively, PCR techniques using oligonucleotide primers that are designed based on known genomic DNA, cDNA and protein sequences can be used to amplify and identify genomic and cDNA sequences. Synthetic DNAs corresponding to the identified sequences and variants may be produced by conventional synthesis methods. All the polynucleotides provided by the present invention are isolated and purified, as those terms are commonly used in the art.

In specific embodiments, the polynucleotides of the present invention comprise a DNA sequence selected from the group consisting of sequences provided in SEQ ID NO: 1-119, 198-274, 349-372 and 399-405, and variants of the sequences of SEQ ID NO: 1-119, 198-274, 349-372 and 399-405. Polynucleotides that comprise complements of such DNA sequences, reverse complements of such DNA sequences, or reverse WO 99/55865 PCT/NZ99/00051 sequences of such DNA sequences, together with variants of such sequences, are also provided.

The definition of the terms "complement," "reverse complement," and "reverse sequence," as used herein, is best illustrated by the following example. For the sequence 5' AGGACC the complement, reverse complement, and reverse sequence are as follows: complement 3' TCCTGG reverse complement 3' GGTCCT reverse sequence 5' CCAGGA 3'.

In another aspect, the present invention provides isolated polypeptides encoded, or partially encoded, by the above polynucleotides. As used herein, the term "polypeptide" encompasses amino acid chains of any length, including full length proteins, wherein the amino acid residues are linked by covalent peptide bonds. The term "polypeptide encoded by a polynucleotide" as used herein, includes polypeptides encoded by a polynucleotide which comprises a partial isolated DNA sequence provided herein. In specific embodiments, the inventive polypeptides comprise an amino acid sequence selected from the group consisting of sequences provided in SEQ ID NO: 120-197, 275-348, 373-398 and 406-409, as well as variants of such sequences.

Polypeptides of the present invention may be produced recombinantly by inserting a DNA sequence that encodes the polypeptide into an expression vector and expressing the polypeptide in an appropriate host. Any of a variety of expression vectors known to those of ordinary skill in the art may be employed. Expression may be achieved in any appropriate host cell that has been transformed or transfected with an expression vector containing a DNA molecule that encodes a recombinant polypeptide.

Suitable host cells include prokaryotes, yeast, and higher eukaryotic cells. Preferably, the host cells employed are E. coli, insect, yeast, or a mammalian cell line such as COS or CHO. The DNA sequences expressed in this manner may encode naturally occurring polypeptides, portions of naturally occurring polypeptides, or other variants thereof.

In a related aspect, polypeptides are provided that comprise at least a functional portion of a polypeptide having an amino acid sequence selected from the group consisting of sequences provided in SEQ ID NO: 120-197, 275-348, 373-398, 406-409, WO 99/55865 PCT/NZ99/00051 and variants thereof. As used herein, the "functional portion" of a polypeptide is that portion which contains the active site essential for affecting the function of the polypeptide, for example, the portion of the molecule that is capable of binding one or more reactants. The active site may be made up of separate portions present on one or more polypeptide chains and will generally exhibit high binding affinity.

Functional portions of a polypeptide may be identified by first preparing fragments of the polypeptide by either chemical or enzymatic digestion of the polypeptide, or by mutation analysis of the polynucleotide that encodes the polypeptide and subsequent expression of the resulting mutant polypeptides. The polypeptide fragments or mutant polypeptides are then tested to determine which portions retain biological activity, using, for example, the representative assays provided below.

Portions and other variants of the inventive polypeptides may also be generated by synthetic or recombinant means. Synthetic polypeptides having fewer than about 100 amino acids, and generally fewer than about 50 amino acids, may be generated using techniques well known to those of ordinary skill in the art. For example, such polypeptides may be synthesized using any of the commercially available solid-phase techniques, such as the Merrifield solid-phase synthesis method, where amino acids are sequentially added to a growing amino acid chain. See Merrifield, J Am. Chem.

Soc. 85:2149-2146, 1963. Equipment for automated synthesis of polypeptides is commercially available from suppliers such as Perkin Elmer/Applied BioSystems, Inc.

(Foster City, California), and may be operated according to the manufacturer's instructions. Variants of a native polypeptide may be prepared using standard mutagenesis techniques, such as oligonucleotide-directed site-specific mutagenesis (Kunkel, Proc. Natl. Acad. Sci. USA 82:488-492, 1985). Sections of DNA sequence may also be removed using standard techniques to permit preparation of truncated polypeptides.

In general, the polypeptides disclosed herein are prepared in an isolated, substantially pure, form. Preferably, the polypeptides are at least about 80% pure, more preferably at least about 90% pure, and most preferably at least about 99% pure. In certain preferred embodiments, described in detail below, the isolated polypeptides are WO 99/55865 PCT/NZ99/00051 incorporated into pharmaceutical compositions or vaccines for use in the treatment of skin disorders.

As used herein, the term "variant" comprehends nucleotide or amino acid sequences different from the specifically identified sequences, wherein one or more nucleotides or amino acid residues is deleted, substituted, or added. Variants may be naturally occurring allelic variants, or non-naturally occurring variants. Variant sequences (polynucleotide or polypeptide) preferably exhibit at least 50%, more preferably at least 75%, and most preferably at least 90% identity to a sequence of the present invention. The percentage identity is determined by aligning the two sequences to be compared as described below, determining the number of identical residues in the aligned portion, dividing that number by the total number of residues in the inventive (queried) sequence, and multiplying the result by 100.

Polynucleotide or polypeptide sequences may be aligned, and percentage of identical nucleotides in a specified region may be determined against another polynucleotide or polypeptide, using computer algorithms that are publicly available.

Two exemplary algorithms for aligning and identifying the similarity of polynucleotide sequences are the BLASTN and FASTA algorithms. The alignment and similarity of polypeptide sequences may be examined using the BLASTP and algorithm. BLASTX and FASTX algorithms compare nucleotide query sequences translated in all reading frames against polypeptide sequences. The BLASTN, BLASTP and BLASTX algorithms are available on the NCBI anonymous FTP server (ftp://ncbi.nlm.nih.gov) under /blast/executables/. The FASTA and FASTX algorithms are available on the Internet at the ftp site ftp://ftp.virginia.edu/pub/. The FASTA algorithm, set to the default parameters described in the documentation and distributed with the algorithm, may be used in the determination of polynucleotide variants. The readme files for FASTA and FASTX vl.Ox that are distributed with the algorithms describe the use of the algorithms and describe the default parameters. The use of the FASTA and FASTX algorithms is also described in Pearson, WR and Lipman, DJ, "Improved Tools for Biological Sequence Analysis," PNAS 85:2444-2448, 1988; and Pearson WR, "Rapid and Sensitive Sequence Comparison with FASTP and FASTA," Methods in Enzymology 183:63-98, 1990.

WO 99/55865 PCT/NZ99/00051 The BLASTN algorithm version 2.0.4 [Feb-24-1998], set to the default parameters described in the documentation and distributed with the algorithm, is preferred for use in the determination of polynucleotide variants according to the present invention. The BLASTP algorithm version 2.0.4, set to the default parameters described in the documentation and distributed with the algorithm, is preferred for use in the determination of polypeptide variants according to the present invention. The use of the BLAST family of algorithms, including BLASTN, BLASTP and BLASTX is described at NCBI's website at URL http://www.ncbi.nlm.nih.gov/BLAST/newblast.html and in the publication of Altschul, Stephen et al., "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs," Nucleic Acids Res. 25:3389-3402, 1997.

The following running parameters are preferred for determination of alignments and similarities using BLASTN that contribute to the E values and percentage identity for polynucleotides: Unix running command with default parameters thus: blastall -p blastn d embldb -e 10 -G 0 -E 0 -r 1 -v 30 -b 30 -i queryseq -o results; and parameters are: -p Program Name [String]; -d Database [String]; -e Expectation value [Real]; -G Cost to open a gap (zero invokes default behavior) [Integer]; -E Cost to extend a gap (zero invokes default behavior) [Integer]; -r Reward for a nucleotide match (blastn only) [Integer]; -v Number of one-line descriptions [Integer]; -b Number of alignments to show [Integer]; -i Query File [File In]; -o BLAST report Output File [File Out] Optional. The following running parameters are preferred for determination of alignments and similarities using BLASTP that contribute to the E values and percentage identity for polypeptides: blastall -p blastp -d swissprotdb -e 10 -G 1 -E 11 -r 1 -v -b 30 -i queryseq -o results; and the parameters are: -p Program Name [String]; -d Database [String]; -e Expectation value [Real]; -G Cost to open a gap (zero invokes default behavior) [Integer]; -E Cost to extend a gap (zero invokes default behavior) [Integer]; -v Number of one-line descriptions [Integer]; -b Number of alignments to show [Integer]; -I Query File [File In]; -o BLAST report Output File [File Out] Optional.

The "hits" to one or more database sequences by a queried sequence produced by BLASTN, BLASTP, FASTA, or a similar algorithm, align and identify similar portions of sequences. The hits are arranged in order of the degree of similarity and the length of WO 99/55865 PCT/NZ99/00051 sequence overlap. Hits to a database sequence generally represent an overlap over only a fraction of the sequence length of the queried sequence.

The percentage similarity of a polynucleotide or polypeptide sequence is determined by aligning polynucleotide and polypeptide sequences using appropriate algorithms, such as BLASTN or BLASTP, respectively, set to default parameters; identifying the number of identical nucleic or amino acids over the aligned portions; dividing the number of identical nucleic or amino acids by the total number of nucleic or amino acids of the polynucleotide or polypeptide of the present invention; and then multiplying by 100 to determine the percentage similarity. By way of example, a queried polynucleotide having 220 nucleic acids has a hit to a polynucleotide sequence in the EMBL database having 520 nucleic acids over a stretch of 23 nucleotides in the alignment produced by the BLASTN algorithm using the default parameters. The 23 nucleotide hit includes 21 identical nucleotides, one gap and one different nucleotide.

The percentage identity of the queried polynucleotide to the hit in the EMBL database is thus 21/220 times 100, or The similarity of polypeptide sequences may be determined in a similar fashion.

The BLASTN and BLASTX algorithms also produce "Expect" values for polynucleotide and polypeptide alignments. The Expect value indicates the number of hits one can "expect" to see over a certain number of contiguous sequences by chance when searching a database of a certain size. The Expect value is used as a significance threshold for determining whether the hit to a database indicates true similarity. For example, an E value of 0.1 assigned to a polynucleotide hit is interpreted as meaning that in a database of the size of the EMBL database, one might expect to see 0.1 matches over the aligned portion of the sequence with a similar score simply by chance. By this criterion, the aligned and matched portions of the sequences then have a probability of of being the same. For sequences having an E value of 0.01 or less over aligned and matched portions, the probability of finding a match by chance in the EMBL database is 1% or less using the BLASTN algorithm. E values for polypeptide sequences may be determined in a similar fashion using various polypeptide databases, such as the SwissProt database.

WO 99/55865 PCT/NZ99/00051 According to one embodiment, "variant" polynucleotides and polypeptides, with reference to each of the polynucleotides and polypeptides of the present invention, preferably comprise sequences having the same number or fewer nucleic or amino acids than each of the polynucleotides or polypeptides of the present invention and producing an E value of 0.01 or less when compared to the polynucleotide or polypeptide of the present invention. That is, a variant polynucleotide or polypeptide is any sequence that has at least a 99% probability of being the same as the polynucleotide or polypeptide of the present invention, measured as having an E value of 0.01 or less using the BLASTN or BLASTX algorithms set at the default parameters. According to a preferred embodiment, a variant polynucleotide is a sequence having the same number or fewer nucleic acids than a polynucleotide of the present invention that has at least a 99% probability of being the same as the polynucleotide of the present invention, measured as having an E value of 0.01 or less using the BLASTN algorithm set at the default parameters. Similarly, according to a preferred embodiment, a variant polypeptide is a sequence having the same number or fewer amino acids than a polypeptide of the present invention that has at least a 99% 0 probability of being the same as the polypeptide of the present invention, measured as having an E value of 0.01 or less using the BLASTP algorithm set at the default parameters.

Variant polynucleotide sequences will generally hybridize to the recited polynucleotide sequences under stringent conditions. As used herein, "stringent conditions" refers to prewashing in a solution of 6X SSC, 0.2% SDS; hybridizing at 0 C, 6X SSC, 0.2% SDS overnight; followed by two washes of 30 minutes each in IX SSC, 0.1% SDS at 65 oC and two washes of 30 minutes each in 0.2X SSC, 0.1% SDS at 65 OC.

As used herein, the term "x-mer," with reference to a specific value of refers to a polynucleotide or polypeptide, respectively, comprising at least a specified number of contiguous residues of: any of the polynucleotides provided in SEQ ID NO: 1-119, 198-274, 349-372 and 399-405; or any of the polypeptides set out in SEQ ID NO: 120-197, 275-348, 373-398 and 406-409. The value ofx may be from about 20 to about 600, depending upon the specific sequence.

WO 99/55865 PCT/NZ99/00051 Polynucleotides of the present invention comprehend polynucleotides comprising at least a specified number of contiguous residues (x-mers) of any of the polynucleotides identified as SEQ ID NO: 1-119, 198-274, 349-372 and 399-405, or their variants.

Polypeptides of the present invention comprehend polypeptides comprising at least a specified number of contiguous residues (x-mers) of any of the polypeptides identified as SEQ ID NO: 120-197, 275-348, 373-398, and 406-409. According to preferred embodiments, the value of x is at least 20, more preferably at least 40, more preferably yet at least 60, and most preferably at least 80. Thus, polynucleotides of the present invention include polynucleotides comprising a 20-mer, a 40-mer, a 60-mer, an 80-mer, a 100-mer, a 120-mer, a 150-mer, a 180-mer, a 220-mer, a 250-mer; or a 300-mer, 400-mer, 500-mer or 600-mer of a polynucleotide provided in SEQ ID NO: 1-119, 198-274, 349-372 and 399-405 or a variant of one of the polynucleotides provided in SEQ ID NO: 1-119, 198-274, 349-372, and 399-405. Polypeptides of the present invention include polypeptides comprising a 20-mer, a 40-mer, a 60-mer, an 80-mer, a 100-mer, a 120-mer, a 150-mer, a 180-mer, a 220-mer, a 250-mer; or a 300-mer, 400-mer. 500-mer or 600-mer of a polypeptide provided in SEQ ID NO: 120-197, 275-348, 373-398, and 406-409, or a variant of one of the polynucleotides provided in SEQ ID NO: 120-197, 275-348, 373-398, and 406-409.

The inventive polynucleotides may be isolated by high throughput sequencing of cDNA libraries prepared from mammalian skin cells as described below in Example 1.

Alternatively, oligonucleotide probes based on the sequences provided in SEQ ID NO: 1-119, 198-274, 349-372, and 399-405 can be synthesized and used to identify positive clones in either cDNA or genomic DNA libraries from mammalian skin cells by means of hybridization or polymerase chain reaction (PCR) techniques. Probes can be shorter than the sequences provided herein but should be at least about 10, preferably at least about and most preferably at least about 20 nucleotides in length. Hybridization and PCR techniques suitable for use with such oligonucleotide probes are well known in the art (see, for example, Mullis, et al., Cold Spring Harbor Symp. Quant. Biol., 51:263, 1987; Erlich, ed., PCR Technology, Stockton Press: NY, 1989; (Sambrook, J, Fritsch, EF and Maniatis, T, eds., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring WO 99/55865 PCT/NZ99/0051 Harbor Laboratory Press, Cold Spring Harbor: New York, 1989). Positive clones may be analyzed by restriction enzyme digestion, DNA sequencing or the like.

In addition, DNA sequences of the present invention may be generated by synthetic means using techniques well known in the art. Equipment for automated synthesis of oligonucleotides is commercially available from suppliers such as Perkin Elmer/Applied Biosystems Division (Foster City, California) and may be operated according to the manufacturer's instructions.

Since the polynucleotide sequences of the present invention have been derived from skin, they likely encode proteins that have important roles in growth and l0 development of skin, and in responses of skin to tissue injury and inflammation as well as disease states. Some of the polynucleotides contain sequences that code for signal sequences, or transmembrane domains, which identify the protein products as secreted molecules or receptors. Such protein products are likely to be growth factors, cytokines, or their cognate receptors. Several of the polypeptide sequences have more than similarity to known biologically important proteins and thus are likely to represent proteins having similar biological functions.

In particular, the inventive polypeptides have important roles in processes such as: induction of hair growth; differentiation of skin stem cells into specialized cell types; cell migration; cell proliferation and cell-cell interaction. The polypeptides are important in the maintenance of tissue integrity, and thus are important in processes such as wound healing. Some of the disclosed polypeptides act as modulators of immune responses, especially since immune cells are known to infiltrate skin during tissue insult causing growth and differentiation of skin cells. In addition, many polypeptides are immunologically active, making them important therapeutic targets in a whole range of disease states not only within skin, but also in other tissues of the body. Antibodies to the polypeptides of the present invention and small molecule inhibitors related to the polypeptides of the present invention may also be used for modulating immune responses and for treatment of diseases according to the present invention.

In one aspect, the present invention provides methods for using one or more of the inventive polypeptides or polynucleotides to treat disorders in a patient. As used herein, a "patient" refers to any warm-blooded animal, preferably a human.

WO 99/55865 PCT/NZ99/00051 In this aspect, the polypeptide or polynucleotide is generally present within a pharmaceutical composition or a vaccine. Pharmaceutical compositions may comprise one or more polypeptides, each of which may contain one or more of the above sequences (or variants thereof), and a physiologically acceptable carrier. Vaccines may comprise one or more of the above polypeptides and a non-specific immune response amplifier, such as an adjuvant or a liposome, into which the polypeptide is incorporated.

Alternatively, a vaccine or pharmaceutical composition of the present invention may contain DNA encoding one or more polypeptides as described above, such that the polypeptide is generated in situ. In such vaccines and pharmaceutical compositions, the DNA may be present within any of a variety of delivery systems known to those of ordinary skill in the art, including nucleic acid expression systems, and bacterial and viral expression systems. Appropriate nucleic acid expression systems contain the necessary DNA sequences for expression in the patient (such as a suitable promoter and terminator signal). Bacterial delivery systems involve the administration of a bacterium (such as Bacillus-Calmette-Guerin) that expresses an immunogenic portion of the polypeptide on its cell surface. In a preferred embodiment, the DNA may h introduced using a viral expression system vaccinia or other poxvirus, retrovirus, or adenovirus), which may involve the use of a non-pathogenic, or defective, replication competent virus.

Techniques for incorporating DNA into such expression systems are well known in the art. The DNA may also be "naked," as described, for example, in Ulmer, et al., Science 259:1745-1749, 1993 and reviewed by Cohen, Science 259:1691-1692, 1993. The uptake of naked DNA may be increased by coating the DNA onto biodegradable beads, which are efficiently transported into the cells.

Routes and frequency of administration, as well as dosage, will vary from individual to individual. In general, the pharmaceutical compositions and vaccines may be administered by injection intradermal, intramuscular, intravenous, or subcutaneous), intranasally by aspiration) or orally. In general, the amount of polypeptide present in a dose (or produced in situ by the DNA in a dose) ranges from about 1 pg to about 100 mg per kg of host, typically from about 10 pg to about 1 mg per kg of host, and preferably from about 100 pg to about 1 p.g per kg of host. Suitable dose WO 99/55865 PCT/NZ99/00051 sizes will vary with the size of the patient, but will typically range from about 0.1 ml to about 5 ml.

While any suitable carrier known to those of ordinary skill in the art may be employed in the pharmaceutical compositions of this invention, the type of carrier will vary depending on the mode of administration. For parenteral administration, such as subcutaneous injection, the carrier preferably comprises water, saline, alcohol, a lipid, a wax, or a buffer. For oral administration, any of the above carriers or a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, and magnesium carbonate, may be employed. Biodegradable microspheres polylactic galactide) may also be employed as carriers for the pharmaceutical compositions of this invention. Suitable biodegradable microspheres are disclosed, for example, in U.S. Patent Nos. 4,897,268 and 5,075,109.

Any of a variety of adjuvants may be employed in the vaccines derived from this invention to non-specifically enhance the immune response. Most adjuvants contain a substance designed to protect the antigen from rapid catabolism, such as aluminum hydroxide or mineral oil, and a non-specific stimulator of immune responses, such as lipid A, Bordetella pertussis, or M. tuberculosis. Suitable adjuvants are commercially available as, for example, Freund's Incomplete Adjuvant and Freund's Complete Adjuvant (Difco Laboratories, Detroit, Michigan), and Merck Adjuvant 65 (Merck and Company, Inc., Rahway, New Jersey). Other suitable adjuvants include alum, biodegradable microspheres, monophosphoryl lipid A, and Quil A.

The polynucleotides of the present invention may also be used as markers for tissue, as chromosome markers or tags, in the identification of genetic disorders, and for the design of oligonucleotides for examination of expression patterns using techniques well known in the art, such as the microarray technology available from Synteni (Palo Alto, California). Partial polynucleotide sequences disclosed herein may be employed to obtain full length genes by, for example, screening of DNA expression libraries using hybridization probes or PCR primers based on the inventive sequences.

The polypeptides provided by the present invention may additionally be used in assays to determine biological activity, to raise antibodies, to isolate corresponding ligands or receptors, in assays to quantitatively determine levels of protein or cognate WO .99/55865 PCT/NZ99/00051 corresponding ligand or receptor, as anti-inflammatory agents, and in compositions for skin, connective tissue and/or nerve tissue growth or regeneration.

Example 1 ISOLATION OF cDNA SEQUENCES FROM SKIN CELL EXPRESSION LIBRARIES The cDNA sequences of the present invention were obtained by high-throughput sequencing of cDNA expression libraries constructed from specialized rodent or human skin cells as shown in Table 1.

Table 1 Library Skin cell type Source DEPA dermal papilla rat SKTC keratinocytes human HNFF neonatal foreskin fibroblast human MEMS embryonic skin mouse KSCL keratinocyte stem cell mouse TRAM transit amplifying cells mouse These cDNA libraries were prepared as described below.

cDNA Library from Dermal Papilla (DEPA) Dermal papilla cells from rat hair vibrissae (whiskers) were grown in culture and the total RNA extracted from these cells using established protocols. Total RNA, isolated using TRIzol Reagent (BRL Life Technologies, Gaithersburg, Maryland), was used to obtain mRNA using a Poly(A) Quik mRNA isolation kit (Stratagene, La Jolla, California), according to the manufacturer's specifications. A cDNA expression library was then prepared from the mRNA by reverse transcriptase synthesis using a Lambda ZAP cDNA library synthesis kit (Stratagene).

cDNA Library from Keratinocytes (SKTC) Keratinocytes obtained from human neonatal foreskins (Mitra, R and Nikoloff, B in Handbook of Keratinocyte Methods, pp. 17-24, 1994) were grown in serum-free KSFM (BRL Life Technologies) and harvested along with differentiated cells (108 cells).

Keratinocytes were allowed to differentiate by addition of fetal calf serum at a final WO 99/55865 PCT/NZ99/00051 concentration of 10% to the culture medium and cells were harvested after 48 hours.

Total RNA was isolated from the two cell populations using TRIzol Reagent (BRL Life Technologies) and used to obtain mRNA using a Poly(A) Quik mRNA isolation kit (Stratagene). cDNAs expressed in differentiated keratinocytes were enriched by using a PCR-Select cDNA Subtraction Kit (Clontech, Palo Alto, California). Briefly, mRNA was obtained from either undifferentiated keratinocytes ("driver mRNA") or differentiated keratinocytes ("tester mRNA") and used to synthesize cDNA. The two populations of cDNA were separately digested with RsaI to obtain shorter, blunt-ended molecules. Two tester populations were created by ligating different adaptors at the cDNA ends and two successive rounds of hybridization were performed with an excess of driver cDNA. The adaptors allowed for PCR amplification of only the differentially expressed sequences which were then ligated into T-tailed pBluescript (Hadjeb, N and Berkowitz, GA, BioTechniques 20:20-22 1996), allowing for a blue/white selection of cells containing vector with inserts. White cells were isolated and used to obtain plasmid DNA for sequencing.

cDNA library from human neonatal fibrobiasts (HNFF) Human neonatal fibroblast cells were grown in culture from explants of human neonatal foreskin and the total RNA extracted from these cells using established protocols. Total RNA, isolated using TRIzol Reagent (BRL Life Technologies, Gaithersburg, Maryland), was used to obtain mRNA using a Poly(A) Quik mRNA isolation kit (Stratagene, La Jolla, California), according to the manufacturer's specifications. A cDNA expression library was then prepared from the mRNA by reverse transcriptase synthesis using a Lambda ZAP cDNA library synthesis kit (Stratagene).

cDNA library from mouse embryonic skin (MEMS) Embryonic skin was micro-dissected from day 13 post coitum Balb/c mice.

Embryonic skin was washed in phosphate buffered saline and mRNA directly isolated from the tissue using the Quick Prep Micro mRNA purification kit (Pharmacia, Sweden).

The mRNA was then used to prepare cDNA libraries as described above for the DEPA library.

cDNA library from mouse stem cells (KSCL) and transit amplifying (TRAM) cells Pelts obtained from 1-2 day post-partum neonatal Balb/c mice were washed and WO 99/55865 PCT/NZ99/00051 incubated in trypsin (BRL Life Technologies) to separate the epidermis from the dermis.

Epidermal tissue was disrupted to disperse cells, which were then resuspended in growth medium and centrifuged over Percoll density gradients prepared according to the manufacturer's protocol (Pharmacia, Sweden). Pelleted cells were labeled using Rhodamine 123 (Bertoncello I, Hodgson GS and Bradley TR, Exp Hematol. 13:999- 1006, 1985), and analyzed by flow cytometry (Epics Elite Coulter Cytometry, Hialeah, Florida). Single cell suspensions of rhodamine-labeled murine keratinocytes were then labeled with a cross reactive anti-rat CD29 biotin monoclonal antibody (Pharmingen, San Diego, California; clone Ha2/5). Cells were washed and incubated with anti-mouse CD45 phycoerythrin conjugated monoclonal antibody (Pharmingen; clone 30F11.1, followed by labeling with streptavidin spectral red (Southern Biotechnology, Birmingham, Alabama). Sort gates were defined using listmode data to identify four populations: CD29 bright rhodamine dull CD45 negative cells; CD29 bright rhodamine bright CD45 negative cells; CD29 dull rhodamine bright CD45 negative cells; and CD29 dull rhodamine dull CD45 negative cells. Cells were sorted, pelleted and snap frozen prior to storage at -80C. This protocol was followed multiple times to obtain sufficient cell numbers of each population to prepare cDNA libraries. Skin stem cells and transit amplifying cells are known to express CD29, the integrin pi chain. CD45, a leucocyte specific antigen, was used as a marker for cells to be excluded in the isolation of skin stem cells and transit amplifying cells. Keratinocyte stem cells expel the rhodamine dye more efficiently than transit amplifying cells. The CD29 bright, rhodamine dull, negative population (putative keratinocyte stem cells; referred to as KSCL), and the CD29 bright, rhodamine bright, CD45 negative population (keratinocyte transit amplifying cells; referred to as TRAM) were sorted and mRNA was directly isolated from each cell population using the Quick Prep Micro mRNA purification kit (Pharmacia, Sweden). The mRNA was then used to prepare cDNA libraries as described above for the DEPA library.

cDNA sequences were obtained by high-throughput sequencing of the cDNA libraries described above using a Perkin Elmer/Applied Biosystems Division Prism 377 sequencer.

WO 99/55865 PCT/NZ99/00051 Example 2 CHARACTERIZATION OF ISOLATED CDNA SEQUENCES The isolated cDNA sequences were compared to sequences in the EMBL DNA database using the computer algorithms FASTA and/or BLASTN. The corresponding predicted protein sequences (DNA translated to protein in each of 6 reading frames) were compared to sequences in the SwissProt database using the computer algorithms FASTX and/or BLASTP. Comparisons of DNA sequences provided in SEQ ID NO: 1-119 to sequences in the EMBL DNA database (using FASTA) and amino acid sequences provided in SEQ ID NO: 120-197 to sequences in the SwissProt database (using FASTX) were made as of March 21, 1998. Comparisons of DNA sequences provided in SEQ ID NO: 198-274 to sequences in the EMBL DNA database (using BLASTN) and amino acid sequences provided in SEQ ID NO: 275-348 to sequences in the SwissProt database (using BLASTP) were made as of October 7, 1998. Comparisons of DNA sequences provided in SEQ ID NO: 349-372 to sequences in the EMBL DNA database (using BLASTN) and amino acid sequences provided in SEQ ID NO: 373-398 to sequences in the SwissProt database (using BLASTP) were made as of January 23, 1999.

Isolated cDNA sequences and their corresponding predicted protein sequences were computer analyzed for the presence of signal sequences identifying secreted molecules. Isolated cDNA sequences that have a signal sequence at a putative start site within the sequence are provided in SEQ ID NO: 1-44, 198-238, 349-358, and 399. The cDNA sequences of SEQ ID NO: 1-6, 198-199, 349-352, 354, and 356-358 were determined to have less than 75% identity (determined as described above), to sequences in the EMBL database using the computer algorithms FASTA or BLASTN, as described above. The predicted amino acid sequences of SEQ ID NO: 120-125, 275-276, 373-380, and 382 were determined to have less than 75% identity (determined as described above) to sequences in the SwissProt database using the computer algorithms FASTX or BLASTP, as described above.

Further sequencing of the some of the isolated partial cDNA sequences resulted in the isolation of the full-length cDNA sequences provided in SEQ ID NO: 7-14, 200-231, and 372. The corresponding predicted amino acid sequences are provided in SEQ ID NO: 126-133, 277-308, and 396, respectively. Comparison of the full length cDNA WO 99/55865 PCT/NZ99/00051 sequences with those in the EMBL database using the computer algorithm FASTA or BLASTN, as described above, revealed less than 75% identity (determined as described above) to known sequences. Comparison of the predicted amino acid sequences provided in SEQ ID NO: 126-133 and 277-308 with those in the SwissProt database using the computer algorithms FASTX or BLASTP, as described above, revealed less than identity (determined as described above) to known sequences.

Comparison of the predicted amino acid sequences corresponding to the cDNA sequences of SEQ ID NO: 15-23 with those in the EMBL using the computer algorithm FASTA database showed less than 75% identity (determined as described above) to known sequences. These predicted amino acid sequences are provided in SEQ ID NO: 134-142.

Further sequencing of some of the isolated partial cDNA sequences resulted in the isolation of full-length cDNA sequences provided in SEQ ID NO: 24-44 and 232-238.

The corresponding predicted amino acid sequences are provided in SEQ ID NO: 143-163 and 309-315, respectively. These amino acid sequences were determined to have less thll /70% identity, uetermined as described above to known sequences in the SwissProt database using the computer algorithm FASTX.

Isolated cDNA sequences having less than 75% identity to known expressed sequence tags (ESTs) or to other DNA sequences in the public database, or whose corresponding predicted protein sequence showed less than 75% identity to known protein sequences, were computer analyzed for the presence of transmembrane domains coding for putative membrane-bound molecules. Isolated cDNA sequences that have either one or more transmembrane domain(s) within the sequence are provided in SEQ ID NO: 45-63, 239-253, 359-364, 400-402. The cDNA sequences of SEQ ID NO: 45-48, 239-249, 359-361, and 363 were found to have less than 75% identity (determined as described above) to sequences in the EMBL database, using the FASTA or BLASTN computer algorithms. Their predicted amino acid sequences provided in SEQ ID NO: 164-167, 316-326, 383, 385-388 and 407-408 were found to have less than 75% identity, determined as described above, to sequences in the SwissProt database using the FASTX or BLASTP database.

WO 99/55865 PCT/NZ99/00051 Comparison of the predicted amino acid sequences corresponding to the cDNA sequences of SEQ ID NO: 49-63 and 250-253 with those in the SwissProt database showed less than 75% identity (determined as described above) to known sequences.

These predicted amino acid sequences are provided in SEQ ID NO: 168-182 and 327-330.

Using automated search programs to screen against sequences coding for molecules reported to be of therapeutic and/or diagnostic use, some of the cDNA sequences isolated as described above in Example 1 were determined to encode predicted protein sequences that appear to be family members of known protein families. A family member is here defined to have at least 25% identity in the translated polypeptide to a known protein or member of a protein family. These cDNA sequences are provided in SEQ ID NO: 64-76, 254-264, 365-369, and 403, with the corresponding predicted amino acid sequences being provided in SEQ ID NO: 183-195, 331-341, 389-393 and 409, respectively. The cDNA sequences of SEQ ID NO: 64-68, 254-264, and 365-369 show less than 75% identity (determined as described above) to sequences in the EMBL database using the FASTA or BLASTN computer algorithms. Similarly, the amino acid sequences of SEQ ID NO: 183-195, 331-341, and 389-393 show less than 75% identity to sequences in the SwissProt database.

The likely utility for each of the proteins encoded by the DNA sequences of SEQ ID NO: 64-76, 254-264, 365-369, and 403, based on similarity to known proteins, is provided below: WO 99/55865 PCT/NZ99/00051 Table 2 FUNCTIONS OF NOVEL PROTEINS P/N A/A SEQ SEQ. SIMILARITY TO KNOWN PROTEINS ID ID NO: NO.

64 183 Slit, a secreted molecule required for central nervous system 372 396 development 184 Immunoglobulin receptor family. About 40% of leucocyte membrane polypeptides contain immunoglobulin superfamily domains 66 185 RIP protein kinase, a serine/threonine kinase that contains a death 403 409 domain to mediate apoptosis 67 186 Extracellular protein with epidermal growth factor domain capable of stimulating fibroblast proliferation 68 187 Transforming growth factor alpha, a protein which binds epidermal growth factor receptor and stimulates growth and mobility of keratinocytes 69 188 DRS protein which has a secretion signal component and whose expression is suppressed in cells transformed by oncogenes 89 A33 receptor with immunoglobulin-like domains and is expressed in greater than 95% of colon tumors 71 190 Interleukin-12 alpha subunit, component of a cytokine that is important in the immune defense against intracellular pathogens.

IL-12 also stimulates proliferation and differentiation of TH1 subset of lymphocytes 72 191 Tumor Necrosis Factor receptor family of proteins that are involved in the proliferation, differentiation and death of many cell types including B and T lymphocytes.

73 192 Epidermal growth factor family proteins which stimulate growth and mobility of keratinocytes and epithelial cells. EGF is involved in wound healing. It also inhibits gastric acid secretion.

74 193 Fibronectin Type III receptor family. The fibronectin III domains are found on the extracellular regions of cytokine receptors 194 Serine/threonine kinases (STK2 HUMAN) which participate in cell cycle progression and signal transduction 76 195 Immunoglobulin receptor family 254 331 Receptor with immunoglobul in-like domains and homology to A33 receptor which is expressed in greater than 95% of colon tumors 255 332 Epidermal growth factor family proteins which stimulate growth and mobility of keratinocytes and epithelial cells. EGF is involved in wound healing. It also inhibits gastric acid secretion.

WO 99/55865 PCT/NZ99/00051 P/N A/A SEQ SEQ. SIMILARITY TO KNOWN PROTEINS ID ID NO: NO.

256 333 Serine/threonine kinases (STK2_HUMAN) which participate in cell cycle progression and signal transduction 257 334 Contains protein kinase and ankyrin domains. Possible role in cellular growth and differentiation.

258 335 Notch family proteins which are receptors involved in cellular differentiation.

259 336 Extracellular protein with epidermal growth factor domain __capable of stimulating fibroblast proliferation.

260 337 Fibronectin Type III receptor family. The fibronectin III domains are found on the extracellular regions of cytokine receptors.

261 338 Immunoglobulin receptor family 262 339 ADP/ATP transporter family member containing a calcium binding site.

263 340 Mouse CXC chemokine family members are regulators of epithelial, lymphoid, myeloid, stromal and neuronal cell migration and cancers, agents for the healing of cancers, neurodegenerative diseases, wound healing, inflammatory autoimmune diseases like psoriasis, astha, Crohns disease and as agents for the prevention of HIV-1 of leukocytes 264 341 Nucleotide-sugar transporter family member.

365 389 Transforming growth factor betas (TGF-betas) are secreted covalently linked to latent TGF-beta-binding proteins (LTBPs).

LTBPs are deposited in the extracellular matrix and play a role in cell growth or differentiation.

366 390 Integrins are Type I membrane proteins that function as laminin and collagen receptors and play a role in cell adhesion.

367 391 Integrins are Type I membrane proteins that function as laminin and collagen receptors and play a role in cell adhesion.

368 392 Cell wall protein precursor. Are involved in cellular growth or differentiation.

369 393 HT protein is a secreted glycoprotein with an EGF-like domain.

It functions as a modulator of cell growth, death or differentiation.

These isolated sequences thus encode proteins that influence the growth, differentiation and activation of several cell types. They may usefully be developed as WO 99/55865 PCT/NZ99/00051 agents for the treatment and diagnosis of skin wounds, cancers, growth and developmental defects, and inflammatory disease.

The polynucleotide sequences of SEQ ID NO: 77-117, 265-267, and 404-405 are differentially expressed in either keratinocyte stem cells (KSCL) or in transit amplified cells (TRAM) on the basis of the number of times these sequences exclusively appear in either one of the above two libraries; more than 9 times in one and none in the other (Audic S. and Claverie J-M, Genome Research, 7:986-995, 1997). The sequences of SEQ ID NO: 77-89, 265-267, and 365-369 were determined to have less than identity to sequences in the EMBL and SwissProt databases using the computer algorithm FASTA or BLASTN, as described above. The proteins encoded by these polynucleotide sequences have utility as markers for identification and isolation of these cell types, and antibodies against these proteins may be usefully employed in the isolation and enrichment of these cells from complex mixtures of cells. Isolated polynucleotides and their corresponding proteins exclusive to the stem cell population can be used as drug targets to cause alterations in regulation of growth and differentiation of skin cells, or in gene targeting to transport specific therapeutic molecules to skin stem cells.

Example 3 ISOLATION AND CHARACTERIZATION OF THE HUMAN HOMOLOG OF MUTR1 The human homolog ofmuTR1 (SEQ ID NO: 68), obtained as described above in Example 1, was isolated by screening 50,000 pfu's of an oligo dT primed HeLa cell cDNA library. Plaque lifts, hybridization, and screening were performed using standard molecular biology techniques (Sambrook, J, Fritsch, EF and Maniatis, T, eds., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor: New York, 1989). The determined cDNA sequence of the isolated human homolog (huTR1) is provided in SEQ ID NO: 118, with the corresponding predicted amino acid sequence being provided in SEQ ID NO: 196. The library was screened using an [a 32 P]-dCTP labeled double stranded cDNA probe corresponding to nucleotides 1 to 459 of the coding region within SEQ ID NO: 118.

The polypeptide sequence of huTR1 has regions similar to Transforming Growth Factor-alpha, indicating that this protein functions like an epidermal growth factor (EGF).

WO 99/55865 PCT/NZ99/00051 This EGF-like protein will serve to stimulate keratinocyte growth and motility, and to inhibit the growth of epithelial-derived cancer cells. This novel gene and its encoded protein may thus be used as agents for the healing of wounds and regulators of epithelialderived cancers.

Analysis of RNA transcripts by Northern Blotting Northern analysis to determine the size and distribution of mRNA for huTR1 was performed by probing human tissue mRNA blots (Clontech) with a probe comprising nucleotides 93-673 of SEQ ID NO: 118, radioactively labeled with [a32P]-dCTP.

Prehybridization, hybridization, washing and probe labeling were performed as described in Sambrook, et al., Ibid. mRNA for huTR1 was 3.5-4kb in size and was observed to be most abundant in heart and placenta, with expression at lower levels being observed in spleen, thymus prostate and ovary (Fig. 1).

The high abundance of mRNA for huTR1 in the heart and placenta indicates a role for huTR1 in the formation or maintenance of blood vessels, as heart and placental tissues have an increased abundance of blood vessels, and therefore endothelial cells, compared to other tissues in the body. This, in turn, demonstrates a role for huTRI in angiogenesis and vascularization of tumors. This is supported by the ability of Transforming Growth Factor-alpha and EGF to induce de novo development of blood vessels (Schreiber, et al., Science 232:1250-1253, 1986) and stimulate DNA synthesis in endothelial cells (Schreiber, et al., Science 232:1250-1253, 1986), and their overexpression in a variety of human tumors.

Purification ofmuTRl and huTRI Polynucleotides 177-329 of muTR1 (SEQ ID NO: 268), encoding amino acids 53-103 of muTR1 (SEQ ID NO: 342), and polynucleotides 208-360 of huTR1 (SEQ ID NO: 269), encoding amino acids 54-104 of huTR1 (SEQ ID NO: 343), were cloned into the bacterial expression vector pProEX HT (BRL Life Technologies), which contains a bacterial leader sequence and N-terminal 6xHistidine tag. These constructs were transformed into competent XL1-Blue E. coli as described in Sambrook et al., Ibid.

Starter cultures of these recombinant XL1-Blue E. coli were grown overnight at 37 0 C in Terrific broth containing 100 jpg/ml ampicillin. This culture was spun down and WO 99/55865 PCT/NZ99/00051 used to inoculate 500 ml culture of Terrific broth containing 100 jLg/ml ampicillin.

Cultures were grown until the OD 595 of the cells was between 0.4 and 0.8, whereupon IPTG was added to 1 mM. Cells were induced overnight and bacteria were harvested by centrifugation.

Both the polypeptide of muTR1 (SEQ ID NO: 342; referred to as muTRla) and that of huTR1 (SEQ ID NO: 343; referred to as huTRIa) were expressed in insoluble inclusion bodies. In order to purify the polypeptides muTR1a and huTRIa, bacterial cell pellets were re-suspended in lysis buffer (20 mM Tris-HCl pH 8.0, 10 mM beta mercaptoethanol, 1 mM PMSF). To the lysed cells, 1% NP40 was added and the mix incubated on ice for 10 minutes. Lysates were further disrupted by sonication on ice at for 4 x 15 seconds and then centrifuged for 15 minutes at 14,000 rpm to pellet the inclusion bodies.

The resulting pellet was re-suspended in lysis buffer containing 0.5% w/v CHAPS and sonicated on ice for 5-10 seconds. This mix was stored on ice for 1 hour, centrifuged at 14,000 rpm for 15 minutes at 4 OC and the supernatant discarded. The pellet was once more re-suspended in lysis buffer containing 0.5% w/v CHAPS, sonicated, centrifuged and the supernatant removed as before. The pellet was re-suspended in solubilizing buffer (6 M Guanidine HC1, 0.5 M NaC1, 20 mM Tris HCI, pH sonicated at 95 W for 4 x 15 seconds and then centrifuged for 20 minutes at 14,000 rpm and 4 °C to remove debris. The supernatant was stored at 4 °C until use.

Polypeptides muTR1a and huTRla were purified by virtue of the N-terminal 6x Histidine tag contained within the bacterial leader sequence, using a Nickel-Chelating Sepharose column (Amersham Pharmacia, Uppsala, Sweden) and following the manufacturer's recommended protocol. In order to refold the proteins once purified, the protein solution was added to 5x its volume of refolding buffer (1 mM EDTA, 1.25 mM reduced glutathione, 0.25 mM oxidised glutathione, 20 mM Tris-HC1, pH 8.0) over a period of 1 hour at 4 The refolding buffer was stirred rapidly during this time, and stirring continued at 4 OC overnight. The refolded proteins were then concentrated by ultrafiltration using standard protocols.

WO 99/55865 PCT/NZ99/00051 Biological Activities of Polvpeptides muTRIa and huTRIa muTR1 and huTR1 are novel members of the EGF family, which includes EGF, TGFac, epiregulin and others. These growth factors are known to act as ligands for the EGF receptor. The pathway of EGF receptor activation is well documented. Upon binding of a ligand to the EGF receptor, a cascade of events follows, including the phosphorylation of proteins known as MAP kinases. The phosphorylation of MAP kinase can thus be used as a marker of EGF receptor activation. Monoclonal antibodies exist which recognize the phosphorylated forms of 2 MAP kinase proteins ERK1 and ERK2.

In order to examine whether purified polypeptides ofmuTRIa and huTR1a act as a ligand for the EGF receptor, cells from the human epidermal carcinoma cell line A431 (American Type Culture Collection, No. CRL-1555, Manassas, Virginia) were seeded into 6 well plates, serum starved for 24 hours, and then stimulated with purified muTR1a or huTRla for 5 minutes in serum free conditions. As a positive control, cells were stimulated in the same way with 10 to 100 ng/ml TGF-alpha or EGF. As a negative control, cells were stimulated with PBS containing varying amounts of LPS. Cells were immediately lysed and protein concentration of the lysates estimated by Bradford assay.

ug of protein from each sample was loaded onto 12% SDS-PAGE gels. The proteins were then transferred to PVDF membrane using standard techniques.

For Western blotting, membranes were incubated in blocking buffer (10mM Tris- HC1, pH 7.6, 100 mM NaC1, 0.1% Tween-20, 5% non-fat milk) for 1 hour at room temperature. Rabbit anti-Active MAP kinase pAb (Promega, Madison, Wisconsin) was added to 50 ng/ml in blocking buffer and incubated overnight at 4 oC. Membranes were washed for 30 mins in blocking buffer minus non-fat milk before being incubated with anti rabbit IgG-HRP antibody, at a 1:3500 dilution in blocking buffer, for 1 hour at room temperature. Membranes were washed for 30 minutes in blocking buffer minus non-fat milk, then once for 5 minutes in blocking buffer minus non-fat milk and 0.1% Membranes were then exposed to ECL reagents for 2 min, and then autoradiographed for to 30 min.

As shown in Fig. 2, both muTRla and huTRla were found to induce the phosphorylation of ERK1 and ERK2 over background levels, indicating that muTR1 and 28 WO 99/55865 PCT/NZ99/00051 huTR1 act as ligands for a cell surface receptor that activates the MAP kinase signaling pathway, possibly the EGF receptor. As shown in Fig. 11, huTRla was also demonstrated to induce the phosphorylation of ERK1 and ERK2 in CV1/EBNA kidney epithelial cells in culture, as compared with the negative control. These assays were conducted as described above. This indicates that huTRla acts as a ligand for a cell surface receptor that activates the MAP kinase signaling pathway, possibly the EGF receptor in HeLa and CV1/EBNA cells.

The ability of muTRla to stimulate the growth of neonatal foreskin (NF) keratinocytes was determined as follows. NF keratinocytes derived from surgical discards were cultured in KSFM (BRL Life Technologies) supplemented with bovine pituatary extract (BPE) and epidermal growth factor (EGF). The assay was performed in 96 well flat-bottomed plates in 0.1 ml unsupplemented KSFM. MuTRla, human transforming growth factor alpha (huTGFa) or PBS-BSA was titrated into the plates and 1 x 10 3 NF keratinocytes were added to each well. The plates were incubated for 5 days in an atmosphere of 5% CO 2 at 37 0 C. The degree of cell growth was determined by MTT dye reduction as described previously Imm. Meth. 93:157-165, 1986). As shown in Fig. 3, both muTRIa and the positive control human TGFa stimulated the growth of NF keratinocytes, whereas the negative control, PBS-BSA, did not.

The ability of muTRIa and huTRla to stimulate the growth of a transformed human keratinocyte cell line, HaCaT, was determined as follows. The assay was performed in 96 well flat-bottomed plates in 0.1 ml DMEM (BRL Life Technologies) supplemented with 0.2% FCS. MuTRla, huTRIa and PBS-BSA were titrated into the plates and 1 x10 3 HaCaT cells were added to each well. The plates were incubated for days in an atmosphere containing 10% CO 2 at 370C. The degree of cell growth was determined by MTT dye reduction as described previously Imm. Meth. 93:157-165, 1986). As shown in Fig. 4, both muTRla and huTRIa stimulated the growth of HaCaT cells, whereas the negative control PBS-BSA did not.

The ability of muTRIa and huTRIa to inhibit the growth of A431 cells was determined as follows. Polypeptides muTRla (SEQ ID NO: 342) and huTRla (SEQ ID NO: 343) and PBS-BSA were titrated as described previously Cell. Biol. 93:1-4, 1982) and cell death determined using the MTT dye reduction as described previously WO 99/55865 PCT/NZ99/00051 Imm. Meth. 93:157-165, 1986). Both muTRla and huTR1a were found to inhibit the growth of A431 cells, whereas the negative control PBS-BSA did not (Fig. These results indicate that muTR1 and huTR1 stimulate keratinocyte growth and motility, inhibit the growth of epithelial-derived cancer cells, and play a role in angiogenesis and vascularization of tumors. This novel gene and its encoded protein may thus be developed as agents for the healing of wounds, angiogenesis and regulators of epithelial-derived cancers.

Upregulation ofhuTRl and mRNA expression HeLa cells (human cervical adenocarcinoma) were seeded in 10 cm dishes at a concentration of 1 x 106 cells per dish. After incubation overnight, media was removed and replaced with media containing 100 ng/ml of muTR1, huTR1, huTGFa, or PBS as a negative control. After 18 hours, media was removed and the cells lysed in 2 ml of TRIzol reagent (Gibco BRL Life Technologies, Gaithersburg, Maryland). Total RNA was isolated according to the manufacturer's instructions. To identify mRNA levels of huTR1 from the cDNA samples, 1 pl of cDNA was used in a standard PCR reaction.

After cycling for 30 cycles, 5 pi of each PCR reaction was removed and separated on a agarose gel. Bands were visualized by ethidium bromide staining. As can be seen from Fig. 12, both mouse and human TR1 up-regulate the mRNA levels of huTR1 as compared with cells stimulated with the negative control of PBS. Furthermore, TGFa can also up-regulate the mRNA levels of huTR1.

These results indicate that TR1 is able to sustain its own mRNA expression and subsequent protein expression, and thus is expected to be able to contribute to the progression of diseases such as psoriasis where high levels of cytokine expression are involved in the pathology of the disease. Furthermore, since TGFc can up-regulate the expression of huTR1, the up-regulation of TR1 mRNA may be critical to the mode of action of TGFa.

Serum response element reporter gene assay The serum response element (SRE) is a promoter element required for the regulation of many cellular immediate-early genes by growth. Studies have demonstrated that the activity of the SRE can be regulated by the MAP kinase signaling pathway. Two cell lines, PC12 (rat pheochromocytoma neural tumor) and HaCaT (human transformed WO 99/55865 PCT/NZ99/00051 keratinocytes), containing eight SRE upstream of an SV40 promotor and luciferase reporter gene were developed in-house. 5 x 103 cells were aliquoted per well of 96 well plate and grown for 24 hours in their respective media. HaCaT SRE cells were grown in fetal bovine serum (FBS) in D-MEM supplemented with 2mM L-glutamine (Sigma, St. Louis, Missouri), ImM sodium pyruvate (BRL Life Technologies), 0.77mM L-asparagine (Sigma), 0.2mM arginine (Sigma), 160mM penicillin G (Sigma), dihydrostreptomycin (Roche Molecular Biochemicals, Basel, Switzerland), and mg/ml geneticin (BRL Life Technologies). PC12 SRE cells were grown in 5% fetal bovine serum in Ham F12 media supplemented with 0.4 mg/ml geneticin (BRL Life Technologies). Media was then changed to 0.1% FBS and incubated for a further 24 hours. Cells were then stimulated with a titration of TR1 from 1 tg/ml. A single dose of basic fibroblast growth factor at 100 ng/ml (R&D Systems, Minneapolis, Minnesota) or epidermal growth factor at 10 ng/ml (BRL Life Technologies) was used as a positive control. Cells were incubated in the presence of muTR1 or positive control for 6 hours, washed twice in PBS and lysed with 40 pl of lysis buffer (Promega). 10 gl was transferred to a 96 well plate and 10 p. of luciferase substrate (Promega) added by direct injection into each well by a Victor 2 fluorimeter (Wallac), the plate was shaken and the luminescence for each well read at 3x1 sec Intervals. Fold induction of SRE was calculated using the following equation: Fold induction of SRE Mean relative luminescence of agonist/Mean relative luminescence of negative control.

As shown in Fig. 13, muTR1 activates the SRE in both PC-12 (Fig. 13a) and HaCaT (Fig. 13b) cells. This indicates that HaCaT and PC-12 cells are able to respond to muTR1 protein and elicit a response. In the case of HaCaT cells, this is a growth response. In the case of PC-12 cells, this may be a growth, a growth inhibition, differentiation, or migration response. Thus, TR1 may be important in the development of neural cells or their differentiation into specific neural subsets. TR1 may also be important in the development and progression of neural tumors.

Inhibition by the EGF receptor assay The HaCaT growth assay was conducted as previously described, except that modifications were made as follows. Concurrently with the addition of EGF and TRI to the media, anti-EGF Receptor (EGFR) antibody (Promega, Madison, Wisconsin) or 31 WO 99/55865 PCT/NZ99/00051 negative control antibody, mouse IgG (PharMingen, San Diego, California), were added at a concentration of 62.5 ng/ml.

As seen in Fig. 14, an antibody which blocks the function of the EGFR inhibits the mitogenicity of TR1 on HaCaT cells. This indicates that the EGFR is crucial for transmission of the TR1 mitogenic signal on HaCaT cells. TR1 may bind directly to the EGF receptor. TR1 may also bind to any other members of the EGFR family ErbB-2, and/or -4 that are capable of heterodimerizing with the EGFR.

Sequence of splice variant ofhuTRi, huTRl f A variant of huTR1 was isolated from the same library as huTR1 (SEQ ID NO: 118), following the same protocols. This sequence is a splice variant of huTR1 and consists of the ORF of huTR1 minus amino acids 87 to 137. This has the effect of deleting the third cysteine residue of the EGF motif and the transmembrane domain.

However, cysteine residue 147 (huTRl ORF numbering) may replace the deleted cysteine and thus the disulphide bridges are likely not affected. Therefore, huTRl p is a secreted form of huTR1. It functions as an agonist or an antagonist to huTRI or other EGF family members, including EGF and TGFcc. The determined nucleotide sequence of the splice variant of TR1, referred to as huTR13, is given in SEQ ID NO: 371 and the corresponding predicted amino acid sequence is SEQ ID NO: 395.

Example 4 IDENTIFICATION, ISOLATION AND CHARACTERIZATION OF DP3 A partial cDNA fragment, referred to as DP3, was identified by differential display RT-PCR (modified from Liang P and Pardee AB, Science 257:967-971, 1992) using mRNA from cultured rat dermal papilla and footpad fibroblast cells, isolated by standard cell biology techniques. This double stranded cDNA was labeled with [c32p]dCTP and used to identify a full length DP3 clone by screening 400,000 pfu's of an oligo dT-primed rat dermal papilla cDNA library. The determined full-length cDNA sequence for DP3 is provided in SEQ ID NO: 119, with the corresponding amino acid sequence being provided in SEQ ID NO: 197. Plaque lifts, hybridization and screening were performed using standard molecular biology techniques.

WO 99/55865 PCT/NZ99/00051 Example ISOLATION AND CHARACTERIZATION OF THE HUMAN HOMOLOG OF MUKS1 Analysis ofRNA transcripts by Northern Blotting Northern analysis to determine the size and distribution of mRNA for muKS1 (SEQ ID NO: 263) was performed by probing murine tissue mRNA blots with a probe consisting of nucleotides 268-499 of muKS1, radioactively labeled with [a32P]-dCTP.

Prehybridization, hybridization, washing, and probe labeling were performed as described in Sambrook, et al., Ibid. mRNA for muKS1 was 1.6 kb in size and was observed to be most abundant in brain, lung, muscle, and heart. Expression could also be detected in lower intestine, skin, and kidney. No detectable signal was found in testis, spleen, liver, thymus, stomach.

Human homologue ofmuKS] MuKS1 (SEQ ID NO: 263) was used to search the EMBL database (Release plus updates to June, 1998) to identify human EST homologues. The top three homologies were to the following ESTs: accession numbers AA643952, HS1301003 and AA865643. These showed 92.63% identity over 285 nucleotides, 93.64% over 283 nucleotides and 94.035% over 285 nucleotides, respectively. Frame shifts were identified in AA643952 and HS1301003 when translated. Combination of all three ESTs identified huKS1 (SEQ ID NO: 270) and translated polypeptide SEQ ID NO: 344. Alignment of muKS 1 and huKS 1 polypeptides indicated 95% identity over 96 amino acids.

Bacterial expression and purification ofmuKS1 and huKS1 Polynucleotides 269-502 of muKS1 (SEQ ID NO: 271), encoding amino acids 23-99 of polypeptide muKS1 (SEQ ID NO: 345), and polynucleotides 55-288 of huKS1 (SEQ ID NO: 272), encoding amino acids 19-95 of polypeptide huKS1 (SEQ ID NO: 346), were cloned into the bacterial expression vector pET-16b (Novagen, Madison, Wisconsin), which contains a bacterial leader sequence and N-terminal 6xHistidine tag.

These constructs were transformed into competent XL1-Blue E. coli as described in Sambrook et al., Ibid.

WO 99/55865 PCT/NZ99/00051 Starter cultures of recombinant BL 21 (DE3) E. coli (Novagen) containing SEQ ID NO: 271 (muKSla) and SEQ ID NO: 272 (huKSla) were grown in NZY broth containing 100 pg/ml ampicillin (Gibco-BRL Life Technologies) at 37 0 C. Cultures were spun down and used to inoculate 800 ml of NZY broth and 100 ig/ml ampicillin.

Cultures were grown until the OD 5 95 of the cells was between 0.4 and 0.8. Bacterial expression was induced for 3 hours with 1 mM IPTG. Bacterial expression produced an induced band of approximately 15kDa for muKS a and huKS 1 a.

MuKSla and huKSla were expressed in insoluble inclusion bodies. In order to purify the polypeptides, bacterial cell pellets were re-suspended in lysis buffer (20 mM Tris-HCl pH 8.0, 10 mM PMercaptoethanol, 1 mM PMSF). To the lysed cells, 1% was added and the mix incubated on ice for 10 minutes. Lysates were further disrupted by sonication on ice at 95 W for 4 x 15 seconds and then centrifuged for 10 minutes at 18,000 rpm to pellet the inclusion bodies.

The pellet containing the inclusion bodies was re-suspended in lysis buffer containing 0.5% w/v CHAPS and sonicated for 5-10 seconds. This mix was stored on ice for 1 hour, centrifuged at 14000 rpm for 15 minutes at 4 0 C and the supernatant discarded.

The pellet was once more re-suspended in lysis buffer containing 0.5% w/v CHAPS, sonicated, centrifuged, and the supernatant removed as before. The pellet was resuspended in solubilizing buffer (6 M guanidine HC1, 0.5 M NaC1, 20 mM Tris-HCI pH sonicated at 95W for 4 x 15 seconds and centrifuged for 10 minutes at 18000 rpm and 4 0 C to remove debris. The supernatant was stored at 4 0 C. MuKSla and huKS a were purified by virtue of the N-terminal 6x histidine tag contained within the bacterial leader sequence, using a Nickel-Chelating sepharose column (Amersham Pharmacia, Uppsala, Sweden) and following the manufacturer's protocol. Proteins were purified twice over the column to reduce endotoxin contamination. In order to re-fold the proteins once purified, the protein solution was dialysed in a 4 M-2 M urea gradient in 20 mM tris-HC1 pH 7.5 10% glycerol overnight at 4 0 C. The protein was then further dialysed 2x against 2 litres of 20 mM Tris-HCl pH 7.5 10% glycerol.

Peptide sequencing of muKS] and huKS1 Bacterially expressed muKS1 and huKS were separated on polyacrylamide gels and induced bands of 15 kDa were identified. The predicted size ofmuKS is 9.4 kDa.

WO 99/55865 PCT/NZ99/00051 To obtain the amino acid sequence of the 15 kDa bands, 20 pg recombinant muKS 1 and huSK1 was resolved by SDS-PAGE and electroblotted onto Immobilon PVDF membrane (Millipore, Bedford, Massachusetts). Internal amino acid sequencing was performed on tryptic peptides of muKS1 and huKS1 by the Protein Sequencing Unit at the University of Auckland, New Zealand.

The determined amino acid sequences for muKS 1 and huKS 1 are given in SEQ ID NOS: 397 and 398, respectively. These amino acid sequences confirmed that the determined sequences are identical to that predicted from the cDNA sequences. The size discrepancy has previously been reported for other chemokines (Richmond A, BalentienE, Thomas HG, Flaggs G, Barton DE, Spiess J, Bordoni R, Francke U, Derynck R, "Molecular characterization and chromosomal mapping of melanoma growth stimulatory activity, a growth factor structurally related to beta-thromboglobulin," EMBO J 7:2025-2033, 1988; Liao F, Rabin RL, Yannelli JR, Koniaris LG, Vanguri P, Farber JM, "Human Nig chemokine: biochemical and functional characterization," J Exp. Med. 182:1301-1314, 1995). The isoelectric focusing point of these proteins was predicted to be 10.26 using DNASIS (HITACHI Software Engineering, San Francisco, California).

Oxidative burst assay Oxidative burst assays were used to determine responding cell types. 1 x 107 PBMC cells were resuspended in 5 ml HBSS, 20mM HEPES, 0.5% BSA and incubated for 30 minutes at 37 0 C with 5 tl 5 mM dichloro-dihydrofluorescein diacetate

(H

2 DCFDA, Molecular Probes, Eugene, Oregon). 2 x 105 H 2 DCFDA-labeled cells were loaded in each well of a flat-bottomed 96 well plate. 10 p.1 of each agonist was added simultaneously into the well of the flat-bottomed plate to give final concentrations of 100 ng/ml (fMLP was used at 10 iM). The plate was then read on a Victor 2 1420 multilabel counter (Wallac, Turku, Finland) with a 485 nm excitation wavelength and 535 nm emission wavelength. Relative fluorescence was measured at 5 minute intervals over 60 minutes.

A pronounced respiratory burst was identified in PBMC with a 2.5 fold difference between control treated cells (TR1) and cells treated with 100 ng/ml muKS1 (Fig. 8).

WO 99/55865 PCT/NZ99/00051 Human stromal derived factor-lax (SDFla) (100 ng/ml) and 10 (tM formyl-Met-Leu-Phe (fMLP) were used as positive controls.

Chemotaxis assay Cell migration in response to muKS1 was tested using a 48 well Boyden's chamber (Neuro Probe Inc., Cabin John, Maryland) as described in the manufacturer's protocol. In brief, agonists were diluted in HBSS, 20mM HEPES, 0.5% BSA and added to the bottom wells of the chemotactic chamber. THP-1 cells were re-suspended in the same buffer at 3 x 105 cells per 50 t 1. Top and bottom wells were separated by a PVPfree polycarbonate filter with a 5 p.m pore size for monocytes or 3 p.m pore size for lymphocytes. Cells were added to the top well and the chamber incubated for 2 hours for monocytes and 4 hours for lymphocytes in a 5% CO 2 humidified incubator at 37 0

C.

After incubation, the filter was fixed and cells scraped from the upper surface. The filter was then stained with Diff-Quick (Dade International Inc., Miami, Florida) and the number of migrating cells counted in five randomly selected high power fields. The results are expressed as a migration index (the number of test migrated cells divided by the number of control migrated cells).

Using this assay, muKS1 was tested against T cells and THP-1 cells. MuKS1 induced a titrateable chemotactic effect on THP-1 cells from 0.01 ng/ml to 100 ng/ml (Fig. Human SDFla was used as a positive control and gave an equivalent migration.

MuKS1 was also tested against IL-2 activated T cells. However, no migration was evidence for muKS1 even at high concentrations, whereas SDF-la provided an obvious titrateable chemotactic stimulus. Therefore, muKS 1 appears to be chemotactic for THP-1 cells but not for IL-2 activated T cells at the concentrations tested.

Full length sequence ofmuKS1 clone The nucleotide sequence of muKS1 was extended by determining the base sequence of additional ESTs. Combination of all the ESTs identified the full-length muKS1 (SEQ ID NO: 370) and the corresponding translated polypeptide sequence in SEQ ID NO: 394.

Analysis of human RNA transcripts by Northern blotting Northern blot analysis to determine the size and distribution of mRNA for the human homologue of muKS1 was performed by probing human tissue blots (Clontech, WO 99/55865 PCT/NZ99/00051 Palo Alto, California) with a radioactively labeled probe consisting of nucleotides 1 to 288 of huKS1 (SEQ ID NO: 270). Prehybridization, hybridization, washing, and probe labeling were performed as described in Sambrook, et al., Ibid. mRNA for huKS 1 was 1.6 kb in size and was observed to be most abundance in kidney, liver, colon, small intestine, and spleen. Expression could also be detected in pancreas, skeletal muscle, placenta, brain, heart, prostate, and thymus. No detectable signal was found in lung, ovary, and testis.

Analysis of human RNA transcripts in tumor tissue by Northern blotting Northern blot analysis to determine distribution of huKS1 in cancer tissue was performed as described previously by probing tumor panel blots (Invitrogen, Carlsbad, California). These blots make a direct comparison between normal and tumor tissue.

MRNA was observed in normal uterine and cervical tissue but not in the respective tumor tissue. In contrast, expression was up-regulated in breast tumor and down-regulated in normal breast tissue. No detectable signal was found in either ovary or ovarian tumors.

Iniection of bacterially expressed muKSla into nude mice Two nude mice were anaesthetised intraperitoneally with 75 al of 1/10 dilution of Hypnorm (Janssen Pharmaceuticals, Buckinghamshire, England) in phosphate buffered saline. 20ug of bacterially expressed muKSla (SEQ ID NO: 345) was injected subcutaneously in the left hind foot, ear and left-hand side of the back. The same volume of phosphate buffered saline was injected in the same sites but on the right-hand side of the same animal. Mice were left for 18 hours and then examined for inflammation. Both mice showed a red swelling in the ear and foot sites injected with the bacterially expressed protein. No obvious inflammation could be identified in either back site. Mice were culled and biopsies taken from the ear, back and foot sites and fixed in 3.7% formol saline. Biopsies were embedded, sectioned and stained with Haemotoxylin and eosin.

Sites injected with muKSla had a marked increase in polymorphonuclear granulocytes, whereas sites injected with phosphate buffered saline had a low background infiltrate of polymorphonuclear granulocytes.

Injection of bacterially recombinant muKS1 into C3H/HeJ mice Eighteen C3H/HeJ mice were divided into 3 groups and injected intraperitoneally with muKS1, GV14B, or phosphate buffered saline (PBS). GV14B is a bacterially WO 99/55865 PCT/NZ99/00051 expressed recombinant protein used as a negative control. Group 1 mice were injected with 50 ug ofmuKS1 in 1 ml of PBS; Group 2 mice were injected with 50 gg of GV14B in 1 ml of PBS; and Group 3 mice with 1 ml of PBS. After 18 hours, the cells in the peritoneal cavity of the mice were isolated by intraperitoneal lavage with 2 x 4 ml washes with harvest solution (0.02% EDTA in PBS). Viable cells were counted from individual mice from each group. Mice injected with 50 gg of muKS1 had on average a 3-fold increase in cell numbers (Fig. jIg of bacterial recombinant muKS I was injected subcutaneously into the left hind foot of three C3H/HeJ mice. The same volume of PBS was injected into the same site on the right-hand side of the same animal. After 18 hours, mice were examined for inflammation. All mice showed a red swelling in the foot pad injected with bacterially recombinant KS1. From histology, sites injected with muKS1 had an inflammatory response of a mixed phenotype with mononuclear and polymorphonuclear cells present.

Chemokines are a large superfamily of highly basic secreted proteins with a broad number of functions (Baggiolini, et al., Annu. Rev. Immunol., 15:675-705, 1997; Ward, etal., Immunity. 9:1-11, 1998; Horuk, Nature. 393:524-525, 1998). The polypeptide sequences of muKS and huKS1 have similarity to CXC chemokines, suggesting that this protein will act like other CXC chemokines. The in vivo data from nude mice supports this hypothesis. This chemokine-like protein may therefore be expected to stimulate leukocyte, epithelial, stromal, and neuronal cell migration; promote angiogenesis and vascular development; promote neuronal patterning, hemopoietic stem cell mobilization, keratinocyte and epithelial stem cell patterning and development, activation and proliferation of leukocytes; and promotion of migration in wound healing events. It has recently been shown that receptors to chemokines act as co-receptors for HIV-1 infection of CD4+ cells (Cairns, et al., Nature Medicine, 4:563-568, 1998) and that high circulating levels of chemokines can render a degree of immunity to those exposed to the HIV virus (Zagury, et al., Proc. Natl. Acad. Sci. USA 95:3857-3861, 1998). This novel gene and its encoded protein may thus be usefully employed as regulators of epithelial, lymphoid, myeloid, stromal, and neuronal cells migration and cancers; as agents for the treatment of cancers, neuro-degenerative diseases, inflammatory autoimmune diseases WO 99/55865 PCT/NZ99/00051 such as psoriasis, asthma and Crohn's disease for use in wound healing; and as agents for the prevention of HIV-1 binding and infection of leukocytes.

We have also shown that muKS1 can promote a quantifiable increase in cell numbers in the peritoneal cavity of C3H/HeJ mice injected with muKS1. Furthermore, we have shown that muKS1 can induce an oxidative burst in human peripheral blood mononuclear cells and migration in the human monocyte leukemia cell line, THP-1, suggesting that monocyte/macrophages are one of the responsive cell types for KS1. In addition to this, we demonstrated that huKS1 was expressed at high levels in a number of non-lymphoid tissues, such as the colon and small intestine, and in breast tumors. It was also expressed in normal uterine and cervical tissue, but was completely down-regulated in their respective tumors. It has recently been shown that non-ELR chemokines have demonstrated angiostatic properties. IP-10 and Mig, two non-ELR chemokines, have previously been shown to be up-regulated during regression of tumors (Tannenbaum CS, Tubbs R, Armstrong D, Finke JH, Bukowski RM, Hamilton TA, "The CXC Chemokines IP-10 and Mig are necessary for IL-12-mediated regression of the mouse RENCA tumor," J1 Immunnol 161: 927-932, 1998), with levels of expression inversely correlating with tumor size (Kanegane C, Sgadari C, Kanegane H, Teruya-Feldstine J, Yao O, Gupta G, Farber JM, Liao F, Liu L, Tosato G, "Contribution of the CXC Chemokines and Mig to the antitumor effects of IL-12," J Leuko. Biol. 64: 384-392, 1998).

Furthermore, neutralizing antibodies to IP-10 and Mig would reduce the anti-tumor effect, indicating the contribution these molecules make to the anti-tumor effects.

Therefore, it is expected that in the case of cervical and uterine tumors, KS1 would have similar properties.

The data demonstrates that KS is involved in cell migration showing that one of the responsive cell types is monocyte/macrophage. The human expression data in conjunction with the in vitro and in vivo biology demonstrates that this molecule may be a useful regulator in cell migration, and as an agent for the treatment of inflammatory diseases, such as Crohn's disease, ulcerative colitis, and rheumatoid arthritis; and cancers, such as cervical adenocarcinoma, uterine leiomyoma, and breast invasive ductal carcinoma.

WO 99/55865 PCT/NZ99/00051 Example 6 CHARACTERIZATION OF KS2 KS2 contains a transmembrane domain and may function as either a membranebound ligand or a receptor. Northern analysis indicated that the mRNA for KS2 was expressed in the mouse keratinocyte cell line, Pam212, consistent with the cDNA being identified in mouse keratinocytes.

Mammalian Expression To express KS2, the extracellular domain was fused to the amino terminus of the constant domain of immunoglobulinG (Fc) that had a C-terminal 6xHistidine tag. This was performed by cloning polynucleotides 20-664 of KS2 (SEQ ID NO: 273), encoding amino acids 1-215 of polypeptide KS2 (SEQ ID NO: 347), into the mammalian expression vector pcDNA3 (Invitrogen, NV Leek, Netherlands), to the amino terminus of the constant domain of immunoglobulinG (Fc) that had a C-terminal 6xHistidine tag.

This construct was transformed into competent XL1-Blue E. coli as described in Sambrook et al., Ibid. The Fc fusion construct of KS2a was expressed by transfecting Cos-1 cells in 5 x T175 flasks with 180 ig of KSla using DEA-dextran. The supernatant was harvested after seven days and passed over a Ni-NTA column. Bound KS2a was eluted from the column and dialysed against PBS.

The ability of the Fc fusion polypeptide of KS2a to inhibit the IL-2 induced growth of concanavalin A stimulated murine splenocytes was determined as follows. A single cell suspension was prepared from the spleens of BALB/c mice and washed into DMEM (GIBCO-BRL) supplemented with 2 mM L-glutamine, 1 mM sodium pyruvate, 0.77 mM L-asparagine, 0.2 mM L-arganine, 160 mM penicillin G, 70 mM dihydrostreptomycin sulfate, 5 x 10-2 mM beta mercaptoethanol and 5% FCS (cDMEM).

Splenocytes (4 x 10 6 /ml) were stimulated with 2 ug/ml concanavalin A for 24 hrs at 37°C in 10% CO 2 The cells were harvested from the culture, washed 3 times in cDMEM and resuspended in cDMEM supplemented with 10 ng/ml rhuIL-2 at 1 x 10 5 cells/ml. The assay was performed in 96 well round bottomed plates in 0.2 ml cDMEM. The Fc fusion polypeptide of KS2a, PBS, LPS and BSA were titrated into the plates and 1 x 104 activated T cells (0.1 ml) were added to each well. The plates were incubated for 2 days in an atmosphere containing 10% CO 2 at 370C. The degree of proliferation was WO 99/55865 PCT/NZ99/00051 determined by pulsing the cells with 0.25 uCi/ml tritiated thymidine for the final 4 hrs of culture after which the cells were harvested onto glass fiber filtermats and the degree of thymidine incorporation determined by standard liquid scintillation techniques. As shown in Fig. 6, the Fc fusion polypeptide of KS2a was found to inhibit the IL-2 induced growth of concanavalin A stimulated murine splenocytes, whereas the negative controls PBS, BSA and LPS did not.

This data demonstrates that KS2 is expressed in skin keratinocytes and inhibits the growth of cytokine induced splenocytes. This suggests a role for KS2 in the regulation of skin inflammation and malignancy.

Example 7 Characterization of KS3 KS3 encodes a polypeptide of 40 amino acids (SEQ ID NO: 129). KS3 contains a signal sequence of 23 amino acids that would result in a mature polypeptide of 17 amino acids (SEQ ID NO: 348; referred to as KS3a).

KS3a was nrepared vsntheticallv (Chiron Technologies, Victoria, Australia) and observed to enhance transferrin-induced growth of the rat intestinal epithelial cells IEC-18 cells. The assay was performed in 96 well flat-bottomed plates in 0.1 ml DMEM (GIBCO-BRL Life Technologies) supplemented with 0.2% FCS. KS3a (SEQ ID NO: 348), apo-Transferrin, media and PBS-BSA were titrated either alone, with 750 ng/ml Apo-transferrin or with 750 ng/ml BSA, into the plates and 1 x10 3 IEC-18 cells were added to each well. The plates were incubated for 5 days at 370C in an atmosphere containing 10% CO 2 The degree of cell growth was determined by MTT dye reduction as described previously Imm. Meth. 93:157-165, 1986). As shown in Fig. 7, KS3a plus Apo-transferrin was found to enhance transferrin-induced growth of IEC-18 cells, whereas KS3a alone or PBS-BSA did not, indicating that KS3a and Apotransferrin act synergistically to induce the growth of IEC-18 cells.

This data indicates that KS3 is epithelial derived and stimulates the growth of epithelial cells of the intestine. This suggests a role for KS3 in wound healing, protection from radiation- or drug-induced intestinal disease, and integrity of the epithelium of the intestine.

WO 99/55865 PCT/NZ99/00051 SEQ ID NOS: 1-409 are set out in the attached Sequence Listing. The codes for polynucleotide and polypeptide sequences used in the attached Sequence Listing confirm to WIPO Standard ST.25 (1988), Appendix 2.

All references cited herein, including patent references and non-patent references, are hereby incorporated by reference in their entireties.

Although the present invention has been described in terms of specific embodiments, changes and modifications can be carried out without departing from the scope of the invention which is intended to be limited only by the scope of the appended claims.

EDITORIAL NOTE NO 39614/99 Sequence listing page 1-169 is part of the description.

The claims are to follow.

WO 99/55865 WO 9955865PCT/NZ99/00051 SEQUENCE LISTING <110> Watson, James D.

Strachan, Lorna Sleeman, Matthew Onrust, Rene Munison, James Greg Kumble, Anand <120> Compositions isolated from skin cells and methods for their use <130> 11000.1O11PCT <160> 409 <170> FastSEQ for Windows Version <210> 1 <211> 696 <212> DNA <213> Rat <400> 1 aattcggcac gaggccgagg gaccaoaca attacra gcagctgcac ccggtccttt cctcctgtct ctgctgctac cccggcctcc ttcctggagg ttccccaagc ctgctgccgc gcccacagct ccggtcggcc cttccgccag tatgtgatgc catagtctgc gcggcactca ctctttzcccc gaaaagaagt cagcgaggtc cctgacaggg gcagctccag gctgacattc cgggcaggca gacagtcgaa tcccagagct ttgtgaggcc aagtggcggg cccggactcc ctgtgccacc tcattgcggt tcacgcgcca atgtggacca cacctgacag tggcttgcta ccagccagag rrr-, t- taa,ggttctgtgg tgcgcctgtg cagtggggaa agccttcagt caccaacctc ggtgggctcg gaagcacaag gagagaccgg ccggcaggaa ct Caga cagctggcgg gtcaacatgg gtggcctact gctgagggtt cccacaccag ctggatggga ctgacctttc gccacagcct gctggggggc gagggcctgg cagacagtcg tcccctgctt ctgtgtccct cttcagcctc ggaggaccca tcgtggactt tcatcatgtt actacccgtc cccatgcctt acttcttcca <210> 2 <211> 475 <212> DNA <213> Rat <400> 2 cggtatcgat aagcttgata cggcacgaga aaataaccaa tttaaggatg gagctgctct gacccagaag ctgcccacca attgtttcac gattcatccg agatacacct agaaggtatt agtgacacct tgtgatgcgc gtccagtgca gatgggtcag tcgaattcct ccaaacaaac actggtgttt gagatgagga tgattccaga tcttcatggt ctttggaatg gtgacccaga gcaggtcgac tttcctcttc gctgtgcctc actttttcag tggagctgaa tgaggaagat gaagcttagc accacttgac actagtggat ccgctagaaa ctgttaccac atgcagatcc atcagcagtt aacaccccac ctccaggagc cagcagaagc ccaaagaatt aaacaaattc tcacctccag gggataaggc acctatttag tgtcagtcac tgcctgagga agcag <210> 3 <211> 381 <212> DNA <213> Human WO 99/55865 <220> PCT/NZ99/00051 <400> 3 ctggagatcc tggggatcca ggtgatcccg tggctggtga ggttagtctt cgttccactg cgtccagaaa ggtttgtttt cagaagcact ctttccatga atttacttat tggatccata ggagacacta cagcttctcc atcttccatg tcttcatctt ctagtgtctg gcatctcttc tactgtcaag tttgggggta a gtagaaccag gacagggaaa tccttttcct atattatcat tcatcttcat gatatctgtg gcagatttgt gcttgaaact cactttcttt catttttagt ctgtgttaaa at tcc tc aaa tgtagatgac tgggctctgc taatttcttc tttgtcagat ccacatctct atggaacgca <210> 4 <211> 311 <212> DNA <213> Human <400> 4 agcgtggtcg cggccgaggt cctagaaacg gtggccacag gatcctcgtc tgcaaggtgc Cttcctcctg ggtgtgttgg cgggagcaca gggcccacac ctgcctgctg g actacagact ttgtgataag ctggggttgt gacctcggtg aggactccaa caggcgaaaa gcatctttgg cctcaccttc gcttcttcct ctttgggatc gctgaagctt gccttcatgc atgctgccta gccttcatca ctcttttcca ggggcatcgt tcactctccc ctcagtttct tcggactgga tctgcttctc 120 180 240 300 311 <210> S <211> 514 <212> DNA <213> Mouse <400> ctggagctcg cgcgcctgca ccactccagt agaccgggga aatagctatt tcacagcagt gaccatgatc agcccagcct ccaagtggca cctctgtcag aggcttcatt tactgtaacg tgctacaaca ctctaccttc gaagaacttg ctgaaagtac taccaacctt ccaaagtatg ggtcgacact c taaaacaga aacagaagct ggagcctctt ttgtggctaa atcgctctct agaacaacca aaagaatata tcaaagagtt agtggatc ca aattctgaga acctgctata Cctcatcggg atcctgtcca gacatccatt aataaacaat cctataccac acat aagcttaaaa aagcagcaag ataaagacct actaaaattg tctgtatgtc ccagtgggaa gttgggattc aacagtttag gagactccac aagcagaaga caacactgct ggctgttctt gctgtgacgc ttccggagga cttccgattt atgaattccc 120 180 240 300 360 420 480 514 <210> 6 <211> 1059 <212> DNA <213> Mouse <400> 6 ggcacgagcc cagaagctca atcggcctcg tgtctcctgg ctcttggtga ccagcatcct atttccatcc tcagctgcag gaattctcct cccaaggcca ccttttgata Cttctgccct aagtgt ccc t ttcactgact tgctgccctc tggggagccc ctgtgtctgc cctaccgtgt ggaaatctaa tccagaggaa cctcctcagc aaggaagaga ttgatttgct gtgtgcgcct cccagaaaat gcatgtgcat tccagagctg acagccagca ttgcagacag cagactggca tcgggttgcc ggataaacgt aagtcctcct gctgctaggc catctcccac acatctccct gcccgaggtg ttgttatcag tgtgtctgga agaggcctcc gcctgaagct caatcagatg gaaagacatg gccttgctcc tgcccctgcc tttgctggcc aaatttgaag agcccttccc agaggccaac gaagcagggt caggctgttc tgggcactgg ggccacactg tacctgcaag tatggctcag gtcatggctc gtctctgcgc tgt ct ctcc c tgcggagttg ttcagtgggg actattggag tgtc tgagga gcaccaaaag cacaaaagtg gggtgactat aatgtgaaga tagacctgcc aggacactgt acttctggca tgacactccg c cggat cc ta gctactgctc gaccagccac ctggttccct gcacaggaca aagccatcga ggcccagcct tggaggacct tcctgcaggc cttgagtagc ttatgaattc gaggcgcaaa gtcaatacgc ctgcccactg WO 99/55865 1 aaactggagg octccctctg ctggaggcag gacccactca caccctgcga aacoottoccc aacgooacag cacaggagtc agaaggatgg tatatcctgg agaatgtgga cttgoaoooc cagctotgot ttaagttctc atttgaaaac agcagccaog ttgaatgtco coaccagagt ggotctctoo catcctggac tgtgagcatg gatacccag <210> 7 ':211> 861 <212> DNA ':213> Rat ~CT/NZ99/0OO51 900 960 1020 1059 <400> 7 gaattoggca cgagaggaga ttagcaccta gcttgtttgt gaagaaaaaa aaaaaacaaa tgagagaaca gacccagttc agcaagatgg tgttgotctg ggttttggtt oaggctcooa ggttcttctg tcotcaccc ggctctggaa gaaatatooa gogctgggtg tcctggttgg tgatagactc cctggootta aaaaaagatt tagaggaagg tctactcagg atccogagtg gocagtgaga gacatcccca atcaotcaaa aggggtttoc ttottgaagt catcgaacct gaaagagaag gtctgataca aaaaccaaac tcgacccttg atccagtcag tattcatacc ccttactctc ccatttgcag cagaatcact gtcatggggt agctgaggaa tttctgtaga aggacctgcc tagaaagaaa a tgtgcacaaa ccaccaagta agtgggtact ott ctc aagg tattcttttg ctggctcatt cccactgata agctgatgtt cctgtattac gt tt totaga agaaagacag tgtagattgg aggctttcct gacaagtgac gaaacttgta gtaattgttg caaataagat tcctcccacc actttttttt tagctttccc ttcttcccag c tgtagatcg tctggtacat ggcagactaa ttgtgggagg aatgtgtcca tcgctccagg ttaaaaaatc ttattattaa aaaaaacgaa aggagaaaaa aggctgccaa ttaatctcca tcatgttgtg tcaagactgt taatgttgaa aggtgtctc gacaggagt c aaaatcaagt taacagagag aagacgcaoo tgccagtggg ':210> 8 ':211> 398 <212> DNA <213> Mouse <400> 8 gtoaccagoa aaggtggaaa gotgctggga ocagtcttag agggggatoa gaaatggggt cttcgtagcc ctggggtgga catgtctgct ggtttoooat ooccagagcc atgaaaaotc ctggttgcca agtggtgaaa caaattcttt cctcttgtgg ctccoattto ttttcotcct aatctccctc ccaccagttt aaaggaatgg gaaggactct caagtggtag tggtgtctgc cttocacaga aaacccacac ccaggataga ccccoctg gacagccctg gaatgtgaat ccagtccttc gatgcttttt caccctccac gtctggacag ggtctccaag ctttgcgaco caggtgggct ctctgcatac tgaggctcag .aactggggcc <210> 9 <211> 1060 <212> DNA <213> mouse <220> <400> 9 agaacattcg agaatatgtt cagcagaaac cttcacagac ggggttggga agggoctcao cottgcttao aoacaggtto tgctctcacc ttaoaccaag tatcogcca tgagaaggag aaaccatgot oagttttggg otgotaooaa gagtoaaggc tgogctotat oootgaoaco aggtaococg aogtagaooo oagaggatga gtgttggtoa oggtggatga atottoattt oaooaooaoo oogttttatt ggggocagcc atogaogoat aagoggagoo gototagotg ootgtcoooa octattggat gacaatgaga tgtattggat ootggtcogg aootggooto aogagttoaa tgotttaoog gtatogtgoa toaaoatogo gaaggotaog ootaooaaga aooggooagg ttgtcccooa tgtotttgog oooaoggatt tggotoaoao gatggotttt aaagtttgto ggoaaaggag tgootoagot gagtttotot toooototao oggootgoag gccacctgtt atottcatgg gaggccat aaaooootoo gtgotgtggo caoooatooo ogoagotatg gotgtgoagg atgoaagacc otggaagao o ggcagtgaoa oggcogag WO 99/55865 WO 9955865PCT/NZ99/00051 agaagcctct agggcacctc acagctagag tgctacacca ggtaccctgc ttgccttcct gacgaaacca aggccgcagc acgctccctg tctgcagatt gctaccgggg acagggagac ctgccttttg aaagtccaac cagagccttc aaggtccgaa gaggccacct ttctgctccg attcactgta ctttctcaga cagctgtgtt gggtggtcaa cccggaaaaa tacctctgga tctggcttgt ccaaagcagc catgggacca cattccttct gaggaagcca ggccatgccc gccagcaggg gcctaaatgg ccaggcctgg gagccccacc ttgactcgag tcagacatgg gacctttcgc cacatggcgt ggcctattta agt ccc tac c 720 780 840 900 960 1020 1060 <210> <211> 353 <212> DNA <213> mouse <400> ggaaagtcat ctacctgctg ggagaccgca ttgatagctt gcctaggagc aagcccagtg tgtgtagtag gttcggaagc gccttagcac agacaggcgt tccgcttatt gaggggcagg gtggcctcca actctcttcc cttgcttttc aaagtgcctc tgtctcattc tgagtcatct tcagagccgg tgaactacag tcctctctgg agt tt Ctgaa ctctcacctg gagatgctat gagatctcca gatgaaggcc gtacagtgat ctagaactac ccctacccat ttgaaacatg ctgtgtgtat atggctctga ggttaccaag agctctgtct gcatgactcg aga <210> 11 <211> 969 <212> DNA <213> mouse <400> 11 cggcacgaga gagtatgaag caaagagacc gacaaggtga tcttgtctcc atcatcttca ctatagaatc tccacagctg catccgggtt acagtcacgg ggatgaagtt tacggctgca ggacagcata ggcagcatgg cagaactgtg gctagtccca ggcacagtca gtaccgtatg gagaggctaa ccttcaaggc tatgtcgcct tcttcaaagg cgctctttcc ggatggagga ctgagcatca ttatgctggg ccgaagatga aaaagttcat gaagagtacg tgaagcggaa ggcctcacgc ccgagtacat gcgtccttc ccagagtctt agctgacctg tgatcgcagt cagccttggc ccaccgctgt ttgccaggtg gcctagggca acttcccctg tctctcctca cttcctgctc ccggtttgtt gtgtgccccg caagcagcta ccgctacctg gcagcgctat ggaaatgatc agagaagtca gagggaccga gacatttgca catgaactcc tatcatcaac gctcaccaag gggccagcct gcctggcctg gaggtcccaa aagtttgtga ggtcggcccg ggcggctgcc atccagaaca aagctgcgca gaggtggact attcagttcg ctgagaaaag ttcccagcct atcgtcctcg tccccgtctg ctcgtggtca attggtgagt tgaagtgggc gctgtgagtg agacagagaa actcttacac gtgactacgt tcatggagct atctcttcga gacagagccc tcaacctcga gctttgtcac aatccagaaa atttcaccaa gagttatcat tgcggtccaa tcattctgct gccatgtgca agcctggtca gctagcagct gagctttgag tcccatcttc gtacatcttc ctgtatccag gattggcatc ctcagaccgt acctttcgcc cctgtttgtt <210> 12 <211> 1411 <212> DNA <213> mouse <400> 12 ggcacgaggc aacttggaca aattcaggtc agggtctctg ataatacata tgtcatgtgt aagtgtaacg catgtgtagt tgtttggact tgtgcacgtg tgtgtatttg ctcctgtggc Cagaggttag gtaccttcct gttttggacc aggtctatca tctctgtccc cctgccccty cttgtccttt caagtagcct ctaaagctag aaatggagtc catttgaata gggtggttgt tgcacatgtg tatgtgcatg ctatctctcc ctgataagct ctccccccag ctagggatcc gtaccagcct tgaatttaaa gtttcagtca agtatgattt tgtgtgtgtg tgccatgtgg accctggtgg aggttggatg cc ctc aggt t aggctcatat gttagtttac agctttggcc cacacacttt ctccgtcttt tgtgtgtgtg gtgtgtgtgc tttttgtttt gcttctgaga acagataagt ccttgtgctt atgagttcaa tctcatgtga gtatttctct cttgtttgaa tgtgtgtgtg ttgtgggggc gttttgtttt agagtctgcc gccacaagtc actgactgag 120 180 240 300 360 420 480 540 600 WO 99/55865 WO 9955865PCT/NZ99/00051 ccacctctca ctctcttcag gagagactat ttagagtctc ttttgccatt ccctgagggt ctatctcagg ttctttttaa cacacatgtg atgttgggga ttatctgatg tggcaaccac aaaaaaaaaa tcgacggtat gctccctcag tgaccccttc tatcatatgg tttagcttta gatcctttat ctatctcagg atagatggat acttttaatt tacacaggta cagtcagatt gtgaccctgt aattttgctc aaaaaaaact cgataagctt CCCCgtttta cgttttcctt atgcataaat tgactgtaaa tagagatcaa ctaggccctg ttaactgctt gacattgtac cacacacagt ggtattgttt gcctactaac tatttccatg cgagagtact gatatcgaat cacgttaact tcactctttt atcatctgca ggattccgct ttagagtcgt agggtctatc ttctcaagac ttgcattctt caggtcagca ttgcactgtg agccctcact agtccagcat tctagagcgg t ttgtctcctg ctctgaatag aagtcaatcg tcttgccatt atacaaagac tcaggctagg gcttttactc atgggaaaca tagctggtat ctgtggaaca aggatacatt ctctactact ccgcgggccc tctatgcctg atttgtgtgc caggaaagac gattcagctt cttggctggg ccctgagggt tctcgttgaa gggtgaccca gttgttgttt ttggaaaacc ttggagtctc gcatagaagt cccctcgagg 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1411 <210> 13 <211> 888 <212> DNA <213> mouse <400> 13 ggcacgagag gaccttgacc cccctgcagg ccctgtccct aacttaaatt tgcttggggg aaagagcaac ttgccgatgt caggttatcg atcttggggc acttgttgct ctcacattgt tgacactgtt gtgataaaaa agccaagtgt ggtggtgtac ctgaatttga gagcctcctg acaccaacac ctttccccca agcaaggatg gctgctctga aaatggagtc tgattttagc tcctgatccc agattgctag katgttcatt gatttaaagt aaaaaaaaaa aaaaaaaaaa gacatccaga tccaaaacag aggggagcag ctcttctctc tgagccatct cagtgtacag tgttgatgag ccttaattcc gcccacatag caaatagaat gcccctcctg acctgcactt aactttgacc gctctttaca aaaaaaaaaa ccacgggacc gcacttctgt ttctagttcc ctcccactgt ctgtggccca cttggtggcc tttacacaaa agcactttgg tgagttccat tgtactgaag tgcacttctg gactgctgtg aaaatgggac ttttaaggaa aaaaaaaaaa cgaclzggatg cacaggatac atgaggcaca gtgggtagta cagagcactt tttgtcactg tctagtaaat gggcaagttc ggctgcgtag gtcacagtca tagacctagc ctccaccctg ttaattggag actaaccctt aaaaaaaa tctcaccctg tttttttttt aatggaggtc ggaattgaat atatgtggtt gcatgctctg tgaacccaag aggtagttct ttgcaaaaga gag aaagc at cc cggtgt ct acccgcctty ttgtgattgg tgggtaagaa 120 180 240 300 360 420 480 540 600 660 720 780 840 888 <210> 14 <211> 547 <212> DNA <213> mouse <400> 14 gaattcggca cgagcctaaa aaaagtcacc caatgcttga aaaactttcc attatggata aatttctgta cttgactccc tgaggttaca tgaaattgct tatttggcct gagagcagag ctgactactt tagaaaggca gttaaattga ggttttttgt tgtggtt tgctgggatt attaatgatc agtcactata atacattatc agttgagtac gatgatgtct tttttaaaat ctgtttgaag ttttttaagt aaaggcgtgc tgccagacaa tttgattagc tattattatt aaggtgcctt gttgaaagca agagcctgct cacaggccat Cwttagtgta gccactactg agagatgtcc tctgtaactg tatctcttgt tggtggtttt ttgtatggag ggaaaagcta gaagtaagac tagagatttc ccaggctgtt t t tttggtgc atacacaaat tcatttttgc ccaaggatct gcctgaggta gctggagctt ttgctttcta ctacattttt <210> <211> <212> <213> .<400> ctgacatgaa gccccctaag acccaaagat tggttcctgc tgtgacatgc ctaccatgtg WO 99/55865 WO 9955865PCT/NZ99/00051 gccacttctt catgtcctct ggcttgctct ggtctgtggc tctgttcaca ccaccctgtc aaagtcagat gccaaaaaag ctgcctcaaa gacgctgctg gaaaagactc agttttcgga taaacctgtc caagaccggg gtctggtggt gacggacatc aaagctgagg atgtggttct tgaacatcgt agctactgct cagcaagggc tcgggagaga aactttgctg gagaggtcct aggcatatgt cactccat <210> 16 <211> 856 <212> DNA <213> Rat <400> 16 gaattcggca cgagcggcac atggctcgag ctccggcggc tcctgggctt gggcccggcg tggcgggctg gctgtgcctg tgcggagccc gctctcccgc cggcggccac cggcggcggg tatgcgaatc acttcagtct tcttaaacaa cagcattgag tatcatctgt ttttaccctg gctccatgtt tgtgttctca ggaaaaccca tagacttctt gccctcattt tgaagaaatt agaagaagaa atacagagtg atgtcatcag ctgcttaaat atatcagaat gtcttg gagcggcccc gacgacggtg gtgatccgag agcctggcgt tctctgtacg aaggac acgc gtctttgttc aaatctggct tttatgtcta ccagatcagt gatttaggtg tatgccactg cttggtataa ctgctggatc gaagggggct gccggaggcg ctggcggccg ccgtgtggct tgaacatgac accagtggta agagttatct ggctgtttat gaacatctat ttcagagact ctggagatgg aactttctga atgaatggca gctgtgatca gcacgggcga gcggctcctc cggcccccck ggcgcggarg tagcggccct tgtgtgcaac tgaccaagga ccaactctat taacgggttg gcttaaaatt agaagtcacg aacaatgatc gaatacaggg gcctctgaca cttggcggcg ctccttctcc atgagactgt atgtggacgc ggcgggccag agagagaaat a cac agat ct cattcttttg ctaggaagag aatccggact aaaatcatga tggcagctcc ttccagtatg ttgttaaaag <210> 17 <211> 349 <212> DNA <213> Rat <400> 17 ccaaagaatt cggcacgagg gccgggcagc ccgggcgctg tgagcggcct ggcgggtgct agccgccggc ctcccgcacc tggagtacgg cttccacccc agactgggtg ggcctatctg cggctcggga cggcgggctc ctccccaccc cgctcgctgc gatgcggtgg gacctgggca tggcggcccc tggcgctggc tcgggcccgg tgctggacgc cctgggctaa caaatggcag catggaccgg acccatggtg ctcgctggcc gggctattgc ctggcggcgc caaaaccccg cgcttcgggc cagctgcgcc cctcaccaac gccatccgcg ctacaagtg <210> 18 <211> 1057 <212> DNA <213> Rat <220> <400> 18 cctgcaggaa gggtggcccc gtacctcccg cagagagtac aatgggacac tccttcccgc gcggaagcag ccgcaggtat gtgctagtgg ggcagggctg gaactcgtta tcactccgct cgttgggatt ccgatctgca ctgggacagt tgatctccaa ttttggagga cccgatactg tgggtctggt tccaagacac gtcctctcag ggatcttctg cagtatcggg atggagatca tgcaggtcga ggcggctgcc ctgtggccgc gccttccggc gcgggaagga gtactctctg ggggccaccc tgtcacagat cgcgtccctc tcccccaaaa actgtcccag cactagtgga atgccgctgg gtggagggcc gacgtggccg gtgtcccatt cgggagctac ttcctgcagg gtggataagt aacttcatcg cccttgcgtg ggctgtaggg tccaaagaat gtttatcgtt cacgcgacag ccacattcca acaggctctt acctgtcatt ctccatcagg cttggaagga actccaccaa aatgacaggt aaaagcctgt tcggcacgag gctgttgctg cctgcgagag gttccgcacg CCctaaagcc cacgcaaggc tgcagagct c gctcagtaat taccgtcact WO 99/55865 WO 9955865PCT/NZ99/00051 cccacagcct tatgctgtgc ctgccctgta accagttacc agtatctcct caggggaaga ggct ac agc c ccttcaaacc tgccccggga gctccaaggc actcccaggc gggagc tgag aagaggcctg aggacaacga tctggggctg ggtcgtctgc agggctgtcc agtgcatatc gcagaccctt tccattggca aacactggag gccaatgaca accgagaatc gtgctactga cggccaatct tcagttgtct tctcagagcc gtgagca ctgaccacta tcacgccgtg aagcagatcg gcagaaatgc ttgatgcctt tagtttatgt cttcctgcgc gaagaagctc attgttccac tcactgcacc catcaccgga ggacatcaca 720 780 840 900 960 1020 1057 <210> 19 <211> 750 <212> DNA <213> Rat <400> 19 ggcacgagcg cggatggcc c tcttcccaac catgatctcc tgcctttgct tccccaaggc gggttttcct agaaggtcca ggccattggg tggtataccg ctgtagctgc cccacgtgag caatgcatcc gcatctcaag tggacgtggc ccatatccag tggatgctct cgcagggact ccacctggcc ggtaaggatg cctggcagga agagcgggt c ggcaagaagg ggcagtagcc cgactgccca agtggcaagt ctgctgcaag acgcgcgggg aaagaacgat tggcctgtgc tccagaaggg ctccaggagc gccaagacgg caggcaaccg ctcgaggacc gacctaaggg gagccaagtc tcaagtttga tcgtctgcag caggactgag cacagaggca ttagatgaca ccttccgtgt tggtcctcaa accaggatcc ccaggacgga aggaaaacaa caagggggtc caagaaaggg ggccttttcg caagattctg cactaccaga agaagacttg gtttttagaa gctgctgacc ctggtgtgca tcaggaatgg gaccgagggg ggaccaaagg agtggtaccc gaacctgggc gtggcggtaa atgaatgagg gcagcaacct atgaagcctc aggtgaccac caatgcttgg gtctgcctgg tgggaagaat acagtggaga gcaaagctgg ccgggaaaca tcccaggccc ccaagagtta gaggccacta <210> <211> 849 <212> DNA <213> Rat <400> gataatycgg tgcgacgctc tccggcCtcg cctagaagag tacaaatgaa gaagaaacca gtacactgtg cattacttta gaggtcattt caatcttttg tattatccta aaaagaatgc attaatgaat taataaagcg gcccggggg s acgaggggc gtgggtgccg ggtctgacgc gtcaaagtgc aaatccaaga gaatttgata aaaatcagta actggagttc gatcttttgg aaacctatct tgtagaaaga aaagagaaag gttctaaaga tgggtggaat cgccgagt cc tgttcggctt gccacagcat tgctggaaaa ttgagacgga atgaaaagcc attatggatg atcaggttcc taaaaaacct ctgtggaaag aagcagaaaa aaaagccttc aaatttatga cccgagagaa cgccgggtcg ttcctgtcta ggcttccgct gtccactagg actaaggaac agctgctgtg ggatcagtca tgctgagaat caatggcaag cagttcaaaa cacacgatgg ctacgacact agatggagat gcaagccagg gtgtagctcg cttcagtgca ttggaggagt aaaagactac aagatgcagc gttgctcctc gataagtttg gtgcaagtac aattactcca aaagtcaaga gactacttaa gaggcagatc gatgacatga gaagacacag ctgccgacgc ccgctgcagc tgcagaaaga gtgatactct agaagtcaca ttacaacagg tgaaaatcta acttcacaga tgattgtgaa ctgatacagt ctcaggtgga ctagtgaggg agcgaaccat aattcctgca 120 180 240 300 360 420 480 540 600 660 720 780 840 849 <210> 21 <211> 312 <212> DNA <213> Human <400> 21 ttcgagcggc cgcccgggca acctcactca cactcagccc atggcctttc tgctctggag gtagaggact cacagtcatg ccaggtccgc cttcctggga ggtaccagca tggcatctcc ctcgtCcctg gggcttgcgc gtacctcggc catgctgtgg tctcctggct tggctgctga tctgccttgc cgcgaccaac tgatgctggt ctgtttgagt agtagtcttc ctctgcgggc gctaatcaag ttgtgttccc ggcagcgtca ctcactaaca atctctgggt cttatcgata 120 180 240 300 WO 99/55865 WO 9955865PCT/NZ99/00051 ccgtcgacct cg <210> 22 <211> 1023 <212> DNA <213> mouse <400> 22 gcgcggcccg gacgccagat gagccacccg aatgtagcgg cggaagaact tttggcaatg gaatccaccc tcctatctga gccacatcac ctggcgctgg cccatgtzacc gaagcactta cctgtcatga actgccggcc agaagctctc gacagcttca atgatgtttg 9gg ggggactcac ggtgggcagt aagcccctcc gctatgccag acctggagac agcccaaggc cgtcttggca cttggggcat caggagagca ttgtggcagg ggtactcctt agttcgtcag tgatgggaaa tcatctccat c agc cac cac cctcaaattg gggtcaattt attccccggt agtggtactc gcagtcctgg Ct tt atggt a aggcaggggt tcctgatgag ggtcctgaag actgcaggaa tttcacagac cctctactgt tgccagtctg cttccctacc gctggtgtcc tggagtgagc actctctggc gcaggatgcc attctcctgt cccccctccg gccacactcc acacagctgt cc tggc tac c ctctgcttcc gttCtcctgg ctggtcttct agagtgatga tcccagtttc gtcctgcgca tcaaatgtgc caggtgctgg cggcgcagct atgtttcttc ttggtcctac ctgtttgcct cttttcacag ccccacgcgg cttccttggg ggCtcttccg tcctggtgca ccctggtgaa ctccgcggac gtgcctcggg ctggcagcta tggtgctgat agcagccccg ttagcagctg cgaaggcctc atgaacactg tatccagtgg tggcaggcta ataagatgtc taggctcact ctgggccatg agcaggtgga cttcttgttg gtacttaaga agcctgtgtg agagacagcg tctccaggtg cggggccaca gaaccgtgtg tcatggtgca gtgccagtat caaggtgatc ggaatacctg accagagcct tattgctttc atcggtgcag actggaacag 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1023 <210> 23 <211> 997 <212> DNA <213> mouse <400> 23 ggcacgagga catgctctgc ctttgagtcc cccctctcaa caaggacctt gaaaaaactg tcaggagatc gaagatt ctt ggact ac a c ctcgacgatc gaggcagacg cagaacctgc cagcaacaac gtcactctgg attcatggca ccacgaaagg aatggaggtt cttctgctag ctgtgcctgt aaggggctt c gagttctcca gatgggcaac aggctggtgt atgcagtccc aagagcatgg ctcctgcacc ttcgatgtcg gggatgtggt actgcccccc atgtgcatcg cggggcaacg tatgagcaga cttgtggcag ctgaagaccc tacttgctcc atgtgcccat ctgccgagct cataccgcca tggactttga tcaagagtct tgcgggacct ataagaatgg ctgtggagaa gtgagaatct ggaggcacct tggacagact taggtggatt gcatcaatgt tgaaacggct gctccttggc gaatggcc ct tggcggtggc cgccggggcg gaaatccatc atggaagcag agagtttgta ggacaaaaag gggtgtcaag cacgatgacc cat cc cggag gacagtccca ggtggcagga gaaggtgctc cacacagatg cctcaaaatt tgtcggtagt cggagccatt gcggaaa tgagcaaccg gctcagactg ttcaaactca aaaattgtgc cattacctcc aatgatggtc atctcggaac atcgactgga atcatcctgt gatgagttca ggtggggcag atgcaggtcc attcgagaag gcccctgagt gatcaggaga gcccagagta.

gtctcaccag agttccagta gtgtctttat aagcaggtga aagatcatga gaatcgatgc agcaggcgga acgagtggag actggaagca cagtggagga gggcagtttc atgcctcccg ggggagccaa cggccatcaa cgctgaggat gcatctaccc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 997 <210> 24 <211> 529 <212> DNA <213> Rat <400> 24 aaagcttcca tcctcaacat gccactagtg acgacactct tctacgcctg cttctatcac tacacggagt ccgaggggac cttcagcagt ccagtcaacc tgaagaaaac attcaagatc ccagacagac agtatgtgct gacagccttg gctgcgcggg ccaagcttag agcctggaat gatgtcgacg ccttgttcac cacaaagaac tggttgggtt acaccaagaa gagagcaccc WO 99/55865 WO 9955865PCT/NZ99/00051 attggcttcc atcgagttgt caggaatatg tcaatctggt aagtgccatg atgttgtcat gcatacagga gcaaagtaga agcagctcgc aaattcgatg ggaaattttg ggaagatgtg tgatacttgc taaaggatct gaagaactaa cacaagaaca gacacaaagt cgagacctga gc tgaggaag ggttcttttg gtgcccctgt ccagatattg tgaacttagc cactaagttc aggatcgtca acagttgctt agaaaatcga tgtcatcctc ctacccaga <210> <211> <212> <213> 1230

DNA

Rat <400> aagaat tcgg gctgcgtgcg ggcgcccgcc gaccaagcag gtacttttct gtctcagtct tcttggggtc aggcgagc tg gagactcttc gtactgtttc catgaatgac ccacatcttg cattctcagc cccctttgga ctacatctcc ctatgtcttc atttgtgtcc tatggtgaag aagtacactt acctcatccg cgggggatcc cacgaggcca tggctggttg ggcgggggcc gagctctcgg tcctgaaccc ctgtggctgt aggctgctac tccggctcgc cacttctacg ctgttcctgg acgcagttcc gctctgtcta gagtgcttct gggctggtct aagaacgtgt ggaatgatga aatctcagga gactggtt cg atggctgtca ttcagccaag tacccaaagc agcgcagccc tctgcagctg ctacgggaag actagttcta tgctggccgc cgagctgcgc ggcgccccgc tcgtctcagt gagcgccgtt aagccctggg cc ttct tagt acgtcagcgt actatgtcct acgctctggg tgttct tc tg gaaataagaa agtatgtgtc ccttcgggct ccttgtctgc ataggaaagc aggtgacagg gcgcccgcca accaagcagt gagcgccgcc cgccttcctg gctcttccag cgtctgcagg gttatggaat tccaagctgg gatggagtcc gttggtgttc cttctctaac tgttggcctg gaagaatcta gtcctctgcc aggtgtggtc ttctgctaac ccacaacgta gttcttcaac tttcctcCcg ttcccttcct ggctgctacc ccggctcgcg ctcgcactgc gacctcatcc gccttcgacg ggctccctgc ctttgggctt aaggcttctc ctctgggtcc acggccattc accgtactga ctgctacaag catcagtata atccactgcc tacctagcag acctggtggc cacaggttct ttcttgtttt cgagacgctg gagctgcgcg gcgccccgcc tgctgcagct gctacgggaa tccccaagag tctggttcct tgctcagaac ggatacaagc atagtcttcg acgtcgtgca gccaagtgcc ctcggtggtt agtgccacgt agcacagaat agctgatgat tggtggtgac acaaaagcac gaacaggctt agacaggctg CtCttccagg gtctgcagcc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1230 <210> 26 <211> 393 <212> DNA <213> Rat <400> 26 ggcagcaaga agcaacccgc ggggtaggag tgggagcagg ctgggagagc tggggagccg ggcctcctgg gtcatcacca aggctctcct cctctggacg Cccaggcaca ccaggccacc cgcgacggtg cacccggagt aagctaggag gccagcagga ggaagggcct tgaggccact acaacaagat acggcagcca c cgggagaga tctgtcagcg gggtctgagg acagactaca tcttgccctg ccccagcctg aggc ctgc ct aac agggcagggg aagccattca agagaggatc ctgcttctgg tgtcccgggc ggccgtgacg ctgcctggtt aagcgagcag ctggcgtctg gtctggcatc agcccggcct gcctgatggc <210> 27 <211> 778 <212> DNA <213> Rat <400> 27 ctgcaggtcg acactagtgg aaaataaaaa aaaaggaaat aaatgaaatg gaaaacattt aaatcagatg gagctcaatc acctcctgga ttcgcccgcg cactgttgta aagaacagcg tttgcgcagg tgcctccctt atccaaagat ttacttagcc attacacaaa tgcaggcgct accaggcagt tcacatttag cccccacccg tcggcacgag gcatgtcagt tttaattaca gatcctctcc cagaggcctg cgcatctggc cgctttgtta ataaggcaca cacccaaatt attctaggga ccCtggtttg gctcttgcag gtagtagcag ggtctacctc tttgcttcat ttgagtgtac ataaacatgc cagtctgtgc gcaggaggat tttttaacac tctaaatctc 120 180 240 300 360 420 WO 99/55865 WO 9955865PCT/NZ99/00051 tgccttcCtc aatcaatgtg gcttggtggc aagttcaagg aacaactcct agtgacttga gcacagtaag ttttgggttt acttgccttt ccagcctggt attgaatcca gctcctgtca tgacctctcc gtttgtttgt aatagtagcg ctacacagtg ctacaggaag cagcctttcc atgacaaagg ttgttttgtt cttggtagac agaccgggtc ggggggcgcg agcaagggca gcccccagac ttaaagaaaa agaggcaagc t caaaaacaa gatcactgtc agcttCttta agcagttata acccggccat ggttCtctgt aacaacaaaa tgcaaactaa ttagttat 480 540 600 660 720 778 <210> 28 <211> 1123 <212> DNA <213> Rat <400> 28 gggccccccc ctagtggatc cgggtgccta tgc tcaggag tgtgtcaaga agtgttgcca ctcctggcat gggccaaggg atggccccaa tggcttCtct agaccaacat gcgtgtattt accttatgca cagatacatc gaatgggcaa tgct t tttga ggtgagctag taactgttac tttaggggct <210.- <211.

<212.

<213z tcgagtcgac caaagaattc cagcccccat gcagctcgtc tgaatacatg tggagattat tccaggaaac tgagaaagga aggatagaag agcgactcac tggaaacttc cttcaccttc caatggtaac cagcaaccat cggtgccctc aactaagtga ggttgttagg attggtcaca aggaagaata gktatcgata ggcacgagcc c agc t tccc c tggtggcacc gagtctccac ggattccgtg catggaaaca gacaaaggcg ggatacccag ttcagcaatc ttcgatgtca agcatgatga acggtgttca gcagtgctga catggggacc tgaggaagtc atctgagggg ctgctactca gaccacaagg agcttgatat tgaggcgact ggggagattc tgctggcttt aagctggagg gttaccaagg atggaaataa acctggggcc gggtgccacc agaacagtgg tgactggtag agcatgagga gcatgtacag agttggccaa accagcgctt aggatagctc tgttggagtt ttctaatggc taatattccc cgaattcctg acggtgcggg tgccgatttg gcttttcCtc actgccccca gccccctgga cggagccact tcgaggggaa agagctgcag cattatcttc atttggggcc cgtggaggaa ctatgaaaca aggagatgaa ctctaccttc catgctaagg gggct t ctc t ataccaatta aga caggtcgaca tgccgggtgc tcacgagcca ccattttgcc gactgcagca cccccaggtc ggccacgaag cgggggcagc attgcgttca agcagtgttg cccgtatcag gtgtatgtgt aagggaaaat gtctggctaa gcaggctttc gcgatttgta atggagtatt tgttggatac 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1123 29 849

DNA

Rat <400> 29 aattcggcac gttattctcc tatgcttggg ctctgttgat tatctacatt cggcatggcc tgcaccgggc gaacatagtg ctggagaaca ggc cc agc ag ctgccacaga cctaattctc ggttggtttc gttcagggcc gacccagcc gaggtgccct tggttcactg gcaacttcac gccattggca agcatcttct atcttcagct agcgaggggg cctaccagac agggccaagc gatgcttgtc ggtggcctga catgctgccc ttcccctcct at ccaggc ct ccgccgggtc gggatggagc tgcctgccgt gaacttgaag gctgttgaca tatcctggcc tgtttcttgg actcaagcgt tgctgctgca tgagctcccg aattgactcg tgCcccccgg accttcttta gtcatgtgcc ctccattcaa ccccatcact tatgggccaa acctggggct ctgggtgctg tggcttggtt tgccgttggg agcccttctc ctccgctcgg tcagactcac gggtactgaa ctggacctac ctcggaggtc gacacctgtt ataacacaca tgatcactgc gcttggcgt t tgggctgtgg gccaccatct gacactggcc ctgctgcctc atttcttcgg ctgcagaccc gctgtccctg aatggggtat ccagctgaga aacc cc tggg accgccgagc ctctcaggct ctcaggctcc cccagcggga tcctggacat gcttcagtgc gtctaccaca accttctcag ccttgcaagc gccgtcctgg cctccattcc agagcccagt ctagaactgt tgtgcagagt accccaaggt 120 180 240 300 360 420 480 540 600 660 720 780 840 849 <210> <211> 1015 <212> DNA <213> Rat <220> WO 99/55865 WO 9955865PCT/NZ99/00051 gaattcggca ggctgcctgg caaagcgagc tcctggcgtc gggtctggca gc agc ccggc cggccgtgat accgggacta ggctatcggg atcagagagc caatgagcag ctactacttt aaatggccaa gctctcaggg tgtgggtgat tctcgtctat gctggcactt <210- <211- <212.

<213- <400> cgagggagca ttggggtagg agctgggaga tgggcctcct tcaggctctc ctcccaggca ggccgcgacg cc tgggc ca c cctgcggggg cgggtacctc ggacattacg gctgtccatg tccatagctt ggtgcgatgg tacattggca tctgactggc gctcctagtg agaagcaacc agtgggagca gctggggagc gggtcatcac ctcctctgga caccaggcca gtgcacccgg gtggggagcc agtgctcggt cgccagccga atgccactac ccactgtcta ctttcttcca tgaggctaga tctatgccag acagctcccc gagggtgtga cgaagctagg gggccagcag cgggaagggc catgaggcca cgacaacaag ccacggcagc agctccggga cgggccgcgt gcccccacga cacaccccta cggcaagttc ccgggccagc gt t tt ttggg acctgaggac catcaaaaca agtcttcgct cattggtcca agtctgtcag gagggtctga ctacagacta Cttcttgccc atccccagcc caaggcctgc gagaaaggcg ggagaggcag tcagccttca cccttcgacc acctgccaag ctacagtttg gggtggccaa caggtatggg gacagtacct taaaatacag gcgcgcatac cgagggcagg ggaagccatt caagagagga tgctgcttct tgtgtcccgg ctggccgtga agggcgggag gacctgtggg gtgccaagcg gtgtgctgct tgcctggtgt atcttgtcaa agccagcctc t tcaggtggg tc t ctggat t t ga ac ccgga cagga 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1015 31 452

DNA

Human <400> 31 ttcgagcggc cgcccgggca ttgttaggaa aatgtaggct tgcgacacac ataattgtcc atgtgttggc aggccccatt ttttagggct ttctgggaat tctgagtgag ctaactgaca tcttttctgc tttttaacag caggacacca aggcctactg ggttgaaact accagtagaa caatttttaa aaatgcataa tgtcttgaca caatgaaact gtgtcttcag cactcgggaa ttagaaagaa aatgacattc gattgatggg actgcatagg gagaacct ca gtcaggcatg tcagggagga cc gagccgggag tctattaata gagcatgaag actcatgtgg gctggacaaa tttctgctcc caggttgact gatgtattgg agatctgagg cattttttta tctgaatgta gcagccttga tctctctggc gtggtgagtc 120 180 240 300 360 420 452 <210> 32 <211> 434 <212> DNA <213> mouse <400> 32 accaccaagc agatggaatg attgttaaaa aattgacatc agagatgaaa tttttgctaa agtcctgtgt ttgcacttcc acatattctt tttcttggaa tgtgtgaaga gtctggtcac gcccattttg gtccatgtaa gaaagagcgt cgcc ctggcacacc agaaatattt acttcaaccg tgtactgtta ttttgaatgt ctttaccaat c agctg ca ac catgcacctg acagaaatag aagcttagat aagcttgaac tcccattgtg attgttcctg agtaaatcac catggcgtca atacctgttt gcacattagg cccatgttga gacaccagta agtggcatcc aaataagaaa caggtggaag gaataaagtt tgacatggaa aagcctcttt ccaaaacagg actcaatgct aatggtgttg 120 180 240 300 360 420 434 <210> 33 <211> 903 <212> DNA <213> mouse <400> 33 ctgcaacaag gctgttggtt CCCtgggccc aatggtcaca tttttcccac ctgctgccct ctcccagggc ctcggcggcc aggggtcgac accagagaig gtatttgtgt tttctgggat cctctccaat gtcacctgct cacctgagcc actacgcgga ctccaagggc tttattttta gggctccagt gaagacccca cagcccagag Ctcctacctg ctgcaccaag ttattttttt gaagggctcc ctgggtggcc ggcagctacg aagcggaaga ttgcttttgg taatgtcctt tgggcctggg agaaacgcag tgggccagca ggattttcta gttttttctg tctttgggta 120 180 240 300 360 WO 99/55865 WO 9955865PCT/NZ99/00051 atagagaaat gtatctgggg agagagaggg cgtcactcct cagagacagt attatttttt ccccaaattg caacagctta ctgcctgcct cct ctctgcaaaa ccacaccatt gcctgacctg gtgt tctggc ccccgttttt aaaacaacca attccttcag accctattct attctggcca gactttgctg acctgtgggc ctctctttcc ctcttgagtg aaacttcgac ggatgattat ggtctggcct cttcccagtc gtaccctaag accaaccagc ttgct cctgg Ctccctagct cctttggagg aattgacttt cacatctact gcccaggctc atctgctgca ccccaagatc tggagctcaa agccaaaccc ccaggcctcc tgtctctgac tatttccttt cccccatccg tattccacat ggtatagctg tccagcccct ggaatgtggg tgcagcctta tctcctgcct ctgtgaggat tctaattttt tccagaaaag gtgcaggttc tctcatgccc gc cccagt at <210> 34 <211> 1359 <212> DNA <213> mouse <220> <221> unsure <222> (644) (644) <400> 34 caaagaattc ggcacgagac ttgactgtaa tcttgctgct atcctggaca gaaataaaac gaacgcaaga gtccttatgt atacagtagc tttggaaact cctccagaaa ataatgggaa aacttcaaga tgctgttctc aagatgtaac agttcaatac tccagtatta cattctgcaa ttcgggcacg aagtagaaac aataatgtct tcacagaatg ttgttctatt tttgttgttg gattgctaac cagagtacct agtattttaa acaaaactct aagatacagc tgccacactg gtgagcaagt aagcaccgtg tgtagtcttg tcttccaaat gttcttaatg cagtgcttta ttgtaacttt gtaggttata aagtacattt cagctttgac tttgtatcca acatttcttc gaattaaatc ctagctgaaa gctcttttta aaagtttgaa cggcctcact tatatgtaca tggactattg cgccatatgc accagcatgt gaatggttaa tatttttatg acaggaatgt atgtcattct ccagtggcaa gtacctctag ttactgttct Ct attcttgg gaatttcttt tgacgaagag cagtcttcgt agaacgtcca agtctagtgt aacatatctc acagaatgtg aggttcagct actatacata aaaaaaaaaa atgtctgcca tgtgcttata ggaatatttt tgtatagtga gcttgctatc gccatttgtc ctattggacc gattgtatcc gttgtgtcag attccaaggc cgactgtcct tatggattgc caaattccgc agttagccta caccttagaa gcaagtaagc tcgtagttac atgttctgtc atatctgctt aatagacgaa gaaaatcagt gcatttatta aaaaactcg ttttcaattt tccgatccct ggaagtgtgc tggccttcag agactgtaaa tctgaacatg aatgagctga atcaacctca gactgctttt tcctttgact attnttattg attcatattt agtttattac agagttggct agaaaagcag accgtgcagt ccaaaggtgg agcttgaact tagtctgggt tatcaaagga tactgtttca attaattact tcagagtctg ggcacccagc ccgaattggg catcctcttc caaggacttg gaatgagata atgaataatt gttctctcac cataaggtt c agggcttcaa agaaaaaaac aaaccctttg aggtgtttaa tctagtcaca caagtgagcg cttcgttctc tatttgtggt ggaatctctc actatgctct tacttacaag aaacaaagag gggtttaact 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1359 <210> <211> 797 <212> DNA <213> mouse <400> aattcggcac gaggctagtc ggttgcgggc tcgcgcctgc catctggtgg ggaacacagc cttaagtcag gaggaggctc cgtggatcaa ctcatggagc tccCcccacg tctatgtcca taacggaggg gatgggctgg tatctattac cccaaaagac gaaaatggac attcctttcc aaccctagcg gaatccaacc gaatgtccgg cacgggtcat gccggggctc aggc cgtgga tggccgggtt agagtccccc tctgtgcgcg ctaacaagcc ttggtgaaat agacttactc gctgcggacg cagccagcag ggagaccatg ccaagagctt gagctgtgcc gactgtcttg acacctcaaa cctcttcact gcccccagag atctcactga ctgctggggc agtgtgtgtc gcgggcgctg tttaacgagt acggctattg gtcatctgtg C tt tttggt t gggctagtga gatgggatgt cggcacccaa tggggctgct gtgcaaggcc cggtgaagta atcagttcag ccaaggctta gccccggaaa accagccaac ctcagtgtca agagaaggga gaagtctgca WO 99/55865 WO 9955865PCT/NZ99/00051 actcacttta ctggccgata aagaagtacc agctgaacct taagggaggt gggtaggcag aaaaaaaaaa aaactcg tcattacctt gggggtcgct ttgtaccacc tgctctagag gccatcttac cctgacacag agtgtgtcta ccgtctacag gattctcaat aaagacttgg tactttctgt cttgaaaaaa 660 720- 780 797 <210> 36 <211> 896 <212> DNA <213> mouse <400> 36 ttaaggtttt cagactttat agataccatg cagctccctc cccatcccag atttgcttag agaagcagat ggatgcttca tgtacctgtc cttggctgga ttacaatgga ccaactgagg aaaccaggaa tgaccgcact tggttaggag cctggctagg aagcaatgga ggtcagccac gaagtgggta aggccagctg ttccagcctc cggggacagg tcagtttttt gatatcacag gtgaggctgg ccctcagcac atgttacttg gtttaatgaa agttctcacc caattacaca ttcatggtat tagcctcgga tttgtctccc gtttcagtca ccctgggcag gatgccctca tccacatcag tatct t tgag accctatcgt aaggccagtc caaacacatt tattgtcaca acacaggaga ggccccctca ttaataacac ttgacattga tcaccgaagc aatgtgctgg tttttggctc taactgtcac tattagacca aaatcaaaca agatggatgc gatgcactcc agggcaactt ttgggaagta gggagcactg gcagcttaag accccaacag acaaacagtg cacatactga aggaagaagg actttaaaga tatagtgatc tcagatgagg attaaaagtt aaatcaatgg agctggctac ccatgttcag agatgtagcc agatgatgtc ggggtccagg tgggacctaa cccctcctgc cctagcaatg gttagtaaca tcagactgcc cagggaatgg tctgccttcc acgatcatca gctgtgagtt ttgaagaaca tcaggcaggt ggtaactgaa tggcttctac ccaattatta ctagcctggg aaaggaccca tcagggacac ggccag 120 180 240 300 360 420 480 540 600 660 '720 780 840 896 <210> 37 <211> 501 <212> DNA <213> mouse <400> 37 ctgcaggtcg acactagtgg atccaaagaa tggaaggggc ttgtaggtgt cgggcttttt cagcatcgtt cttatatgcg actaacagaa gttcttcaga cacttctggc ctttgcagtt gagttcaaag acatggatgc cacttcagaa aatcacccat ctttttatgt gtttaaccat gcaacaaatt cttcaaacct agatgcattg tttgactcac tgcgccgtta agctttttac agtattggag tttggggtgt a ttcggcacga gccctagccc aaggaagatg acctgttatg ttaaagaata cgtggtcgag tcctctaata aaattaaata gaatcatggc acgctgcctt aatcattacc gcatagttca agacatttga tgctgttccg catcgttgaa acaggacaga gccgtcgctg ttcagctgcg aatagatata tatcgcaggg t acc t taagg gccttcagat gttacgaaag cacagaattg <210> 38 <211> 766 <212> DNA <213> mouse <400> 38 gcagcaccca gcgccaagcg ggcgtactgg agcgagccga cgggcggcat cccccggccg ccaccgcgcc cctccggcca ggcgctgtgc gcctcgcgcg gatccgctac agcgacgtga gaagatggtt atcgtcacca ctgcacccta agctgcagag aagcgcaggg tctacgaaga tgagagactt cagcagagga ataagacaaa ttatatattg tagctgtgtg tgaaaggctt caccaggcac gcagagcaga ccgcacgcac gcatgaggct tggacgggtc agaagctgga ccaaagagca caccaaacgc atagggtgga ctttgcagat ctatgaagct ccagatgtga cgcgacagac gagaggcgtg aggccggcgc cctggcggcc caagtgtaag aatgaagcca tgtccaaggt ttcatcaagt cgatcatgga taaaataaaa cttcttacca gatccagctc ggcaggagca cttgaaaccg cctccttgcc gcgctgctcc tgttcccgga aagtacccac accggggcca ggtacaatgc aagaaaaact gccctttctt gggtcagttt gcctgcgcac cccatcgacg agaaccaagc tccctgctcc tgctgctcct aggggcccaa actgcgagga ggagcactgc ctggaacgag ccaggccagt tctcacaagc ttacatttta cagacttcat WO 99/55865 WO 9955865PCT/NZ99/00051 tacaagtggc tttttgctgg gcggttggcg gggggcgggg ggaccz <210> <211> <212> <213> 39 480

DNA

mouse <400> 39 ggcacgagga agcctcttcc cgcctggcct ggcattatga tggctttcct ttttagtttt aatcattctc acatgcttcc gtaggcccca gtccataagg caggaacgcc caggagggga ctgttgcttt tgcatgttta cagatatgca cacgaccttt catggaagca atgcagtggg tttacttttt atgtttgttt aggtgtgaac gggggagggg atatagacgt gaattgtgcc cactctagga gtcagtgtgt agtttagttt ctgagaggtg acaccccctt aagaggtgag tcctgtcgat tactaattat gagagaaggc ggtggatgtg gttcttttcc ggggctcaaa actgcttatc ttctgcacag ccttgggaga agc aggggac ctctgggctc tgtactgggt ttccccaata tgtatagaaa acccatttga tcggacattt tcatggcctt ttgggtaccc <210> <211> 962 <212> DNA <213> mouse <400> ggcacgagat tagcggctcc cattcatctc tctctcattc aaatgatgcc acagaaatcc cagcaacagc accctgaatc ggatcgaaac agtcgagttc ggacggccag tgcaccagca gaggagctct caggagtggc gcagtgtcag gacggcagca caagaggtac acccgtcagc caagcccgcc cagcaccaca gagctagacc tggactgact ctctctcgag cctgccattg aagcccagca ggctgtcctt aatgagtggt ttgcagtgaa gtcatttctt taaaagcacc aa tcagcccagc ccctgctctg tttattcaca aagccaggaa aagtgggctg tcagccctct actggatcgg ggtgtgtcaa cgcgcaccta acaacgagtc gagagcggaa aggaagcatc ctctttcctc ctctgggact agccaggcat tgatgctgca aaatcctcca catcctgatg tgtggttaaa tggaggcagg cagggaactg gaaggagctg a ggaggctac cgacaagacg caaaatcacc cagccacaac gagagccagc tgctacccag acttgaaagt agcttttcct cctgtagttt ttctgttaca ctcatcatgc agaaactgttI cctgtcccgg catt t cagt a cggtccacca gtgtgcgcgg ggaacaaagt cgcacccaga gtggtcacgg tttgaaagcg aaatccagca atttgattgc atatgctttc ttgcaagtgt ccatcccctc gtttaaaaaa ttcctcctgc tggcttttaa cacaccccag gcactggact aatacatttc gcgagtgctt actggagccg ggatccagct cgtgcaagtg tgtcgccagc agcacagtct ttggaagact tgc tt tgat c ctcaagatgt Ccccatccca aaaaaaaaaa <210> 41 <211> 794 <212> DNA <213> mouse <400> 41 ggcacgaggc tagtcgaatg cgggctcgcg cctgccacgg ggtggggaac acagcgccgg gtcaggagga ggctcaggcc atcaactcat ggagctggcc ccacgtctat gtccaagagt gaggggatgg gctggtctgt attaccccaa aagacctaac tggacattcc tttccttggt tagcggaatc caaccagact ctttactggc cgatatcatt gtaccagctg aacctgccat gaggtgggta ggcaggattc aaaaaaaact cgag tccgggctgc gtcatcagcc ggc tcggaga gtggaccaag gggttgagct cccccgactg gcgcgacacc aagcccctct gaaatgcccc tactcatctc accttggggg cttaccctga tcaataaaga ggacgctgct agcagagtgt ccatggcggg agctttttaa gtgccacggc tcttggtcat tcaaactttt tcactgggct cagaggatgg actgacggca tcgctttgta cacagagtgt cttggtactt ggggctgggg gtgt cgtgca cgctgcggtg cgagtatcag tattgccaag ctgtggcccc tggttaccag agtgactcag gatgtagaga cccaagaagt ccacctgctc gtctaccgtc tctgtcttga ctgctggttg aggcccatct aagtacttaa ttcagcgtgg gcttatcccc ggaaataacg ccaactatct tgtcagaaaa agggaaaccc ctgcaactca tagagaagaa tacagtaagg aaaaaaaaaa WO 99/55865 <210> 42 <211> 1152 <212> DNA <213> mouse PCT/NZ99/0OO51 <400> 42 ggcacgagct tctcagggcc caggctgggc cacaggaagc tctgtgacta tagggaggtt ccatccctca cccgctcttg ctttccctga gcctgaggtt gtatgcattc atgcctgtga cgcgggtctt ccctctgtag gttggggggt ggacccaggg tgacacgagg ctaagcccga magactgcag agggagctgc aaacaaaaca aaaataactc gtccctagac ttcagcaact aattttttgg agtccgtgcc tttggctgcc ctcacctcgc gagaagctcc tgcaccagaa ccagggactc ccaggtggga accctgtctc ctggcattgg tctcagccta gcaccacctg acacaggtga cagtcccaag gcctgcccag cc tgccacccaa tgctgactgg agcacttttt gcctggacca agggcagagt gtgtgtggct atgggt cc tg tgggttgatt gaaaccccgg acttttgttt tgaagggcgg ccgctgcgtg tgtggtgggc actacttgac agc ac caaa r actgctgtgg gctccggctc tccccgagtc tagataacct ataagtctgg ccacttgaca ctaattggaa gatacatgca t tagagggtg tgctgtcgtg ggttctatca gtctctttgt gagacagcac tgaccaaaaa gaggataccc gcctgagccc agtcctgagc cttgaggctc s ccmtggcac cagtgagctc tacctcccca ttctcagctt ccatgggaca ccc tagc ct c ccctccccct ttcttctctg gcctctttct ggctaagtgt tcctctggga cctgcttatt aaggaagtat tgcataagaa caaaaaacaa aagcctgatg agcgggaggg cttcagctga tgagtatctc cccatcttac agcccggaca agcagggcga gcccatcatt agttgggtgt aactctctct aaagctaatg tcctgtggcc ccag ca cag c atgttttcat tcccaagcca tatgtacgag gtgtcggggg actggtttcc aacaaaacaa cctgagagga atggggagag agcagtgctt ctgtgcacag t cc act c tcc gacactgcca ggccccgcct ctcggcgccc tgccttaccc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1152 <210> <211> <212> <213> 43 446

DNA

mouse <400> 43 ggcacgagct tgagtctgga tttgtttgtt aatgtgcact actcctggag ctggagttag ccaggtcctc tggagaaata attatttttt taataagttg ctaatataga ttatttatga aacaagaact agggccagca gttcagtctc caggaaccac gtgctgcaaa ggtgttttgc agacaatggt accagtgctc cctcggtcat attcaggtgg agtggcttaa acagtg taatagtatg ctggatgtgt gagctgcctt ttaaccacta gttgtcttaa cttaatggta gggtgcctgc cactatccct atacttgtga gtggatgttg agccatctca tcagagcgat tatgcatgaa taaccatctc gcctggcatg agatgtcaga ggaattgaac acagccccaa agaaaagtaa ttagtagtaa agccacctga <210> 44 <211> 391 <212> DNA <213> mouse <400> 44 ggcacgagcc cacgtctatg tctgccacgt ctgctttgga acacagagac agatgccgtg tccccaaatc tgcgaaatac gagatggggc tcctgggagc agttgctgat gcctcctgat tcatagagaa tgagattcac ttcaccttcg cacttcaaat agctccagaa atcgctcagg tcaggcgatg ggcctcacgg cagtaagggg ttgttctggt acctcagtgc gtaatggacg tgctgcagga agcccccatc acacagactt t aatcaccatc ccacaactac gccccccact c tcagagggg gtcctcctcc cc ag tcat gc gtcatctgtc aagattgaac gctggcgctg gacggggacg caagacgagg gaggacagcc 120 180 240 300 360 391 <210> <211> 516 <212> DNA <213> Rat WO 99/55865 WO 9955865PCT/NZ99/00051 <400> cCtCctgtCt ctgctgctac cccggcctcc ttcctggagg ttccccaagc ctgctgccgc gcccacagct ccggtcggcc cttccgccag tatgtgatgc catagtctgc gcggcactca ctctttcccc gaaaagaagt cagcgaggtc cctgacaggg gcagctccag gctgacattc t tgtgaggcc aagtggcggg cccggactcc ctgtgccacc tcattgcggt tcacgcgcca atgtggacca cacctgacag tggcttgcta tgcgcctgtg cagtggggaa agccttcagt caccaacctc ggtgggctcg gaagcacaag gagagaccgg ccggcaggaa Ct caga gtggcctact gctgagggtt cccacaccag ctggatggga ctgacctttc gccacagcct gctggggggc gagggcctgg ctgtgtccct cttcagcctc ggaggaccca tcgtggactt tcatcatgtt actacccgtc cccatgcctt acttcttcca 120 180 240 300 360 420 480 516 <210> 46 <211> 306 <212> DNA <213> mouse <400> 46 gtcaccagca aaggtggaaa gctgctggga ccagtcttag agggggatca gaaatggggt cttcgtagcc ctggggtgga catgtctgct ggtttcccaa ccccag caaattcttt gaaggactct gacagccctg ggtctccaag Cctcttgtgg caagtggtag gaatgtgaat Ctttgcgacc ctcccatttc tggtgtctgc ccagtccttc caggtgggct ttttcctcct cttccacaga gatgcttttt ctctgcatac aatctcccgc aaacccacac caccctccac tgaggctcag 120 180 240 300 306 <210> 47 <211> 439 <212> DNA <213> mouse <400> 47 gaaaactcgc aggacgctca catctttctc tttctctttt gcacatatta ctgagccatt acacacacac atacacatac tgtattttgg ccaaacttgg ttgcaagtga tcttccatgc gagcttgccc cacaagtctc gctgttacat ctactggtc ctggacagct tctgtttctt gcaagcaatg acacaccccc aaaataggtt agtatgaaac tcggggatgt tgggcttttt gttccccttt ggaggggtcc gagacagtgc tccttcttcg atgcagacag tgtactcttg tcagttgatt ccccttttcc acaatgacac cagagctaac ttttgcttcc cactggagtg tgtgtgttta ttatggtttg tggtgagaaa acacacacac agcctacatg agccttttat tggcaagagt cagtatcatg <210> 48 <211> 159 <212> DNA <213> mouse <220> <221> unsure <222> <400> 48 cangtacgct cactggaaca gcttgggctt ttttcagttg attttatggt ttgcatcttt Ctctttctct ttttctgttt Cttgttzcccc tttccccttt tcctggtgag aaagcacata ttactgagcc attgcaagca atgggagggg tccacaatg <210> 49 <211> 465 <212> DNA <213> Rat <400> 49 gtgccctccg ccgggtcggg atggagctgc ctgccgtgaa cttgaaggtt attctcctgg WO 99/55865 WO 9955865PCT/NZ99/00051 ttcactggct acttcactat attggcatgt atcttctact ttcagcttgc gagggggtga accagacaat gttgacaacc cctggCcctg ttcttggtgg caagcgttgc tgctgcaagc gctcccgctc tgactcgtca tggggctgct ggtgctgtgg cttggttgcc cgttggggac ccttCtcctg cgctcggatt gactcacctg tggcgttctc gctgtggccc accatcttcc actggccgct ctgcctcgtc tcttcggacc cagaccccct aggctcctat agcgggactc tggacattat tcagtgccgg taccacatgc ttctcaggaa tgcaa gcttggggca tgttgatgcc ctacattagc catggccatc accgggcagc catagtgcct 120 180 240 300 360 420 465 <210> <211> 337 <212> DNA <213> Rat <220> <400> ctcgtgccga aatcggcaga gnatcgtcct cagcgnctgg tccattctgc tgtggtaatt ctcagaacat atacaacctg tctacctcct cctcgggggc acatggtgcg ctagagcgna gcgtcgctcc ggagtgatca tagnatgtcc tacgagcaag ttCtccttct gtccnactct tgtgctgtgg gnctaagctg gncgnctgtg tgttgataat gctcgggata tttttcaatg ccttcacaga gaaagatttt nagaacggcc tcagctacaa ctgtttcatc gccgcgggcc gcnaagttcg tctcaataag cgcaaggaat ccccatt 120 180 240 300 337 <210> <211> <212> <213> <220> <221> unsure <222> (80) <221> unsure <222> (312) (312) <221> unsure <222> (319). .(319)- <221> unsure <222> (353) (354) <400> 51 gatgcgccct ggagccgact ctgctccctc ccttccagcn gtacgtgaag gcggaatact actgtccetg atcttcttcg aagcctgcct cgctgccagc gactgatagt gngcaaggnc tgcccattct t gggctgcggt ggcgaattca tccccaccgg ccaagtttct cttgccctag acgcccaaat ctgcgctttg gcccgacgag ccccatgttt gaggaaagct cgctaaatgg tgcttctacc tggccttcct ctgtggcttt gtcattgcct gacgccgacc tgtctttacc gagtgttccc ggcgaccgag accggaaccc ttctcacccc gacagcgagc aacatcataa cgnncgggat <210> 52 <211> 228 <212> DNA <213> Rat <400> 52 ttccgcgggc gtcatgacgg ctgcggtgtt ctttggttgc gccttcatcg ccttcgggcc cgcgctctcc ctttacgtct tcaccatcgc cactgatcct ttgcgagtca tcttcctcat cgccggtgcc ttcttctggt tggtgtctct gctgctttcg tctgttttct ggttcctagt gagagtcatc actgacaaca gagatggacc agtacagaat tacctgct WO 99/55865 <210> 53 <211> 361 <212> DNA <213> Human PCT/NZ99/00051 <400> 53 cgtggacact gctgaggaat aggactttaa tcttatgctt ctagcagcag atctgtagtt aattattgag gggactaggc cattgtgctt aataatacca gtttcttgtt tcaggaatgg g gataccgagt gaaaatgcca tgtatagcct tatatgcatt agactaagca ttaattcttc ggtaggtcag gatgttgttc caacaacaat tgccttcatc ccataaccaa aacgttggta aagaagatgc gggggacaac tttaaataag cacccatgtt gaaatactaa tgataatgat tgtgaacacc ttgtatcttt atggagaata tattaagaat tgtaaagatt aacttgtttt <210> 54 <211> 403 <212> DNA <213> Human <220> <400> 54 ttgcgtggtc gcggccgagg ggcctgatcg cgatggggac ttggcgatcc tgttgtgctc gaagtcagaa ttcctgagaa tctccccgtg tggagtggaa aacaagatca cagcttccta aagtccgtga cacgggaaga tgtctgttcc aaaggcgcaa cctggcattg taatcctgtg gtttgaccaa tgaggaccgg cactgggaca caggagtcct gtcgagagga ggcagtgtta aagttgtcct ggagacacca gtgaccttct tacacttgta t cggcggctg aactgttgtg cagtgcactc gtgcctactc ccagactcgt tgccaactgg tgg ttgtgtcagt tctcttcata ttctgaacct gggcttttct ttgctataat tatcaccttc <210> <211> 413 <212> DNA <213> Human <400> tagcgtggtc gcggccgagg ctcgagccct aatggtggtc tgggcatgaa gtgcacgcgc tgggtggagg cataattttc atggccatca gattgtcaca agtttggccc tgccatcttt cactgtctcc tgttcctgtc tacgactcgg tccctggtgc tgtgggggag atcgtggcag gacttttata attggctggg ctggggataa tgctcgccct tgggcttcct acgacaaagt gtcttgccgc accctttgat cagggtctgc gagcagggct gtccgcggcc ggccatgttt gaagaaggcc cttggtagct ccctaccaac cctagtcatc gggtacctgc ttgcaggcca gtggccacga cgtatagcca tgctcctggt attaagtatg ctgggaggtg ccg <210> 56 <211> 452 <212> DNA <213> Human <400> 56 ttcgagcggc cgcccgggca ttgttaggaa aatgtaggct tgcgacacac ataattgtcc atgtgttggc aggccccatt ttttagggct ttctgggaat tctgagtgag ctaactgaca tcttttctgc tttttaacag caggacacca aggcctactg ggttgaaact accagtagaa caatttttaa aaatgcataa tgtcttgaca caatgaaact gtgtcttcag cactcgggaa ttagaaagaa aatgacattc gattgatggg actgcatagg gagaacctca gtcaggcatg tcagggagga cc gagccgggag tctattaata gagcatgaag actcatgtgg gctggacaaa tttctgctcc caggttgact gatzgtattgg agatctgagg cattttttta tctgaatgta gcagccttga tctctctggc gtggtgagtc <210> 57 WO 99/55865 <211> 190 <212> DNA <213> Rat <220> PCT/NZ99/00051 <400> 57 ttcgcggccc ngtcgacggc aaaaacaaaa ccaaagaaac cagtgtgcaa catatataaa gcgtattcgg attggcaaat agtcaaacct gggaagtaaa aagcaaaacc aaactaaaac aaaacaagaa aaaccaacat ttcttcaatt acagaaatac taactctaca ggcagtatgt cgacgcggcc <210> 58 <211> 413 <212> DNA <213> mouse <400> 58 ctgcaacaag gctgttggtt ccctgggccc aatggtcaca tttttcccac ctgctgccct ctcccagggc ctcggcggcc aggggtcgac accagagatg gtatttgtgt tttctgggat atagagaaat ctctgcaaaa cctctccaat gtcacctgct cacctgagcc actacgcgga ctccaagggc tttattttta gactttgctg gggctccagt gaagacccca cagcccagag ctcctacctg ctgcaccaag ttattttttt accaaccagc gaagggctcc ctgggtggcc ggcagctacg aagcggaaga ttgcttttgg taatgtcctt tggagctcaa tgggcctggg agaaacgcag tgggccagca ggattttcta gttttttctg tctttgggta gga <210> <211> <212> <22 0> <221> <222> 59 325

DNA

mnou se unsure (213) (213) <221> unsure <222> (223)..(223) <221> unsure <222> (227) (227) <221> unsure <222> (243).

.(243) <400> ggtatcaccc aggctt t ttc tgacaaggct tcttgggtga agnagttaat agagagggag *59 aggcccactt ttttctctct ctgcccctga ccaacatctt taaaccaggt tgaagaaagg atccatctac t cgtggtgc t gctgtgccaa cctgtctttg tcatcgggag ggcca agcgagtagt tgggatggaa gcccacctcc agnaaccagg tttgctgaaa atggcggcct cccagggctt Ctctgtgtac ggncagnatg tgttaagcat tccttgtaac tgtttaggcc aaagctcctt ggagccaccc actctgttct 120 180 240 300 325 <210> <211> 372 <212> DNA <213> mouse <400> ggccagcagg accgcggtca tgagcctctg caggtgtcaa caaggctcaa ggagcaggat ggatctcgat gtggttaaca tgtttgtgat tgcgggtggg accctggcca ttccaatcct ggcatttgtt gcgtctttcc tcctgtggcc ttcagcactg ataagaatct attattggta 120 180 WO 99/55865 PCT/NZ99/00051 ctggcggagg acactgggca tgcaagttcg ctacgcacac catgaggact atcagttctg ttactccttc cggggcaggc caggacacaa gccatccatc cttatgctcc atggattctc cgcacacaaa ggacatgtgg ctcagcgtgg ccaagttcct tcccgaaaga acctgcactt tggctgtgtg ga <210> 61 <211> 363 <212> DNA <213> mouse <220> <221> unsure <222> (15) <400> 61 gggcgcgcag gcggnaccgg gggccgcgac atggactgtc ccaagagctt tccaccaaag gccccaccac cggggtggta gcttgatcct gggctgctgg aggagagcat cgtgggtgat taa tggcggcggg ctgtgcagcc aagcccctcc acggtcattg tgctacctgc ggcgagacaa gctgctgctg cgaattccag aagcactgac tcatcctcat ggctgcagcg aggagccctt gctaattggc cctcgttgta catgtctatt cgccatagct catcagccag ttactggtgc acaggactgc gccaggcaca atggaccaca gccctggggg tcagaggatg agtactctgc 120 180 240 300 360 363 <210> 62 <211> 399 <212> DNA <213> mouse <400> 62 tggtttttgg gaataacgtt ctctccaaca tctcgtccat tgagtggcca gcccgagcct gagagacatt aattaaacac tattctggaa tactctgggc ggtctttttt tttcttcttc t tgcatcaaa tcttggaatc caccgacctc gagctctgtc tcctcaccc tatgttttat tttttctttt tacttcattt ggactgtggg ggtggctttg aatgacatcc caccgcacca gtttatttct gctcccaaa t tggct t caa cgtggaatga acccagtgtg aaggagaaaa aaccagttgg tttttaatcg tgtcatattt aaaaggtgtc gcttttcctc tgaggttaat gttcttctga gt tgt at tt t <210> 63 <211> 399 <212> DNA <213> mouse <220> <400> 63 caaagcccac tgtaggctcc tagtggtctt aaccatcctg gtcccctgca ccacccacct cagagcacct ggtctataat cttaccaggt cctgcttgcc tcttcctacc tctttcctgg tcgcaggagt ctcagctgca gctgaggtag ggctactgtt cccacaccag cacacaaccc aagacagaag gcatacttac ctcaggccag cgattgctgt tcttcaagaa ccagctccac agcctctctg ctagaacctg gctgtctcag ttcctgggg atttctggtc ccaaagaaag tgtttccacc agcctgggac gaaaaacttg aagacagatc atctgcatca gaattccaca acagaggaca tcttgccagt gggaccagac tctgggcctc <210> 64 <211> 2481 <212> DNA <213> Rat <400> 64 gaactgtatc tggatgggaa ccagtttaca ctggtcccga aggaactctc caactacaaa catttaacac ttatagactt aagtaacaac agaataagca cctttccaa ccaaagcttc WO 99/55865 WO 9955865PCT/NZ99/00051 agcaacatga ccacggacct tctgtcgtgc gccaaccctc tataaggaac ctcacaactc aagtgtaacc gtggattttt attcatgcct agagaaacat aatattgatg aacaactaca gacttctgtg aagggattca gatgactgcc tacacatgtg gtcttccttc atcagggtga aaattggtca aaggttcgac ctcttgtaca agctatgaca ggaaacttcc ggaggaagcc ccactttacg gggcagaacg caggacttcc aagaaagtgt tgtgaggaag aacaaatgtg ctggagggcc ggtgatcaag atgcagcagt ataagggatt gcttggagtg ggcggaaata tggtgaagtg tggcgaaggt tttgaaatat ctgcatttgg cccaacttct ttgatggatt ctgaaggtgc tttactgtga ctggaattgc cctccaaaaa cctgcttgtc atcgatgcac gtacaagtaa ggatttggtg attgcgaaga cgtgtctttg cacaagacct agtgtgactg aagataacaa tctgtcctga gcaccagccc atgaaccaat gtgtgtcaat ctcagacaaa agggtgacaa ccggctctca acattgtaga ctaaaatcat taggaggtat gcaccagctt ggaaagtgcc gtgcccatgg ggtggatggg tacatgggac acggcggggt tgcaagcacg ggattcaccg attaccaaag cagaggcggg ctctttcgaa cggctgcacg tgtacacttc attgtaaaat aaaaaaaaaa caccttaatt gaaatctctt ctttggtgac ttgtaacatg ccgctgtgcc ttttacatgt aaatccatgt ctgcccatat tccatgtaaa tacttgtgct taatgattgt cccaccggaa gaatccctgc c act ccggga gtgcaaaaac aggctacagt ctgtgataat atgccagtgt tttggtaaac catcacactt ggaccacatt cccggcttct gctactgacc caccaatttg gcctgggaaa ccatggctgt tatgcaaacc cacatgccag gcccctctgt ctgcttgccc cctctgtgat ggaagtgcag gggacagctg cagcagggta tgtgctgggg tgcacagatg agatgtgcct ttgaccatgt acagaacaga a ct cag t ta ca Cgtttactgt ctttcagcct cagtggttat ggtcccggag caaggtcctg aaaaatgatg ggtttcaagg catggaggaa gatgggtttg gaaaataatt tacacaggcg cagcatgact tacattggtg ggtgctcatt ggcttgttct tttgattgtc ttgcctggct aaagagtcct cagattgcca gctgtggaat gccatttaca ctggattcga tcaaaacaat aataacgtgg atccggaacc ggaattctgc cccagcagcc gaccagagaa atcaacgcct gaagaagaag gctctctggg acacagagaa cgctgcctgt ggcagtgctg gatcttcatt cctaagtgca tggactaatt cttattttta accgtctgag c t ctaca tgg tgtcacactt ccgactgggt aaatggcaga tggatgttac gcacctgtaa gccaggactg cttgccattt aaggagaaag ctacatgcgt aactgtgtga ccaagtgcat agcactgtga gcacagatgc gtgagttttc agaatggagc acttgggaga atcttcagat cagatgaaga ctatcgaggg gtgtggagac gtctttccct ctactctgaa c t tcgc tgcg tttacattaa ctggctgtga aatcaggctt ccaatgatcc tctcctacag atctgtttaa ctcgggcagc tttcttgtcg caaacgacta tggacctctg tgtggacgag gctcgagaag catgcttcat ttatgataat atgtatcct aaatgacatt agcaattgga gaagt cggaa taaattgtta tattcaagcc caatgacccg tgatgtcccc aaaaccaagg ctgtgacatc tgatggaatt ggaaaaactg cctgacgcca catcgacttt agtgaacgga tccacccatg ccagtgtatc gaagtgtgag tccttcagcc cagcggcatc cattcgagcc aatcaatgat ctctgtggat tttcgactct ccaggcccct cagtgaactg accatgccac cacctgtgaa ctgtctcgga ctgcaagtgc ccccctgcca cctattgtgg aggggaacgg gaagtatctc agaagcaaga gtcgagaagg cttctgtctt aatggaaata aaagaattgt 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2481 <210> <211> 3008 <212> DNA <213> mouse <220> tagacgggag ttcccagcaa cagcccaggt tccggtgtcc aggccttgca ttgcccttgg gtactgctgg accagcccaa Cccggggaga aggcccaggt gacgatggga atgtgctagg gtgccaatgt <400> cctgtggcta tggctttctg gacagtcatg ggttcgtgct gctggacaag gaatgaggat accctcccct ggaagaatat Ccctcctcct ggacagcaac atgcagtgcc caccagcccc ctcttgggag caagccactc catccaccgt Cctcccgaga aatcccccac ttccctggct gccttgggag gtgacccggg ttccaagaag attgtctctt aacagcctcg agcaatgctg catgtcgtca cctggctttg agcctgatga cagcttctgc cacccctgcc tactgtttgt g.gt ccc tggg aatactcctg tgctgctcaa tagggcggga gggccaaggt tccttcgacc tagcccgtgt ccaatgtgtc atggtggcta cgccggccac ctatctcact cactggcatg cacctggacc c ccagaaggt caccccctac ggctcccccg gctactcatc gggccggggg cctgaccaag gaccacttcc tgtggt acct tctgcagaga tatacctgtg gtgctctacc cgtggggtga aaagacggac tccctcatca aacagtcttg gcttttatag Ccgtgctccg ctgcagggc gaggcccagg accaatgtat ttacccaagg ttcagtgtct 120 180 240 300 360 420 480 540 600 660 720 780 WO 99/55865 WO 9955865PCT/NZ99/00051 ggtatacccc tgcctatcgg tcagtgtcct taccagaagg tgtgagcctg cggtggcgtc accgccacgc agacctggta acgttgctgg acgtccttga aggatctccc gggatgagtt ctgctcctgg ttcccatcct cggattctcc ggcgctttgt cagaacctcg ccagtggggt cagccgtgcc tcttccgaga cggcttcaaa actcacctcc tcctcagagc ggccttcttt gcctccttcc cc aggagaca tgtggtgaca cggaattccc ggacccatcc tgacTcc fr rc tagctttccg tctcttaccc ttatatggat tctctgtgtc ctgactcttt tgtgtgtgtg tgggtgcagg aaaaaaaa <210;- <211,- <212:' <213-, actagccaag ggctacacac tgctcagaat gcttcctacc acttcccacg gggcagccct ccaagaagca gctgtgtgcg ggtcactgac tgaggccagg agccttggga ctgggggatc ttzcaggcagc acgccagagt acttggccgg gatgggaccc gacctcagct cccacaaccc tagcccccta gatgaatgtg attcatggat tgcaaatctc ccccttacac ctgctgcccc tgcgccctcc caaagcagct gtcacaaaaa aggggacatg tgaacttgag r r, mn cagacgcagg tgaacaggct ttgcaaagga tcggtggcct aattgagttt tgtgtgcgcg tttttttttt cgtcctgacc Ctcctagtgc aagctgggca acaccggctg tggagagaag gcgccgattc gactccaccc ggaggggtac gtagctatca caccagcagc gccttgccgt cctctgatct cctgacagcg ctgctctggg ggacccttac actgtggccc aaacgcttgg ctctgcatta ccaggtccag gacggggact agtcaagccc agggcaagtg agctttggct tcgtggtagc ctcacagccc ggggccagtg ggaggaacca gagctgctag ccagagttag gatgctacca actctgctat gtccaagact ggtggt aggc gggagctgaa cgcaagcgca ttaaaaaaca gagcccacca cagggctgc a gtgggccctt cccctgggct atcagaggcg atcaggcagg acaacaccag acctccaggc gcgaaggcca tggatttctg ccctccagga tctctccacg tgaccaagtt gggagcctgc cattagagcc cctcacaaga cccagtcctt cagacatcag gacccctgct ggccacctct tgccccacct cttcctggga gattggact c ctcaccagcc cctccgcagg gcccccgaaa cctctgtgga agacctggca gtgtcaagac gggcccggct gagcccgctt ttggctccaa ttgagtgagc caggaatgtg agcgcgagtt ggtggataat tgactgggta ggctcacgcg cagtgagatt gcctgcaacc gatcctggcg cagctaggat ccaatacagg cggaagtgga cgaggcgaaa tgcccgccac tgtagccatc tgggaagtca caagctccaa tcgaccgcct catttgcagg aaagttatgt tgactgtagc ccccgtgggg ccagtatctg tgaggagccc atctttcctt cactgatggg tgagggagcg agagcatggg ggaagctacc ggtggccccg tgagaactat cccaggcttg tccagaggag accagcctat agtgtgaaac gctggggtac ttggtataga tgtgtgtgtg cgaaagtggt aaatgtttgg tctctggctg cagtatcagt gtcctgtcta aggagcagag cagacgtttt gctcacaagg ctggggcagg gatgttggct ctcatagaga accttggtcc cagcctccca ggctcacact ggctccccag agccctcacc ggcccagatg ctggagcgcc agtagcagcc cagcctcttg agcctaccct acgcctgctt ccaccaccag ggtcggggtc ggtcttgccg aggggcaagc tcagtccact c aagggaaca gaatgggatt gccagttctc agctgtctcc cagcagtcca taagaaaggc tgcccctacc gttggatgta tgtgtgtgtg gtttatggtq aaccgttaaa 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 z 0 v 2640 2700 2760 2820 2880 2940 3000 3008 66 1888

DNA

mouse <220> <221> <222> unsure (1690) (1690) <221> unsure <222> (1755) (1755) <221> unsure <222> (1864) (1864) <400> 66 aaagtggagg gcgagggccg ggcgaattcg caggctggga cgccatgtgc actggaagac gacagggaac gaatggagct tacattctac ctgtgtacgg gagacaggct ccctggagaa gggccggtgg gaaggtgggc gtggctcgcg cctggaggaa catatgccag gctgctggcc gctctggggc tcgggcggct atcaagtgct gctaagaaga gaacctgtcg tcagagccat tgctgcgcac tcgggcaggt cgcccagtct tggagatggc gcttggtcat tgccttggga cttcgacgcc gtacaaggtg gcacgtcgac caagttccga ggagtacatg cctgcgcttt WO 99/55865 cgcatcgtgc ctgcacctag tttcttgact gatggcctgt ttgtttgaca cagaataatc ggccaccgcc atagggctca attacctctg catgagccag cgcctcaagc tcacagttgg agttcctctg tcagtggact tcaacaggcg tcaggggaca gacagcagtg tggctgctgc catatggctg agtgtcaatg gatgaaggcc tgagggccga cctgctccgn ctatgctgcc agtgtgaatg accngtggct acgagacagc acctgaagcc ttgggctggc ttggtacaat ccaaacatga catttgcaga cagagctgcc tgcaacggtg aaacagaaga gcgagaaaag gcgcctctgc actctgggat aatgcaagct cagccttttc acctgggccc ccagcaggct ccagcctgct ttaacaatgc tggagcggaa ccaaggatga agcacaaggc acacccatgc cgtggtgtgg tgcanggcca cccagacact cgcattctca cgtgggcatg agcgaacatc caagtgcaat cggctacctc tgtatacagc tgaaaagaac acccatctgc ctggcatgca cctttgtgag ctctctagag tccccccttc cttcccaaga cccatcgtcc ctccagagga cacagacatc gatgaagatc gcacctggct caaccccaac gggacgtgga agaccagtgg tgctgctaga atgtagcctg atgtgggcct ccttcccatt aacgggagga ttgacctg aacttcctgc ttgctggatg ggcatgtccc cctccagagc ttcgccattg atcctacaca agaccccggc gacccacagg aagcctgatg tccaagagtg gataacgact ctcttgaaag agcagtggca tcgctgtcac cagaagaaga ctacagcccc gtggaggccg ctgaccaaca attgtggagc actgccctgc gaagaatgct ccagcatgga gcagggaaag gttaagctgc caccctgacc attgcatgtc cccactacca actctcatga gaattcgtga tgatctgggg tcatgatgaa cgcgtgcctg tgcggcccac aggaggtgaa aggccaggcc gcagtctctc gccccgaaga agaggctctc tgtcttttga agctagtgga aagatgtgga gacaggagga ggaagggctc tactgctagc actttgcagc tctgtcaatg caggagaaca gatgcctggt tagccaagca tgctgttcaa tccgccactg aatgtcaaga cctcagcatg gaagagccgc tgtgcttaca agtggtaaag tgccagcctg cttccaagaa agacctggct cgagtcctca cgagttgctg gctcagccga gggggtgtcc gcgggaagct tgccatcata cttggttcta gtgtgtcaag tacaccactg ccggaagacc ccaaaatggg aggtggactt ttgtgcgcac tgcctctgca gcctggggtg aggggcattt CT/NZ99/00051 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1380 1440 1500 1560 1620 1680 1740 1800 1860 1888 <210> 67 <211> 1260 <21 I T)MA <213> Rat <400> 67 gtcg ctttgggtat cagatggatg aaggcaacca gtgtgtggat gtggacgagt gtgcgacaga ttcacaccag tqcaacccta acacctgctc aatgtcgcta cgtgtaaccc gtgaaactga gctgtgaccc gcagcttctc gctcatgccc aatgtgagca gcttcaaatg gctgtatgtg gggacatgga cgacccgata agttctacat aagggcctcg tcagaggcag cgggttaagg ccaacgaggg CCtttCctgc atcgcaaact <210- <211, <212.

<213ctgcactgat tggttactgc tggcttcacc gaacccctgt aggatatgaa cgagttcctc t cc aggc tac ccggaaccac tatcgacccc ccctgctgag tgtggtatca cc ctggcgc c gcggcaaaca ggacatccag ctccgtgatc cctctgacac acaggaggag tgaacatctc gtcactctga gggtactggc cagcagctct ctcaacgatg gttcagacct ctggaggaag tgtcaacatg gtcttgttgg acatgcactc atcgtctgcg aatactggct ggacgctctg tattacattt gggcctatca ctggacttgg cgactgcgga tgccttttac agaagaaacc cctggggcat aggacaccat cccagatctg ttctggaagg gtgcgaatgt atggaaggt c gcgtcaacac atggcattca agtgtgtgaa aagataaccg ccctgcagac aggagcctta gcagggacca ttcctgctga tccagatcaa gtgccaccct agatgatcac tatacgtgtc cacgccgagg agcaagaatg cagcctagca gccccagttc tatcaacacg gcagtgccta tcctggatcc ttgccaagat ctatggttct ctgcagtgat ccagccgggc aagctgccag ttgctacaat tctgctgatt gccattcacc catcttccag atctgggaac ggtgatgaca cgtcaacact ccagtatccg gacaggagga agagcgagac tcctgacccc ctatgatgca gaaggagggt gatattgatg tattcctgta gtgaacgagt ttcatctgcc atggatgagt tcatacttct gatatcaatg ctgcaagggg ggggataacc atcttgtttc atgcaagcaa gagggtcgag cgccccatca gtcatcaact ttctgagcct gagaagaacc agacattgca tacctgtact gtagtatcca 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 68 1729

DNA

mouse <400> 68 WO 99/55865 WO 9955865PCT/NZ99/00051 gaattcggca .aagcaatgaa agagcaactg agttctctca tccaccatga gtgagcattt ggattggcgt aaaggtgtat accttataag ctttggatga gcagtaactg aatgagctac ttgttgtcac ttttaattgt gggcactcaa atggaatttc ttgagtgaac agcataaatc gaagcagata ggtagctggt ttgcctatca aagttcgaca aacagcatgt aaaaaagaaa tctgctacat tctacaagac aactgcatgg caaataccca cttattttga <210- <211, <212,- <213,- <400> 69 ctcgtgccgc gccagctgca cagcatggct cactgcgatg cagtggtctg gctgctggcc cgagcagaat ggcagcactg gacatttaac tccttgtctg gctgaagcaa gaccctaact cggattgcta aaatctgaaa acatagtcat tacaaaatgt accattggtt agtaacagaa tgcaggaaga tttctactac cattttgggc agggaatttg caaagatgca ctacccagct aattcctgag tcctatatcg tctcagcctt attcacctaa ggaatgtaac cagtcgtaga gat t caat ct ccatgcagtt caggcaagat cgaatattat aaagaaataa atggctctgg agcgaagaag aacaccgaag gaagaccata gccatttgca tcgtatgctg attagtgctt tcaccctaca caagccattt gataagctaa cttagctttg gccaagttca tttgttctat acatcaatca cacccgcctc gtatcaattt ttacacctaa ggtgacaaca gactgaaagt accataaagc acattggaag tgactaaaag cattttttga aatacttatt tgggcaagtc ccaaaattga tatcctcaat ccttactata aaaatgaaat gggttctgat cagaggtgat ctgactacat atagttactg gatgctttac tggattctta ttcttgctgt tcatctgctc gtcaaaagcc cttgaaaata gtcatcgttg ctacccttct acttctgacc agtccaagta gatggacct a ttagatgaaa accactaaaa gtttgcaaac cacctggaca ctgtgtgggc actcacactt cttacaattg cgtgttgata agggaatcag tcttatattc actctaatag gctt cc at cc tattgtcatg tacaaagcaa agcagtctgc CCCtCctagc agaagaacct cattaatgga tggttatacg tgaaaaatac cttctattgc t ggagggagc acagggaatc atggtggttt ggtgccatgg ttgggtttgc atctcagatg atgccatttc atagcaaagt acagtgaatg gaaaatggaa ttcattcatg gcagatccag tcatctgtcc ggtatccatc ttcccaaaat gcatatttgc tatccctcct tttgtggttt aactaaaaaa tcagccccgt ttcagtttgt aaaaaaaaa ctcttgttca acagcacagc gtagctctga gcatgtgcat ggacaacgat attgcgattg tacataagaa ccattgtgag caatggagat gggtcacaat aagctatggg tgttgggtgg tgaattttca cgggttcttc atctgtcctt tctcagctcc tatc caaggc tagtttggaa agcaggcaaa cctgatgttt gcttgaactg atataggaac acatgggtta tggaattgct ggttccattc tacctcctat ttctaaccct aaaataataa 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1729 aattcggcac agttcattgt acctcacctg gtggttatga gatcaccac tcctggatca gaggattcgc aaaagtacaa cagctcagcg acgccaaggg tgtctgtact gttctatgag tatactgcat gtgagacgct ggggacaact accccttccc cctatgaaga aaacagcgac atgaccgagc gtcctattct atggtgcgat gagtctgtca ttaatgtcaa tcctcatagt ct ac aac cgg gaaaccacca ctgtgaatac gtcaagtcga tgttaactca ctcag <210> <211> 1421 <212> DNA <213> Human <400> gattagcgtg agtggcctga atattggcga cctgaagtca tcttctcccc aataacaaga ttcaagtccg ggcaacagct acagttaaca caagatggtt aatcccaaaa gagctggtct gtcgcggccg tcgcgatggg tcctgttgtg gaattcctga gtgtggagtg tcacagcttc tgacacggga atggggaggt tcccctcctc CCccaccttc gcacccgtgc ttgatcccct aggtgtctgt gacaaaggcg ctccctggca gaataatcct gaagtttgac ctatgaggac agacactggg caaggtcaag tgccaccatt tgaatacacc cttcagcaac gtcagcctct tcccaggagt caagt cgaga ttgggcagtg gtgaagttgt caaggagaca cgggtgacct acatacactt ctcatcgtgc gggaaccggg tggttcaaag tcttcctatg gatactggag ccttcggcgg ggaaactgtt ttacagtgca cctgtgccta ccaccagact tcttgccaac gtatggtctc ttgtgcctcc cagtgctgac atgggatagt tcctgaatcc aatacagctg ctgttgtgtc gtgtctcttc ctcttctgaa ctcgggcttt cgtttgctat tggtatcacc tgaggaaggc atccaagcct atgctcagaa gatgcctacg cacaacagga tgaggcacgg WO 99/55865 WO 9955865PCT/NZ99/00051 aatgggtatg gtgggggtca .ggcat ctggt aagaaggtga tcattcctgg tgctaccgga caccccacag atcctccttc aagtgtttat tcccttctaa cctggctggc gtacctgccc ggacacccat tcgtggcagc ttgcctatag tttacagcca tgtgagcctg ctctggcccc ggccccctac atgccctccc tccccatttc gtagacagca agggatcttt gggcggccgc gacttcaaat CgtCcttgta ccgaggccac gcctagtgcc gtcggctcac tgatgt ctgk ttcttcggat tccctttcct tttgagggat aaaatggcgg gaataggtat tcgaaatcaa gctgtgcgca accmtgattc tttgacagaa cgaagtgaar cgcctatcat agtttmacag gtgtttttaa accactgmtg caggaaggaa gggtcgcagg cttgagcttg gcttatcgat tggaagctgt tcctgggaat c aaagaaagg gagaattcaa ctgcatttgc gatgccttat taatgtcagc agtggcctgg tcctgggtat aatmtacac t gttctgggct a ggagcggaat cttggttttt gacttcgagt acagacctcg cttactcagg ttgtctttta tatgtgcccc aacttgttta gccattgact caactgccca ctttccttgt 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1421 <210> 71 <211> 378 <212> DNA <213> Human <400> 71 tagcgtggtc gcggccgagg tacaaaaaaa caggcgtaaa tgcaaaccgc ttccaactca aaagacatca gctaagaaag gaaactgggt acccgcaaga caaaacaact ggttcttgcc cctgacacgt taataccctg cacagatcag acagacttgt cttccacaag cacgttctta tacctgcccg ggcggccg ccttacataa aagcaagtaa cctacggctt agcctctaga aggctgctgg ccttagccac attaagaatg cagcccacgg ggactttcca gaaatcccag ccacacagac gaagtgaccc aatacattta tgttctggcc accctgacag aacactcagc tcaccaagcc aagccacacg <210> 72 <211> 267 <212> DNA <213> mouse <400> 72 ggggcatggg ccatgctgta tggagtctcg atgctctgtg tgctggacct aggtcagccg agtgtagttg aggagcctgg ctgtggccct ggcaaggttc agaacggaag tggcaacaac actcgctgct gcagcctgta tgctccaggc aaggaggact gtccaaaaga aaggtgcata tgtgtcacac ctgagtacca ctgtggagac cctcagtgca agatctgcaa gcactacccc tgccaaccag gccaaagggt ggaagtc <210> 73 <211> 1633 <212> DNA <213> mouse <220> 120 180 240 267 <400> 73 ggcacgagcg ctgtccacag gg ca tgt ga c tgagcgcggc gaatgggggc gccacactgt ttcctgtcag cttctatggt gagagtttgc ccctgctggc tggctgcctg ctgcctttgc ctttgggccg cagtgggcag ggagcctgct ggtcgcttcg ccagtgtcgg tgtccccagg ctgtgtcatg gagcacgcc t aacaatggca caagcttgtg gagtgtcaac ttccgtggcc cagcagtgta ccaccagggc ggctgtgccc tgccactgtg actgccctgc gccccagctg ggactztgcat accggtttgg ctaccaatgg gccctgctgg gctgtgagcc aagacacctg agggcgctcc agttctgcga actgccccac gcgcaggaac tgcgctgtga tggac ago ta tgggttcctt tgcccacgtg ctgtcctccc caagggctgt cagctgctcc gcgctatggt cacctccggc ccctgccggc etgtgaccct gagggggtgc gggtgtgccc cacatgtgac ttgtgggggt cacgggaccc ggggccgact tgtacatgcg gggaagacgg gaacacaagt tgccccctgg gctgcctgcc gcttgcctct ttccatggat gtcagtggcc aagccaggct tgtgatccca ctagattgca ggggctgact acttgccggg gtagccttgc ggcaaggggc gaggccattg gtgcctgcag gctggatggg tcctggagtg gtggccctgg ctggttgcca ggtgcctctg tttttggaga tcagcggcct gaagaggccg gcgaccccat aagtgcccac 120 180 240 300 360 420 480 540 600 660 720 780 840 WO 99/55865 WO 9955865PCT/NZ99/00051 acagctgtcc actcagagga tgctggtgac attgctgtgg gaagaaggcc ttacatgggg gggaccaagg catggactgc taaggtattt gaccccagaa aaaacccagt tctatcagac acgcccacag taagatagag acagctatgg tcctttggac accctgcagg tgggaataga tgcagccagc atgggcatct cttaggcagt gagttaaagg cagcacccca gcactccagc aggcccacta ctgtgttcca gtggcacttt tggatccaca atagtcatat agccacacac acaaggaatc caggaagtcg ctgtgctgtg gaalzcctggc caaggcccca cctgcctgcc caactgttta cctggaaatg ccacctgccg ttatggtcct ggcctgtggg gtctccagca cacagtggtgt ccccattgc agcaaggcca gcccaaggga cctcttctgg ccgggctcca gctgggcttc cctcttcagc aggtccttct tagtccagac gggtcagatg agtgggatca ctgggtttct tgaagc act a cccaggcctc aaagccatgg tggtcatggg gggccactgt gacctgggat ggtgctaggc catatttata gaagctgcct agggttttgt gtgctttctg 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1633 tagactccgtg ggtccttcca agagcaggtgg cctgagggtt cttgaatggg aacctcctgt acccctctgt aatgacatgc atgtaatgta atgcttcagt caccttaggg ttcttcctga Cttccagctc tag <210> 74 <211> 1252 <212> DNA <213> mouse <400> 74 ggaagagccg ctgcattact ataccggatc taaagcaaaa tcctcagagc catggtgtac acccagccac ccaggcaatg eaaaagcgtq tgaaatcttc ggtgctggtt ccaaatctca ctgtgtggac acaacagcgt gggcatgatg gtccattttg tggtatgctc gctgtttcgt gtttggctgc aacaataata agagccagtg tgcaataatg gtgggcaaca agaattcagg actcggccat ctgaagctca acactacagc acctacaagg agcgaggcag cetczccaccc tgggagacgg ggaagagact ggcctccaga acgtctcagg gaggttatgc cccaccgacg tttgccttta ggaacgccac tctttgattt acctatttga aataaaggaa tgcccaacga ggtctgaaat ctaccacaca ctatcaatga taccgccttc agtggggaga tggaagacag tccagagact gggaggggcc tcaaagcacc taccaccgat ctgagtacaa gcaacacaga agctcagtgg ttacagggga aacagtttgc tattacagta acgttttaat atacgcttct gatgcaaaac taaagaagag gcttgccttg ccttgcttat cgtgatgaag aattggagtt gcc tcc tagg cagtaactcc gaacaagagg gacagagttt ttactcagaa tcgagtgacg gagaggcgac gcaggtgtac ttacaggttc cgcgttcagc cctgggaggc tgcactcatc cttcttaatg acacatttac cttgttttac taggaagagg aaggaagcgg tcgggcttcc aacatcgatc aacctccttc ggaccattta cttgagtgtg aagacacatg tttatctcaa acctgctact acctacacct cagttagaag cctgtgagct aagggagaag cgcgtgtgtg ccctctgcgg atggaagaag gtgcttggct aagtaaatcc tcagagcctc acatttagct ttaaactgga cgggcaagct cgtgtgcttc tgggagacag cagaaacgac gtcagttcat ctgcgtctgg ctgctggtga tctaccgagg ccttcaggat tcagcacaac ggaattcctg acgttctaca aagccacatt cctgccgccg ctttcatgtt ccaagatgaa tcgcgaccct agcaggccag ccctttttac aggggaaaga ttttttttta ccagacaccg tg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1252 <210> <211> 2411 <212> DNA <213> mouse <400> tcggcacgag agtgggtaca acaacttcaa gtctgacatc agagtccttt ctacggcgac gtgactaccc gcctctcccg tatgcatcaa. cccagatcca agaggatgca tgcatgtacc aagataactt aaaagtgttt gattactgtc tcagagctaa ttttctacca ggctcaatca agaatgcaag cccaacaaga ctgtgtttat agatagtcag agcgatgcag aacctgagga ccttactaca tggtCtcttg aagatgaact tcagatcact gagaagcgac gcaagcacct ttgtgcagat tgcgctttga ccttcccaat gtttttcgtt tgcccgatgg aggacctggg tgtctccaga gctgtctgct tgtattctct attcggagga ccgacatcgc aaactgtaca catacctccc atccttaacc ccacaacttt tgagaattgt tgaagcacac catttgactt gagaatacat atatgagatg gtgtaagaag gctacgacag ctatgtttat agatcctgaa cgcttatgtc agttttcata gggatgctca ttcgagtttc ac ac ataggc gtttgctttt gaaaatggat gctgcactgc atagagcagt ctagttaata gatgtggcaa gacggcaacc tgggtgttaa tgagcttcat gatggcacca tgctgataga acatgtccag aagtcactta 120 180 240 300 360 420 480 540 600 660 720 WO 99/55865 atggacgttg catgttttag aaactttttg gtgaaagcat aaagcctttt ggacttgttt gtacatttga aatctaaata atattgaagt tatattgtgt tttaaaatat tttgggtcat tgtgcctgtg atgttgaaca cccgttgaga ggggtgaaaa ttcatcttaa tggctgttgc ggtcggtcag tttcttacag atctcatctt tgtttttgtt tggctcatag gktatatccc gttgttttct ttaatcccag ctacaaagtg aaactaaatg caaaaaaaaa tagtggacat ttcttagcat agaaagattt agaggtcaaa tttgtgtgtg gcctggcgtg agaatattct cacttaactc tttgatcagt gtgcatttca atttggtatg tctaggtgca aatgtcgata gcgtgaagac tgctttggag aaaaaggagg taccagccaa agaacacggt acagccctgt agtattcttt ttaattcact tttgtttttt gatataccca attgtaatgt ttccatattt cacccgggag agttccagga aaaatacaag gattgtgaac tagagatctc aaaattttta atgtgagttg tttaaatggt atagtcatgt tggaataatc ataactatac tcctcttcag tccattaaat ccaacacttt tctgttttct ttgtttggca tggcccttac taaagtactg ggtatttagg ttccttcaga gtgccatggt gttggggagc ctacagttat atgtatgctg tttgtcttga gaggcatgaa cacaggactg aaaaacatga gcagaggcag cagccaggac gcttctcccc ttctgatttt aaatataatt gtttatacat gacactgaag ataaatgaac ttaacatgca ttgcagtagt actgtaatgc aatctttttt gtttcagatt tttaggattg cttgttagaa gggttataat tgaagacaga tgtatgacga aaaccctgag gaattgtgga agagcattgg ttgtactctg tttcaagtaa tcgtagacaa aggctgaact gaaatggctt attgagatga ggttctgcct gaggatttct tacacagaga ttgtagtgac tttcttttaa cttataagac tcaaaatgca tctatgtttt ccattttaaa caaggctttg tatagttcaa aagcatatat atccaagtta ttctgagaat aaaaaaaatt agaaaaggtg tttagagtat actgttccaa tgacagacat gtggaatttt gccaaagaac gaaggctcat gcccacagag ttgtaaattt aggaaatctg gggtacatcc ccggtgacca aacatcccct ggcagtgatg gagt tcgagg aatcctgtct tttgctttat gtttcaagta atgcagacat actattaaat aatgcctttg acgtggttaa tgtttttatt tttctttaca tgttattcat ctttcttatt gagttccctt tttttaaatg tgtgttaaaa gctctagagt gagcagcatt tttagttaag ggtgaatgt c agagtaatcg cctgccggtg ctcggttgat t caaagt aat ggtttttttt cagatcttag tttgtgttgk tcctacaaga gtacacacct ccagcctggt caaaaaacca gaatttgtct CT/NZ99/00051 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2411 <210> 76 <211> 1335 <212> DNA <213> mouse <400> 76 acccaaacag cccgggacca cctgtgcctg gctctgcact ggtccttgat aacatctaca tggtggggat gtaacctata cctgaaagca gtgaaggagg gtgcaacgac agcagtgtct aaactggaca gttcctactt cgtcaatcgc acagcctcaa aacccctatt cctgagagtt cacagccaag actacagcca cacagccaat accacagccg cactctcggc agccccctgg actcctctty taaagaaaac ctcatttcag gccagtgctt ctccaccacc ttggaccaca cctggatctt tcagggcaca tgtaacctga agttctgact cttgccaaag gtattcccat tttactttca aactgatttc gtgacttatg tgactgtagg tttccactgt gcccagacca agaagccaat gacaggacac caaggaaaaa aaaaa tgctgtcgct tatccccctc CCtccgacat c agtg a cgg t acgacagccc actataactt ccgaggatgt agtcatccgt ctgagaccag aggacacagc tgaccacagc caggtgccct tggggaagca aaacataccc gacctgcaac aattccgctt ctcagtttaa gagcctcctg agatttctgg aaaaagagaa gtcggtaggt atgacttttt ccgctccttg cctctctgcc cttggaaatc ccccgtgaac agtgggcacc gacatcccaa gactaaagtc gaaaatggaa ccagaccata caacaccaca caagaccaca ccatatcctg gatctccaac gaatgaaggt actagtgcac cttgtaaata cctgttgaca ggtgtggggg ccaaacctac atgagtgatc tttgaaggaa ttttctaagt cttccacacc agtgataatg agcactatgg gattcagtca tggagtggaa agccagtcgg aacctgcagg caagtacaac aacacgactc gccgtgacca gccaaaagcc cttgtttttc ctccaggtca tttatgtcct ttgagggata cttagtccat gccaatctga tggggaggga tcaggttgca atcctgtggc gtatatgaaa caaataaaca tgggactgtt ggtcctgcgt ctaacgtctc gtgccgtgat catatgagaa tcttccagac tcctcatcgt cctcagcctc caactgtgaa cagccaatac tggccatc cg tcattagtaa tcctcccgag cagtccgcag caaatgcttg ccatcctgcg acttgtgttt atgatccttc aaggacttat tactagcaga actgtgcctc atatattgaa 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1335 <210> 77 WO 99/55865 <211> 440 <212> DNA <213> mouse <220> PCTINZ99/00051 <400> 77 gagaagcctt gcccactcaa catcagctgc accggctcca tcaggcccct caacctccac aaggcaaccc ttggtggggt ctctgagctg cagcccccag agttctaggg gtctagtatc cttgttcaat gaccaagaat tccgagtaag tcatcaaggc atacctgggc ctcccatctg atcagaacag tggggttgta gccctccagg tggatcaaca atacgaccta ct CCaggccc gcagagcctg aagtagtgat gcagtccagg agtcccagag acctttttta tgaagagaag tggtgtcagc gctaatttct gcagtgccag ttgggcccag tttggttggg ccaacacttt tgttgatcca aagcaacaag ggttcagggt tggctgctga caaccacagc <210> 78 <211> 204 <212> DNA <213> mouse <400> 78 ctCcataaaa ttcctcaaaa cttcctattc tttcccgtct atgagaaggc actcactgtg cctctgtgtc ctcttcatcc tctgttcccc cagcagattt cctgtgccat Cttgggctcc ttagggcctc ctcacagtgt tgttttctaa caacgcaggc tgctccctca ggcctggcct ctcctggtga ttgtcttctt caat <210> 79 <211> 300 <212> fl?~ <213> mouse <220> <400> 79 tatttatgac ttgggttaag ggagtttgct gtgcaatcat gaagaccaga gttcagatcc cagcacccat atagcaagag agcatacaag aagcacctgt gactgcactc tgaagaatcc aacaccttct tctggcctcc atggcacaca gaacccccca acacatgctc atccactctc aaagagacat acataaaaat aaatatttag gtcctgggtc cctcagagac tagtcttcac aggtcctaaa tacaaacga gcggaccgca aagggtgagg gagtggat gaagaagcta 120 180 240 300 <210> <211> 214 <212> DNA <213> mouse <400> cccagaccct gtgtcagcta tcccagcaga aaaagaagat gcggaccctc tcagcaagtc aggtgaggaa acccaggaag cagggtcatg accccgcaga ggtcggggCt cctggtgcag aggatcagat cttgtgtgac ttctgtcttg gggccagcag agtaagggca gtgaaatcct gtctgacctg catggtgaaa tactgtaagg agca <210> 81 <211> 152 <212> DNA <213> mouse <220> WO 99/55865 PCT/NZ99/00051 <400> 81 CCCCttaact aacccaggac cttccactaa gtggaaggct ccaccatcca cagagggggc cagtcatttt taagcacacg gaccttttgt gagacagtcg tgatcttaac tgtggtgtca 120 ctgatggagc tgaacggtat cccctaaaag ta 152 <210> 82 <211> 181 <212> DNA <213> mouse <220> <400> 82 tctcagtgat gatgagaagc tccggaggag gcaggagaaa gcagggcccc gcccctccct gggtctccac ccacccacgc ccgctaaggt cacctgttct cccatggaga tgatgaagaa 120 gctcatagct ggacaaggcc cggaacctca gcccagtaac cgacctactt cccgcctggg 180 a 181 <210> 83 <211> 332 <212> DNA <213> mouse <220> <400> 83 tatagagatg gtgatgtaat gggccagggt gtaagcttca acctggggga ttttgctggt tttgttgttt ccctgtgtag ccctaacaag cctgtgtaga ccaqqctqqc tttaactttgi 120 cagatgacat tcacgtctac ttctctctgt gttggggtta tgggtctgca cacctgccca 180 ggcctaggct gggggatttt gaagtatctt agattatgga gtagacccag agtttgcaag 240 tatctgcttt aaagtgacac ataaacatag cctcctgacc atcttccaca gtgggaccct 300 gatctggcct ctccctggaa gaagagagaa ag 332 <210> 84 <211> 213 <212> DNA <213> mouse <400> 84 gcaggcagat aacaatgatt actggacaga gtgcttcaac gcattggaac aggggaggca atatgtggat aatcccacag gcgggaaagt ggacgaggct ctggtgagaa gtgccaccgt 120 acattgttgg ccgcacagca acgtgctgga cacaagcatg ctctcatccc cagatgtggt 180 gcgcatgctg ctgtccctgc agcccttcct gca 213 <210> <211> 273 <212> DNA <213> mouse <220> <400> ccggctctct ctctcctcct tccccgcctc ttctgcctcc cctgcctgga actctgatga ggagggacca ggtggtcagg caccccagtc tgatcaggac tcctgtggcc tccagagttt 120 cactcccccg tccatcctga agcgggctcc tcgggagcgt ccaggtcacg tggcctttaa 180 cggcatcacc gtctactatt tcccacggtg ccagggattc accagtgtgc ccagccgtg 240 gtggctgtac cctgggcatg gcttctcggc aca 273 WO 99/55865 PCTiNZ99/00051 <210> 86 <211> 218 <212> DNA <213> mouse <400> 86 ctcagccgcc tgctctgggg gctggagggt ctcccactta actgtgtctg ccgttcaggg ggctcaccca gtgctgcgct acacagaggt tttccctcca gctccagtcc gtcctgccta 120 ctccttctat aaccgcctcc aagagctggc ctcactgttg ccccggccgg ataagccctg 180 cccagcctat gtggagccta tgactgtggt ttgtcacc 218 <210> 87 <211> 335 <212> DNA <213> mouse <400> 87 gaggtggggt gggtgcatag gctggccggt ttcctacaca gctgggtgga cagagtgtga aggcaaggtt cagagaacct ctgagctgtt tcgtcctagt tggaaggggc acagaattgc cctgcctgca gcagcacctg ccagaaactc gggcctcctg tggtgagtta aattattctt attgctgccg ccatggagcc cctgtgggtt ttctcaggga agtggcatag gcatg ctgggcttaa tggccacaag ctgataaagg ggcctgtcta ccctcttgag cgtgttgtga gccactcaga attctcccat t ccc cagc ct gcctctgatg <210> 88 <211> 410 <212> DNA <213> mouse <400> 88 aaaccccgcc aggaaacaaa gggaaactga aaagcaacct accttggcaa tgtaacttgg gtctcctgag acgctgagaa ggagctgtag cttcccacga ttctgaaaac aaaaccgtgt catctctctg cacccatacc taccggtgta agggacactg gaggttccca acccttcctt cgtagccctc caacttcttt ccatgcctca tcggctttac taagcagaaa cacacccagg gcagctataa aggaacttca actttacaaa caccccagac tgaatgcatt gctgaggctt gctgtgcatc tgggcctggc ggagggatgc tgcaagtttt cctgtgttag tattcccaaa t taaaaac cc gtgaaattct cgcccagtgt cacagtctat cagaatccac <210> 89 <211> 279 <212> DNA <213> mouse <220> <400> 89 gtgcagagag tggattgtca gtggactgct cagttacaaa tgggacatct aacacacaca cacacacaca cacacacaca cacacacaca caccccaagg cttagagacc attgcagaag agaagagttt atgggaaatc ttggagaaaa cattggatgg tttgagagaa tggttaggag atcagactag ctagtccagg aagcagtgaa ggggggcggg gttagaagat gaggtcagaa gacagggtgg agggcattgt ccgacagaac cattgctgt <210> <211> 398 <212> DNA <213> mouse <400> ccaccaaccc agaaatttga caaaggggtt gaatgttgga ctttgcgtcc ttccccggca gtggatgtac tgttttgagc cctgtgtgga acttctgaac ttcgtgctgt aactttcaga 120 180 240 279 120 WO 99/55865 actcttagac atgggtgtgc ctgtattcag gacctgaagt ctgaagaaca tctgttgcca cttcttaaat aacatcggaa gtccgccgaa tctaaattcc tcactgaact gagtacccgt ga acggc cac ccattcagcc tccaaaaggc PCT/NZ99/00051 ctagggtctg tgtgctagat gctgccaacg 180 gtggatccag accaatceag tgtgagacta 240 accaaacaga tggagtgccc cagcacttag 300 agcgagtctg tgtttgcttt ttgttaaatt 360 ttgtgacc 398 <210> 91 <211> 279 <212> DNA <213> mouse <400> 91 gttgttactt cagttgctct tggcgagaaa gcaagaccca gttcgaggaa gcccggctgg tgaccagtcc aagttaagga cgtaagaaaa aacacttgag cggcgggaat gtggtagaca accatagtgg cgttcgggtc aacccgaaga tcttaaactg catcctgagt gagggagctt gattagcatt actgtacagc ttctttgggt ccacggcggt gaggtaggcg tggacagggc catgttaacc ctgccttgta cgtccagcat ggagatgga <210> 92 <211> 401 <212> DNA <213> mouse <400> 92 aaaaagtttt accaaaacct tgtagaatcg tattctttga cacgctctgc aatgaatcat tccatagatg ggcagatggt attaaaacgg gactttacaa taaatgtaca gagaaaagat atacatccta tggagcttcc tttattgact aactgtactt gtggcaccga tcccaaagtt gcattctaga cttgaagcta gaggagtaca tttataaatt agcagagcag gtctacgcca acactacaga agact caaac ctgaacagag cagacagacc agatagtatt aagaggcctg aggcccccga actacaaatc ttgaagcaat aaccctcatt g tcaaagttta ctgacgctag gaaactttat gactcttaaa ttttggaaaa aaccgagcaa 120 180 240 300 360 401 <210> 93 <211> 339 <212> DNA <213> mouse <400> 93 ccactgacct tcccagaagg ccagcagtgc ctcggtaccc atgagaagtc accacagtga catgatgcag cctggccttt cgtgtcatca agaaccctat tacactagct cagaagagtt tgacagccgg agaagacggg tctcacattt cctagagcct ggatttttcc tgcagctgat cggcggatgt ctgtctcccc tgcgagatta gtgaaccctc accatgcgag gctctgctg tgtcaaggag ccaaaagacg tcctgatgga gcttggtgag aacgcctgct ccgagatagt gcgacattcg gatggagt cc tggataccga ccgtggaggg 120 180 240 300 339 <210> 94 <211> <212> DNA <213> mouse <400> 94 ggggtgtggg caacttggat aacctcagct gcttccatct ggctgacatc tttgg <210> <211> 186 <212> DNA <213> mouse <400> ggactctggc ttcctggggc tgcggccgac ctcggtggat cccgctctga ggcggcggcg gcggggcccc agaaacaaga agcgcggctg gaggaggctc gccgaggagc cgctggggtt WO 99/55865 p agaggtcgac cagttcctgg aagacgtccg gctacaggag cgcacgaccg gtggcttgtt ggcaga <210> 96 <211> 244 <212> DNA <213> mouse <400> 96 ggtgaccaaa accccttctg cccccttccc agagactctg acttgaccct ctttccaatt ccctctcccc aaggccatgg attatgaagc ccctctgtaa gatggtgagc caggggccct aagagggcat gaggcacacc ctgatcactg tctcaggcct ttgtgggcac tgactcgacc ctggcccacc tcacgccccc aggccagttg gcaactggtg gctcttgagg gctcttacgc cctt <210> 97 <211> 116 <212> DNA <213> mouse <220> <221> unsure <221> unsure <222> (13) (13) <221> unsure <222> <400> 97 acccggtctg ngnactgccc gccttctggg gcttccttta naggatacag tcttttaccc atctaggact cctgccaccc tgactgctga cttacagcta tgaggtcccg gcttct <210> 98 <211> 307 <212> DNA <213> mouse CTINZ99/00051 180 186 120 180 240 244 <400> 98 ccccgggcca tctgtcgcca cgaattcatg acacctgtga tgagcaattt cgggatatgc tgcagactgg acaggggcca gttcggtggg gggagtcagt tgggtgg taccgggccc tccaggacaa cctaccagcc cataccagga atgcatattt gtgcaagctt cccctcaggc attcagcaaa caagaggtac ccatgaggag ttgcaggttt tggggtccct ggagatcggc acaaacaagt gatgagacaa tagaagatgg gtgccgttcc tgggaaaggt attcctctca gctttccagc 120 180 240 300 307 <210> 99 <211> 360 <212> DNA <213> mouse <220> <400> 99 ccttggtgca ccagctccag tgtcccagca gaatccagtg tgggaaccag acagccttgc ccaggttgct cagaagcaca ctaaccaaag actctagaac cctcaggact acaggaagga ttcactgtat aagggtgtgg tCtggggtgg tCCtcctcct gtttctgagg aagtgccctg ctactggccc gggagaaaca ggccctgaca gcccagctct caggggagga ggcttctcca atcacacgca gaatgaagtg taaccatgga ctacgtggtt atgtgttctg tgctccagaa 120 180 240 300 WO 99/55865 p 'CT/NZ99/00051 360 ctcggctt cctggcccat atggatgggc ttggcaagga acctacctct tctctaaggt <210> 100 <211> 257 <212> DNA <213> mouse <400> 100 tgccgcgctg agaggggggg ccgcaccacc agcgccacca ccaccaccgc cgccgccgcc gggtggggtg ggaggggcgg gagccaccgc taccgccgcc gcctcccggg tgggcgccct tctccttaga cgccggcgac ccaggacgag ggcttcatca ctgtaaatgg ttgcaagccg acaaagctgc acctcctgaa aaagacggac agcccatcgc gtgagctgta gaaatttgtg gacgcatttc tatcggt <210> 101 <211> 203 <212> DNA <213> mouse <400> 101 ccaaagtgcc cattgtgatt caagacgata gccttcccac ggggccccct ccacagatcc gcatcctcaa gaggcccacc agcaacggtg tggtcagcag ccccaactcc accagcaggc cagcccttcc tgtcaagtcc ctagcacagc gggaggcaga gtatgcagag gctcggagac ggatcctagg cagtgccagc cct <210> 102 <211> 300 <212> DNA <213> mouse 120 180 240 257 120 180 203 <400> 102 agtacagaga cctcggctgc agccaacccc aactcagcca ggagcaagaa tgagcttagg cggcctggtg gcagccggtc cagcggaaac acagagcttg agcttaaacc tctttggggg ttgggaggga gccctacagg tgagtgcatg tcggacagtg agccaggccc atggggcgtg ccccattccc tcagctgtta gcaacgcccc agagaggaag ggggagctgg gcctggcact acaagtggtt tcaatcaagt tggttcagaa agcaagacca gtcctcctta tctagtacat 120 180 240 300 <210> 103 <211> 370 <212> DNA <213> mouse <220> <400> 103 cagcaactgt ttcaggagct ctgggcgtgg cccccaaaga gccatggaga tcctcaaagt gatgaggaag atgctgcccz gttgaagctg ctggggaccg aacttgcccc tcaagtgttt gagtcaatgg gcacggtgta aaaccctccg gctctttaat t taccggt ac cacagaggag ggatgtgctz cgcctgctga gtgatgcttc atcacctttg ctggggactc ttccacggcc ctggccctgg ctgatgcgct cagcccaaga actctgtcaa ttctgcggca acacggtgaa agctccacga ggaactaaca gacggagagg gagggaagt t ctgcgtgatg tctcctgggg aggatc ctt a 120 180 240 300 360 370 <210> 104 <211> 423 <212> DNA <213> mouse <400> 104 tttcccagcc tggtggagca gccgactggc gagtgtgcca actgtcccgt gcttcccagc WO 99/55865 WO 9955865PCT/NZ99/00051 tcctaccttg atcgcctcag gacgtggacg gtagaggcct ggagacctga gagatccgca gat cctgtcttct gcaagagctc tcattgcgcg ttggcactga tcttcaacca aggaaatgat Ctctcctggg cgtcatccag gcacgttgtc agtcttgctg gcctgaccgt gaaggaga cc aagatgttcc gtattccaac cagccagggt gagaatggcg cggcagctgc ttcaagtact tggtggggct agctgggctg atcctgccca acatcgaccg tcaactccat tctccgaggt gacgggaggc tgctgtaatc ccggcgtata caaggtcctc tacccaccct accgatacgt 120 180 240 300 360 420 423 <210> 105 <211> 117 <212> DNA <213> mouse <400> 105 agcttggtgc tgttcatatt taaactgata aagactcttc ataggagctg agggtagcaa gcccgcgtcg gtgactgggg tctcacacag gttcagcact tggagcatag tgaggtg <210> <211> <212> <213> 106 133

DNA

mouse <400> 106 tttttttttt aaaataccac catttccaat cccaaaagaa catggcactt gtttgtttct tccccttctc attcattcca gactttcaag tgttttcttc aatactgagg ctttctcctg cagctctggt ctg <210> <211> <212> <213> <220> <221> <222> 107 217

DNA

mouse unsure <221> unsure <221> unsure <222> (23) <221> unsure <222> (34) (34) <221> unsure <222> (37) (38) <221> unsure <222> (42) <221> unsure <222> (50) (52) <221> unsure <222> (55) (58) <221> unsure <222> (152) (152) <221> unsure WO 99/55865 <222> (155) (155) <221> unsure <222> (165) (165) PCT/NZ99/00051 <400> 107 fttttttttg ngcgcacnnn tttcttctcc aggctgaaga ccaaagcagc ggccgcggcc gcccctcctg tctactccaa nnngnnnncg cccnggnngn nnagcctacn nncannnngt cctgaacgtc aagttggaag gggagccttc catgcggaaa ggagcccctc ancancccca ccaangcggg cactttcatc catcacccct taccaga <210> 108 <211> 346 <212> DNA <213> mouse <220> <400> 108 gggcatagaa ggcatctcga gcaggaaggc tcagaagaca aggcgtcagg acatcgatac tgggtaagtt cggacaggat agcagcagga agcatggttt gacaagtatc gctgctccag aaagaatact ggagtgtttt ctggtgcccc tcgcaaagaa gctttggatc cagcttgact tatttgaatt acctctttca ggcttagccg ttgaagattc taggtctgaa gctgtaaaga gaaggaagat tgacctggat agcagagttg ggtgctggtt gagtgcctcc ggatct gaagaggcct cc tt tgc tcc gaagggctgc gggtgctccg tccagccgtg 120 180 240 300 346 <210> 109 <211> 242 <212> DNA ous <400> 109 ccacattgtc cacaactgga aggcacgatg gttcatcctt cggcagaaca cgctcctgta ttacaagcta gagggtggcc ggcgagtaac cccgcccaag gggaggattg tccttgatgg ctgcaccatc acctgcccct gcctggagta tgaaaaccgg ccgctcctca ttaaactgaa gacccgaact tccactgagt acttcctgga agcctgttct cgagaggaga gagactcctg 9g <210> 110 <211> 310 <212> DNA <213> mouse <220> 120 180 240 242 <400> 110 cccggccggg aatccaggtg cggctccccc gcggcccgcc tcgctgagcg ctgagcagcg gagggcgggc gggcagtggg tggctgtccg gctgtcgcgc ggctgacccg gtagctggtg gagtcgcctc cggagagtga cgcgcagacz ctcctgccgg cctcgccgcg gtctcccttg ctccctgaga gcccgggaga ggaggccttg ggcgacgggg cgcggagagg ggcgccgcgg atctctatat ggcgacggct ctgtcgggtc tcggccgnc cgcccgctcc tatggggtct tctgcaa-gg 120 180 240 300 310 <210> 111 <211> 228 <212> DNA <213> mouse <400> 111 ttctttttta acatttggtg gtttttttct ttactctttt tttcttttcc ttctttttct gccctcaacc ccccaactcc tttggtatga agtactttta acatttatat ttcattgtta 120 WO 99/55865 PCT/NZ99/00051 cactttaaat tttgtaagga aaactctgat atttcattcc tcctgaacca ctaatgttag 180 aatttatttc taagaatcag tcaacatgta tactcttaat agtgaatt 228 <210> 112 <211> 292 <212> DNA <213> mouse <400> 112 gtggggtccc agacttgcca accaaagggc cattcctggt atatggttct ggcttcagct ctggtggcat ggactatggt atggttggtg gcaaggaggc tgggaccgag tctcgcttca 120 aacagtggac ctcaatgatg gaagggctgc catctgtggc cacacaagaa gccaccatgc 180 acaaaaacgg cgctatagtg gcccctggta agacccgagg aggttcacca tacaaccagt 240 ttgatataat cccaggtgac acactgggtg gccatacggg tcctgctggt ga 292 <210> 113 <211> 255 <212> DNA <213> mouse <220> <400> 113 ttagatgact taggacttta atgttttcca tgcagtcgat tgaaaacact gatacatgaa caaccagaaa aagacctcag caatgtatag acctggaata tatagtgttg ccctggttaa 120 actacaagaa cagccacgtg atcacagttt gagggtggaa ggcaggggtg tgactgagtt 180 ttgtttaacg gcctaaccga aaagcaaaga atcaaccatt tcttctactt gtggcaagaa 240 acgagagtca tggtg 255 <210> 114 <211> 197 <212> DNA <213> mouse <400> 114 gacccacatg tgaacagccg cgtgtatgtc acactgctct gtgtgtgatt tcttcacgtg tgcatgtgcg ctcttggtct ttccacttat tgcctcgttc gtaagaaacc aaccataagg 120 tgccaaggag gttttattcc tttttttttt aaagatgaca aatgtacaga tgttagtaca 180 gatgttaatg tacagat 197 <210> 115 <211> 205 <212> DNA <213> mouse <400> 115 aaaacatttc acaaaacagc aaaacaaaat tgatacaatc aaaaaaacaa cactataacc aacataggtg aaaacagcca aacacataat gtacaatctg gtgttccagg acaaacatct 120 gtcatataca tggtatatac atatatactt tttcactcaa tatattatga caatatatat 180 ttaaaatttt gttatagaca aaaaa 205 <210> 116 <211> 202 <212> DNA <213> mouse <220> <400> 116 cctccctcat cctctacttc ccttttcctt cctgcttgat tttctcattc cagaccccta WO 99/55865 PCT/NZ99/00051 tgcacacaca cacacacaca cacacacaca cacgaacaca cgcacacaca cacacacacg cacacacaca ctgtccatcc atagttactt atttagtttt ccattcctag agagatctaa tcatccccta gtcagtgcct aa <210> 117 <211> 240 <212> DNA <213> mouse 120 180 202 <400> 117 ccgccaggag aggagataca cgcttctgct gtgtgaagga acgatggatg cgctccgcac gtaccgaggc cgtgggagcg cagccagtga tgtggaccac cggatggctg ttgctgctgc gcgcaagccc tggagtgcta cagctgcgtg cagaaggcgg aggatgaaga cagtcaaatg tggtcccggg gtggacgtct gtagagacca tccacgggca attctctgtg gcggtgcggg <210> 118 <211> 527 <212> DNA <213> Human <400> 118 ccgtcagtct agaaggataa gttccaatat cagtctatct gtgactgtaa cacctccaat gctcacaaca tagaaggacc aacagttact gcatcaacgg aggtgtttta ctggttatac gtggattctt atgaaaaata tttcttgtta ttttttactg aatgtctatt ctgaaaaga gagaaagaaa tttattcaac cacagcccag catagccttg tgcttgtgca tggagaaagg cattgcaatt ctatataaga gttaagcaac gcaatgacag caaggtaact aagttctcac ttccaccatg tgtgagcact gggattggtg aagaggtgtc tacaggaaat cactgaccga ggacagttaa acctttgcct agctagagaa tgactttaac ttggattact taaaattgaa ggctttggga agaggcagcc caaaacagaa ggaagatcat agccatctgc ttcatatgct attaagtggt atcgccttac <210> 119 <211> 655 <212> DNA <213> Rat <400> 119 atggcgcgcc ccgcgccctg gcgctggtcc gggtgccctc cccccagtac ggctcttcac caacccatct acttggcagt tatggacgtg gagcccccta aagatgtcgc tggatcctgc ctggaagccc tcgatgacat tacacggccc gcaggatcct gaccagcccc attttgacat gggagaggtg aggggacagg tgctctgcat ctgaataaaa gtggtggctg agcccgggcc cgaggaggag gaagggagtg caacgccttg agacctcact cttcagcaag caacgaggat aaaggac gag agttaaatgt ctgatattta cggccgctgg gggcagatgc ctggcccgct gtgttcgatg gccgggaagg catgacattt gtgtacaaag ggcagcccca ttctaatgtc cccacggaac actgggaaaa cggcgctcgc cgcgccccgc acagcggcga tcacctctgg actcgagcag ctggtctcac ccaaataccc acctggactt tagctgagaa aagcagggga aaaaaaaaaa cctggcgctg agagcgcggg ggaggaggat gaaggagttt aggtgtggcc tgccaaggag cattgttggc caagcctgaa gctggttcta agcctctgag aaaaa <210> 120 <211> 176 <212> PRT <213> Rat <400> 120 Met Val Pro Cys Phe Leu Leu Ser Leu Leu Leu 1 5 10 Pro Val Val Ala Tyr Ser Val Ser Leu Pro Ala 25 Val Ala Gly Ser Gly Glu Ala Glu Gly Ser Ser 40 Leu Val Arg Pro Ala Ser Phe Leu Glu Glu Ala Ser Ser Pro Ser Leu Gin Gly Gly Thr Glu Phe 145 Leu Met 1 Ser Gin Gly Phe Pro Giu Gin Met 1 Ser Val Asp WO 99/55865 Leu Pro Pro Pro Thr Ala Ile Val Asp Ser Leu Thr 100 Arg Gin Lys 115 Lys Lys Tyr 1.30 Ser Giu Vai Asp Phe Phe PCT/NZ99/00051 <210> <211> <212> <213> <400> Giu Leu Arg Thr Ile Arg Ala Giu Phe Met Cys Asp Glu Ser Lys Gin 115 <210> <211> <2 12> <213> <400> Asn Leu Asp Gly Leu Asn Ile Cys <210> <211> <212> <213> <400> Arg Pro Phe Phe His Val Pro Gin 165 Tyr 5 Lys Lys Ser Giu Pro Ala Thr Val1 70 Phe Leu Lys Asp Asp 150 Gin Trp Leu Ala Ser Giu 70 Leu Asp Pro Gly Arg Ile Ala Gin 135 Arg Leu Cys Pro Leu Tyr Asp Glu Gly Phe Val Tyr Phe 105 Al a Asp Pro Al a Leu Arg His Phe Thr Lys Gly 105 Ser Pro Val1 Ile Tyr Arg Asp Asp 170 Cys Asp Asp Ara Pro Leu Asp Pro Pro Met Val1 Tyr Aila Ser 155 Ile Leu Giu Ser Asp Leu Ser Pro Pro Asn Ile Ala Ser 125 Giy Gin Ala Leu Leu Val1 Pro Val Gin Pro 122 64

PRT

Human 122 Leu I.

Asp T] His I.

Asp Si 123 68

PRT

Human 123 Giy Ser Ile Ile Leu Ser Ser Phe Leu Val Leu 10 Thr Ala Ser Pro Ser Ser Met Ser Ser Ser Ser 25 Ser Ser Ser Ser Ser Ser Val Trp His Leu Phe 40 Ser Lys Trp, Asn Ala Tyr Cys Gin Val Trp Gly 55 WO 99/55865 Met Leu Thr Leu Pro PCT/NZ99/00051 1.

Arg Ile Gly Ser Met Leu Ser Leu Leu Asn W11 Met Leu Ser Al a Ser Phe Arg Lys Al a Pro 145 Ser Ser Lys Met Phe Gly Pro Thr s0 Cys Leu <210> <211> <212> <213> <400> Ile Ser Phe Phe Val Cys Thr Ser Gin Asn Leu Leu phs. Drc, <210> <211> <212> <213> <400> Gly Ser Ile Gly Trp Thr Gly Leu Pro Pro Gin Arg Ile Ser Arg Ala 115 Gly Ser 130 Glu Val Val Arg Pro Phe 5.- Leu Pro Leu Thr Arg Phe Leu 1.24 110

PRT

mouse 124 Pro Ala Gin Val Arg Cys Ile Pro Asn Gin Lys Val Thr lhc, 2.00 125 330

PRT

mouse 125 Pro Arg Leu Ala Ser His Gin Trp Lys Phe Lys Leu Ile Pro 100 Gin Pro Gin Lys Gin Ala Leu Cys 165 Asp Thr Ile Leu Val Cys Lys Val Gin Asp Ser Asn Arg 10 Thr Gin Phe Leu Phe Leu Leu Gly Val Leu Gly 25 Phe Ala Phe Ile Ile Gly Leu Asp Gly Ser Thr 40 Phe Leu Phe Gly Ile Leu Phe Ser Ile Cys Phe 55 Trp Ala Asp Val Ile 70 Gin

T-,

Ser Pro Ala Gly Asn Arg Pro Phe Ser 25 Phe Pro Val1 Tyr 105 Thr Lys Asn Thr Ser Asn LeU Lys Ser Asp Thr Asp Ser 110 Gly Pro Ser Tyr Lys Asp Leu Ala Ala Leu Leu Leu Ser Leu Pro Leu Leu 10 Vali Tyr Leu Arg Ser 90 Ser Gly Glu Ile Leu 170 Ser Ala Arg Leu His Leu His Arg Phe Pro 155 Glu Gly Pro Asp Arg Thr Glu Giy His 125 Phe Gly Giu His Cys Lys Lys Pro Glu Gin 110 Leu Asp Pro Asp Thr Leu Arg Ser Al a Ser Arg Pro Leu Lys Leu 175 Val Leu Leu Pro 225 Tyr Leu Cys Ile Phe 305 Pro Met 1 Phe Arg Met 1 Phe Ser Met 1 Thr Gly Lys Lys WO 99/55865 180 Pro Tyr Giu 195 Gin Giu Asp 210 Giu Ala Tyr Ser Gin His Lys Leu Giu 260 Glu Thr Leu 275 Leu Giu Asn 290 Giu Asn Ser Ser Trp Thr Leu Val Ser 230 Gin Ser Asn Asp His 310 Ser PCT/NZ99/00051 Pro 200 Arg Phe Val1 Cys Thr 280 His Glu Asp 185 Cys Lys Trp Met Trp 265 Al a Pro Cys Thr Met Lys Gin Al a 250 Arg Gin Gin Pro Gin 330 Ile Pro 220 Ile Thr Asp Ser Cys 300 Gin Ser Ser Thr Cys 255 Thr Trp Phe Ser Tyr Trp Asp 240 Pro Pro Tyr Ser Leu 320 <210> <211> <212> <213> <400> Leu Trp Phe Pro Ala Asp <210> <211> <212> <213> <400> Gly Ser Val Ala Leu His <210> <211> <212> <213> <400> Met Tyr Asp Ile Trp Giu Pro Leu Met Ala 126 37

PRT

Rat 126 Val Val1 Val1 127 42

PRT

mouse 127 Pro Ile 5 Leu Gly Thr Met 128 253

PRT

mouse 128 Trp Ile 5 Phe Ile Gly Pro Pro Leu Phe Val Leu Ser Leu Thr Pro Leu Leu Ser Pro Leu Ile 10 Thr Val Ala Leu Giu Giu Ile Ser Thr Ile Cys 25 Ser Gly Val Cys Pro Val Leu Pro Gly Gly Leu 10. Trp Ile Phe Leu Leu Phe His Arg Asp Ala Phe 25 Ser Ala Gly Phe Pro Val Phe Ala Ile Phe 10 Ser Trp Ser Giy Pro 25 His His His His His 40 Leu Thr His Arg Phe 55 Leu Trp Leu Leu Ser Met Ala Ala Giu Thr Phe Arg Ile Gly Arg Pro Trp Leu Ala Ser Gly Ser His Pro Phe Tyr Tyr Glu Phe Pro Tyr Thr Lys Gly Ala WO 99/55865 70 75 Ser Leu Leu Tyr Arg Lys Phe Val His Pro Ser Leu Ser Arg His Glu 90 Lys Glu Ile Asp Ala Cys Ile Val Gln Ala Lys Glu Arg Ser Tyr Glu 100 105 110 Thr Met Leu Ser Phe Gly Lys Arg Ser Leu Asn Ile Ala Ala Ser Ala 115 120 125 Ala Val Gin Ala Ala Thr Lys Ser Gin Gly Ala Leu Ala Gly Arg Leu 130 135 140 Arg Ser Phe Ser Met Gin Asp Leu Arg Ser Ile Pro Asp Thr Pro Val 145 150 155 160 Pro Thr Tyr Gin Asp Pro Leu Tyr Leu Glu Asp Gin Val Pro Arg Arg 165 170 175 Arg Pro Pro Ile Gly Tyr Arg Pro Gly Gly Leu Gin Gly Ser Asp Thr 180 185 190 Glu Asp Glu Cys Trp Ser Asp Asn Glu Ile Val Pro Gin Pro Pro Val 195 200 205 Arg Pro Arg Glu Lys Pro Leu Gly Arg Ser Gin Ser Leu Arg Val Val 210 215 220 Lys Arg Lys Pro Leu Thr Arg Glu Gly Thr Ser Arg Ser Leu Lys Val 225 230 235 240 Arg Thr Arg Lys Lys Ala Met Pro Ser Asp Met Asp Ser 245 250 <210> 129 <211> <212> PRT <213> mouse <400> 129 Met Lys Ala Met Ala Leu Ser Leu Gly Ala Ser Pro Val Leu Ala Phe 1 5 10 Leu Leu Ser Gly Tyr Ser Asp Gly Tyr Gin Val Cys Ser Arg Phe Gly 25 Ser Lys Val Pro Gin Phe Leu Asn <210> 130 <211> 87 <212> PRT <213> mouse <400> 130 Met Ile Ala Val Thr Phe Ala Ile Val Leu Gly Val Ile Ile Tyr Arg 1 5 10 Ile Ser Thr Ala Ala Ala Leu Ala Met Asn Ser Ser Pro Ser Val Arg 25 Ser Asn Ile Arg Val Thr Val Thr Ala Thr Ala Val Ile Ile Asn Leu 40 Val Val Ile Ile Leu Leu Asp Glu Val Tyr Gly Cys Ile Ala Arg Trp 55 Leu Thr Lys Ile Gly Glu Cys His Val Gin Asp Ser Ile Gly Ser Met 70 75 Gly Leu Gly Gin Gly Gin Pro <210> 131 <211> <212> PRT <213> mouse PCT/NZ99/00051 Met Val1 Cys Ser Gly Met 1 Phe Ser Val1 Met 1 Ile Ser Met 1 Cys Ala Gin Leu Ala WO 99/55865 <400> 131 Phe' Gly Leu Cys Val Cys Gly Cys Val Leu His Pro Leu Ser Leu PCT/NZ99/00051 His Val Cys Thr Cys Val Cys Val Cys Val Cys Cys Ile Cys Ser Cys Gly Tyr Val His Val Pro 25 Leu Trp, Gly Pro Glu Val Arg Tyr Leu Pro Leu 40 Gly Phe Cys Phe Val Leu Phe Cys Phe Gly Pro 55 Ser <210> <211> <212> <2 13> <400> Trp Leu Val Thr Leu His Pro Leu <210> <211> <212> <213> <400> Asp Asn Ser Val Lys Asp <210> <211> <212> <213> <400> Pro Thr Gly Ser Ser Lys Asp Arg Glu His Gly Glu 132 63

PRT

mouse 132 Leu Val Ala Leu Thr Leu Ser Val Tyr Ser Leu Val Ala 5 10 Gly Met Leu Cys Asp Thr Val Val Ile Lys Met Leu Met 25 Lys Ser Ser Lys Leu Asn Pro Arg Ala Lys Cys Gly Gly 40 Ile Pro Ala Leu Trp Gly Gln Val Gin Val Val Leu 55 133 39

PRT

mouse 133 Thr Leu Ser Ile Ile Ile Tyr Leu Leu Phe Ile Phe Ala 5 10 Leu Asp Ser Gin Leu Ser Thr Arg Cys Leu Trp, Trp Phe 25 Leu Giu Vai Thr Trp 5 His Leu Leu Ser Leu Pro Thr Leu Val Tyr 70 Gly Leu Thr Glu Val 55 Cys Ile Leu Leu Lys 40 Thr Ser Cys Val Leu Trp Leu Aia Leu Vai 10 is Lys Ser Asp Ala Lys Lys Ala Gin Phe Ser Asp Lys Pro Val Ile Lys Ala Giu Asp Vai Val Arg Ala Arg Giu Arg Asn Phe 75 Ser <210> 135 <211> 193 WO 99/55865 PCT/NZ99/00051 <212> <213> <400> Met Thr Ser 1 Asp Thr His Leu Gin Ser Phe Leu Asn Tyr His Ser Ser Ile Asn Asp Gin Phe Arg Leu Leu 115 Ser Pro His 130 Ile Trp Gin 145 Trp Gin Asn Leu Asp Arg Ser <210> <211> <212> <213> <400> Met Ala Ala 1 Leu Arg Arg Gly Leu Ala Asn Pro Glu so Ala Ser Gly Ala Trp Ala Leu Asp Leu <210> <211> <212> <213> <400> Met Ala Ala 1 Val Gly Gin

PRT

Rat 135 Gly Pr Gin Tr] Val Ph Asn Se Phe Va Gly Lei Gin Ar 100 Asp Lei Phe G1 Leu G1 Thr Gl 16 Cys As 180 o Gly Gly Pro Ala Ala Ala Thr Gly Giy Gly Lys p r 1 u u n 5

P

Tyr Val Ile Ser 70 Leu Leu Gly Glu Lys 150 Phe Gin Asp Ala Leu Ala Arg 70 Thr Asn Val Gin Glu 55 Ser Gly Leu Ala Ile 135 Lys Gin Pro Arg Leu Pro Ser 55 Leu Asn Gly Cys Ser 40 Lys Val Arg Lys Gly 120 Tyr Lys Tyr Leu Thr Ala Thr 40 Arg Glu Ala Ser Asn 25 Tyr Ser Phe Gly Ile 105 Asp Ala Tyr Asp Thr 185 His Ser 25 Leu Thr Tyr Ile Tyr 105 Arg Leu Gly Thr Ser 90 Asn Gly Thr Arg Va1 170 Leu Gly 10 Leu Gly Arg Gly Arg 90 Lys Glu Asp Trp Leu Met Pro Glu Glu Val 155 Ile Leu Gly Ala Pro Ser Phe Glu Lys Gin Leu Phe Phe Asp Va1 Leu 140 Leu Ser Lys Arg Gly Gly Leu His Thr Leu Gly Phe Met Val Trp Thr 125 Ser Gly Cys Asp Ala Leu Trp Leu Pro Gly Cys Thr Ile Ser Phe Lys 110 Lys Glu Ile Leu Ile 190 Ala Leu Arg Leu Asp Trp Glu Gin Gin Arg Ser Thr Ile Thr Asn Asn 175 Arg Arg Leu Arg Asp Ala Ala 136 106

PRT

Rat 136 Pro Ala Gly Pro Gin Asn Gly 100 137 286

PRT

Rat 137 Ala Gly Met 5 Leu Ala Pro Leu Leu Thr Met Pro Leu Gly Leu Ser Leu Leu Leu Leu Val Leu 5 10 Cys Cys Gly Arg Val Giu Giy Pro Arg Asp Ser Leu WO 99/55865 WO 9955865PCT/NZ99/00051 Arg Thr Val Lys Arg Giu Trp As n 145 Pro Val1 Lys Ala Arg 225 Arg Ile Met 1 Ala Arg Gly Met Asp Gly Arg His Gly 145 Phe Glu Glu Phe Gin Ser His Tyr Ser Thr Arg Leu Trp 115 Lys Giu 130 Phe Ile Leu Gly Leu Pro Leu Leu 195 Asp Arg 210 Pro Ile Gin Thr L.U b U Thr Gly 275 <210> <211> <212> <213> <400> Thr Val Cys Ala Arg Asp Pro Gin Val Gly Gly Asp Asn Arg Ala Gly 115 Gly Ile 130 Leu Pro Ser Val Leu Phe Tyr Leu Tyr 100 Val Leu Asp Leu Arg 180 Pro Leu Cys Leu i-A la 260 Tyr 138 198

PRT

Rat 138 Phe Leu Phe Gly Arg Arg Gly 100 Pro Pro Gly Ala Val Arg Arg Arg Trp Trp Ser Ser Ala 165 Giu Cys Phe Arg Ser 245

CYS

Ser Arg 5 Pro -Gin Pro Met Gly Lys Arg Gly Pro Val Ile Thr Leu 70 Glu Giy Phe Asn Thr 150 Asn Val1 Ser His Asn 230 Vai Pro Gin Lys Cys Lys Pro Gly 70 Asp Gin Gly Lys Cys 150 Thr Thr Arg Phe Leu Pro Gin Val1 135 Asn Asp Val1 Ser Thr 215 Ala Val1 JLeu Asp Val1 Ala Gly Gly 55 Phe Ser Gly Pro Lys 135 Ser Lys Pro 40 Trp Pro His Pro Asp 120 Leu Thr Thr Cys Lys 200 Ser His Phe Al a Asn 280 Thr Al a Gly 40 Pro Pro Gly Pro Lys 120 Gly Cys Ser Leu Asp Lys Leu Phe 105 Thr Ser Val Asp Thr 185 Al a Tyr Cys Asp Ser 265 Glu Thr Asp 25 Pro Pro Gly Giu Lys 105 Gly Pro Gly Tyr Pro Ser Ala Ser 90 Leu Val1 Gly Thr His 170 Giu Gly His Thr Ala 250 Gin Thr Met 10 Pro Gin Gly Lys Giu 90 Gly Val Lys Ser Pro Ser Asp Leu 75 Phe Gin Thr Ile Pro 155 Tyr Asn Leu Ser Ser 235 Phe Ser Leu Ile Met Leu Al a Asp 75 Giy Lys Ser Gly Ser 155 Arg Gly Leu Gly Thr Ala Asp Phe 140 Thr Phe Leu Ser Gin 220 Ile Ile iLeu Giu Ser Leu Val1 Pro Gly Pro Ala Gly Lys 140 Arg Glu Asp Gin Gin Gin Pro Vai 125 Cys Al a Leu Thr Val1 205 Ala Ser Thr Val1 Val1 285 Trp Gly Cys Gly Gin Pro Gly Thr 125 Lys Al a Arg Val1 Arg Leu Gly Ser 110 Asp Al a Ser Arg Pro 190 Leu Val1 Trp Gly Tyr 270 Ser Met Ala Ser Ser Asp Gly Ala 110 Pro Gly Lys Leu Ala Glu Ile Phe Gly Lys Ser Phe Tyr 175 Trp Leu His Glu Gin 255 Val1 Leu Phe Leu Ser Gly Arg Ile Gly Glu Ser Pro Ala Gly Ser Trp Ala Ser Leu Lys 160 Al a Lys Lys Ile Leu 240 Gly Asp Leu Al a Pro Gly Gin Thr Gly Lys Pro Ala.

160 Ile WO 99/55865 PCT/NZ99/00051 Lys Phe Asp Ser Gly Lys 195 <210> <211> <212> <213> <400> Met Ala Ser 1 Val Leu Leu Asn Glu Lys Lys Ser Gin Val Ala Pro Trp Asp Gin Val His Gin Ser Phe Asp 115 Ile Val Asn 130 Lys Val Lys 145 Asn Thr Arg Lys Glu Lys Met Asn Val 195 Arg Thr Ile 210 Glu Asp Thr 225 165 170 175 Lys Ile Leu Met Asn Glu Gly Gly His Tyr Asn Ala Ser 180 185 190 Phe Val Cys 139 233

PRT

Rat 139 Ala Glu Ser Lys Leu Ser Val 100 Leu Asn Thr Trp Pro 180 Leu Asn Glu Leu 5 Lys Lys Lys Thr Asp Pro Leu Leu Asp Asp 165 Ser Lys Lys Glu Ser Ile Pro Thr 70 Lys Ala Val Leu Thr 150 Tyr Tyr Lys Ala Glu Thr Glu Glu 55 Gly Phe Glu Lys Lys 135 Val Leu Asp Ile Trp 215 Leu Arg Thr 40 Phe Tyr Val Asn Asn 120 Pro Ile Thr Thr Tyr 200 Val Gin Lys 25 Glu Asp Thr Lys Val 105 Leu Ile Ile Gin Glu 185 Glu Glu Lys 10 Arg Leu Asn Val Ile 90 Gin Asn Ser Leu Val 170 Ala Asp Ser Asp Leu Arg Glu Lys 75 Tyr Val Gly Val Cys 155 Glu Asp Gly Arg Leu Arg Asn Lys Ile Ile His Lys Glu 140 Arg Lys Pro Asp Glu 220 Glu Asp Lys Pro Ser Thr Phe Asn 125 Ser Lys Glu Ser Asp 205 Lys Glu Thr Met Ala Asn Leu Thr 110 Tyr Ser Lys Cys Glu 190 Asp Gin Val Leu Gin Ala Tyr Thr Glu Ser Ser Ala Lys 175 Gly Met Ala Lys Thr Gin Val Gly Gly Arg Met Lys Glu 160 Glu Leu Lys Arg Phe Leu Gin Pro Gly 230 <210> <211> <212> <213> <400> Met Gly Leu 1 Ser Ala Phe Ile Asp Thr <210> <211> <212> <213> 140 38

PRT

Human 140 Ala Leu Cys Leu Ala Ser Ala Gly Ile Ser Gly Ser Arg 5 10 Leu Gly Val Pro Arg Pro Arg Pro Thr Leu Ile Lys Leu 25 Val Asp Leu 141 322

PRT

mouse WO 99/55865 WO 9955865PCT/NZ99/00051 Met Leu Gin Phe Tyr Val Arg Val Leu Pro 145 Val1 Pro Asn Phe Met 225 Leu Ser Val Gin Gly 305 Gin Met Giu Ile Arg Gly Lys <400> Asp Ala Gly Ala Leu Trp, Met Val so Leu Glu Phe Gly Thr Giu Phe Cys 115 Gin Glu 130 Gly Giu Leu Ala Arg His Val Leu 195 Pro Thr 210 Met Gly Thr Ala Gly Pro Leu Leu 275 Asp Ala 290 Val Asn Gly <210> <211> <212> <213> <400> Leu Cys Phe Gin Phe Lys Gin Trp Gin Leu Lys Leu 141 Arg Gly Leu Pro Thr Asn Thr 100 Ala Arg His Leu Gly 180 Ser Gin Lys Gly Glu 260 Al a Leu Leu Trp Gly Phe Gly Gly Glu Ala Ser Val Phe Val1 165 Ala Ser Val1 Leu Leu 245 Pro Gly Phe Phe Trp, Giu Arg Tyr Arg 70 Pro Glu Gly Met Thr 150 Val Pro Trp Leu Val 230 Ile Arg Tyr Al a Ser 310 Leu Giu Val Lys Glu 70 Val Al a Ser Phe Leu 55 Gly Lys Ser Leu Thr 135 Asp Ala Met Cys Ala 215 Ser Ser Ser Ile Tyr 295 Cys Tyr Ser Phe Ile 55 Giu Phe Val Pro Leu 40 Leu Leu Ala Thr Gin 120 Gly Ser Gly Tyr Gin 200 Lys Arg Ile Ser Al a 280 Lys Leu Val1 Lys Ile 40 Val1 Phe Lys Val Glu 25 Leu Val Cys Pro Pro 105 Val1 Ser Gin Leu Arg 185 Tyr Ala Arg Gly Pro 265 Phe Met Phe Pro Gly 25 Pro Gin Val Ser Val1 Al a Asn Gin Phe Asp 90 Ser Ser Tyr Phe Tyr 170 Tyr Glu Ser Se r Val1 250 Al a Asp Ser Thr Ile Leu Ser Ala His Leu Leu Pro Val Tyr Pro 75 Glu Trp Tyr Gly Leu 155 Cys Ser Al a Lys Tyr 235 Ser Thr Ser Ser Val1 315 Ala Pro Gin Gly Tyr 75 Asp Al a Pro Al a Leu Leu Val Gin Leu Al a 140 Val Val Phe Leu Val 220 Glu Met Thr Phe Val 300 Gly Gly Al a Glu Asp Leu Lys Thr Gin Gly Arg Val1 Leu Val1 Thr 125 Thr Leu Leu Ala Lys 205 Ile His Phe Leu Thr 285 Gin Ser Ala Glu Phe Lys Gin Lys Leu Ser Tyr Arg Lys Leu Leu 110 Trp Al a Met Arg Ser 190 Phe Pro Trp Leu Ser 270 Ser Met Leu Al a Leu Ser Asp Asp Asn Pro Trp Ala Lys Al a Ala Lys Gly Thr Asn Lys 175 Leu Val Val1 Glu Leu 255 Gly Asn Met Leu Gin Lys Thr Leu His Asp Ser Thr Ser Asn Cys Pro Leu Ile Ser Arg 160 Gin Ser Ser Met Tyr 240 Ser Leu Trp, Phe Glu 320 Thr Ser Tyr Asp Glu Gly 142 312

PRT

mouse 142 Leu C, Tyr P1 Leu S( Lys G.' Asp PI Arg L( WO 99/55865 PCT/NZ99/00051 90 Arg Ile Asp Ala Gin Glu Ile Met Gin Ser Leu Arg Asp Leu Gly Val 100 105 110 Lys Ile Ser Glu Gin Gin Ala Glu Lys Ile Leu Lys Ser Met Asp Lys 115 120 125 Asn Gly Thr Met Thr Ile Asp Trp Asn Glu Trp Arg Asp Tyr His Leu 130 135 140 Leu His Pro Val Glu Asn Ile Pro Glu Ile Ile Leu Tyr Trp Lys His 145 150 155 160 Ser Thr Ile Phe Asp Val Gly Glu Asn Leu Thr Val Pro Asp Glu Phe 165 170 175 Thr Val Glu Glu Arg Gin Thr Gly Met Trp Trp Arg His Leu Val Ala 180 185 190 Gly Gly Gly Ala Gly Ala Val Ser Arg Thr Cys Thr Ala Pro Leu Asp 195 200 205 Arg Leu Lys Val Leu Met Gin Val His Ala Ser Arg Ser Asn Asn Met 210 215 220 Cys Ile Val Gly Gly Phe Thr Gin Met Ile Arg Glu Gly Gly Ala Lys 225 230 235 240 Ser Leu Trp Arg Gly Asn Gly Ile Asn Val Leu Lys Ile Ala Pro Glu 245 250 255 Ser Ala Ile Lys Phe Met Ala Tyr Glu Gin Met Lys Arg Leu Val Gly 260 265 270 Ser Asp Gin Glu Thr Leu Arg Ile His Glu Arg Leu Val Ala Gly Ser 275 280 285 Leu Ala Gly Ala Ile Ala Gin Ser Ser Ile Tyr Pro Met Glu Val Leu 290 295 300 Lys Thr Arg Met Ala Leu Arg Lys 305 310 <210> 143 <211> 163 <212> PRT <213> Rat <400> 143 Met Pro Leu Val Thr Thr Leu Phe Tyr Ala Cys Phe Tyr His Tyr Thr 1 5 10 Glu Ser Glu Gly Thr Phe Ser Ser Pro Val Asn Leu Lys Lys Thr Phe 25 Lys Ile Pro Asp Arg Gin Tyr Val Leu Thr Ala Leu Ala Ala Arg Ala 40 Lys Leu Arg Ala Trp Asn Asp Val Asp Ala Leu Phe Thr Thr Lys Asn 55 Trp Leu Gly Tyr Thr Lys Lys Arg Ala Pro Ile Gly Phe His Arg Val 70 75 Val Glu Ile Leu His Lys Asn Ser Ala Pro Val Gin Ile Leu Gin Glu 90 Tyr Val Asn Leu Val Glu Asp Val Asp Thr Lys Leu Asn Leu Ala Thr 100 105 110 Lys Phe Lys Cys His Asp Val Val Ile Asp Thr Cys Arg Asp Leu Lys 115 120 125 Asp Arg Gin Gin Leu Leu Ala Tyr Arg Ser Lys Val Asp Lys Gly Ser 130 135 140 Ala Glu Glu Glu Lys Ile Asp Val Ile Leu Ser Ser Ser Gin Ile Arg 145 150 155 160 Trp Lys Asn <210> 144 <211> 330 Met 1 Al a Gin Leu Val Val Ser Arg Ala Leu 145 Tyr Phe Val Leu Ser 225 Arg Gly Met Trp Phe 305 His WO 99/55865 <212> PRT <213> Rat <400> 144 Ala Gly Trp Leu Trp Leu Leu Ala Pro Ile Arg Tyr Cys Arg Ala Val Ser Val Leu Phe Leu 100 Thr Leu Gly 115 Ser Arg Ile 130 Val Phe Leu Val Ser Val Gly Leu Val 180 Pro Met Asn 1 95 Gin Ala Arg 210 Ser Ala His Asn Lys Lys Asp Trp Phe 260 Ile Tyr Ile 275 Trp Leu Val 290 Phe Asn His Arg Lys Ala PCT/NZ99/00051 Ala Leu Ala Gly Phe Leu Gly Val1 Gin Trp Phe 165 Tyr Asp Trp Gin Gly 245 Glu Ser Val1 Arg Phe 325 Gly Leu Arg Lys Asp 70 Trp Al a Thr Ala Val1 150 Ser Tyr Lys Phe Tyr 230 Val1 Tyr Met Thr Phe 310 Leu Al a Ala Leu Thr 55 Val Asn Pro Gin Gly 135 His Asn Val As n His 215 Lys Val1 Val Al a Tyr 295 Tyr Pro Glu Ala Leu 40 Lys Pro Gly Phe Phe 120 Giu Ser Thr Leu Val 200 Ile Cys Ile Ser Val1 280 Val Lys Phe Leu Ala 25 Pro Gin Lys Ser Pro 105 Gin Leu Leu Ala Val 185 Tyr Leu His His Ser 265 Thr Phe Ser Leu Ser 10 Phe Ser Ser Arg Leu 90 Ser Ala Ala Arg Ile 170 Giy Ala Gly Val1 Cys 250 Al a Phe Phe Thr Phe 330 Leu Leu Al a Ser Phe Trp Leu Giy Ser 140 Leu Val1 Thr Gly Met 220 Leu His Tyr Leu Gin 300 Val As n Ala Leu Arg Ser Phe Trp Met 125 Thr Phe Val1 Val1 Lys Met Ser Arg Leu His 285 Ala Ser Pro Leu Phe Arg His Leu Al a 110 Giu Phe Giu Gin Leu 190 Asn Phe As n Ile Ala 270 Asn Leu Tyr Leu Leu Gin Pro Phe Ser Leu Ser Leu Cys Tyr 175 Ser Leu Phe Leu Pro 255 Glu Val Ser Pro Arg Leu Asp Al a Tyr Gin Leu Lys Val Phe 160 Cys Gin Leu Trp Arg 240 Phe Leu Thr Ala Lys 320 Met

I

Leu Lys Val <210> <211> <212> <213> <400> Leu Val Leu Trp Lys Thr Ser Ser so 145 301

PRT

Rat 145 Ala Lys Asp His Phe Leu Gly Ala Ser Ala 5 10 Lys Ala His Ala Glu Ser 25 Ala Gly Asp Lys Gly Lys 40 Glu Gly Ser Ala Ala Asp 55 Val Thr Ala Ser Thr Gly Pro Pro Ser Val Asn Ser Ser Lys Asp Thr Arg Glu Thr Ala Ala Glu Pro Tyr WO 99/55865 WO 9955865PCT/NZ99/00051 Pro Met Phe Glu Giu Phe 145 Gly Asp Giu Met Met 225 Ser Lys Gin Pro Met

I

His Trp Arg Giu Tyr Tyr Phe Gin Gly Ile Ile Al a 195 Glu Met Leu Lys Cys 275 Gly Lys Giu Phe 100 Met Pro Lys Phe Phe 180 Phe Phe Arg Cys Leu 260 Leu His Lys Asn Ala Thr Giu Lys Tyr 165 Leu Lys Giu His Ser 245 Thr Leu Trp Arg Arg Lys Asp 120 Gly Gin Gly Val Asp 200 Gin Arg Thr As n Pro 280 Glu Ser Ala Val1 105 Phe Leu Giu Giu Leu 185 Leu Ser Pro Thr Phe 265 Val1 Leu Gly Tyr 90 Ile Val Asp Arg Cys 170 Ser Asn Ile Thr Tyr 250 Leu Trp Trp Phe Ser As n Arg Gin Glu 155 Gly Thr Gly Ile Thr 235 Phe Giu Giu Ser Arg Asp Giy 110 Thr Ile Ala Ser Arg 190 Giu Gin Thr Al a Arg 270 Pro Lys Lys Glu Pro Lys Asp Phe 175 Asn Val Thr Leu Asp 255 Lys His <210> <211> <212> <213> <400> Giu Asn Ala Asn Phe Ala Gly Leu <210> <211> <212> <213> <400> Leu Arg Pro Phe Gly Leu Arg Gly Gly Asn 146 Ile Gin Val Ala 147 105

PRT

Rat 147 Arg Cys Pro Tyr His Thr Asn Leu Ile Thr Ile Leu Gly Asn Lys 10 Leu Asn Leu Gin Ala Leu Ile Leu Ser Pro 25 Pro Pro Gly Phe Ala Arg Asp Gin Ala Val 40 Gly Arg Arg Ile Thr Val Val 55 Met 1 Leu Gly Phe Pro Val Trp Trp His 10 Gin Asp Giu Tyr 25 Cys Ser Lys Cys 40 Pro Pro Gly Pro 55 Asn Gly Asn Asn Leu Leu Ala Leu Leu Phe Met Giu Ser Pro Gin Ala Cys His Gly Asp Tyr Gly Pro Gly Pro Pro Gly le Giy Ala Thr Gly His Giu WO 99/55865 WO 9955865PCT/NZ99/00051 Gly Ala Lys Glu Arg Gly Met 1 Al a Val1 Ser Phe Ala Asp His Pro Al a 145 Cys Lys Val1 Ser Met 1 Leu Lys Val1 Pro Met Phe <210> <211> <212> <213> <400> Leu Gly Gin Arg Ala Thr Val Ala Ser Leu Pro Gly Leu Leu Leu Gin 115 Gly Gly Cys His His Arg Ser Pro Asn Pro 195 Leu 210 <210> <211> <212> <213> <400> Leu Val Leu Trp Lys Thr Ser Ser Giu Giu Giu Tyr Arg Tyr Gly Gin 100 148 210

PRT

Rat 148 Ala Asp Ile Val Leu Ser Arg 100 Thr Thr Leu Gly Val1 180 Trp 149 301

PRT

Rat 149 Ala Lys Asp His Lys Glu Phe 100 70 75 Giu Lys Gly Asp Lys Gly Asp Leu Gly Pro Arg Gly 90 His Gly Pro Lys Gly 105 Thr 5 Ser Phe Gly Leu Glu As n Pro Glu Leu Gly 165 Leu Ala Phe 5 Lys Ala Glu Lys Asn Ala Ser Val Leu Asp Gin 70 Gly Ile Leu Ala Tyr 150 Leu Ile Arg Leu Al a Gly Gly Lys 70 Arg Thr Pro 10 Gly Tyr Phe Leu Arg 90 Arg Arg Arg Asn Pro 170 Ala Gly Ala 10 Ser Lys Asp Gly Tyr 90 Ile Trp Met Ile Ser Leu Ser Gin Thr Pro Gly 155 Ser Pro Phe Val1 Pro Ser Thr Phe Ser Asn Leu Leu Ile Gly Arg Arg Thr Ala 125 Ala Ser Val Phe Pro 205 Ala Ser Asp Ala Asp Pro Pro Trp Gly Phe Met Leu Ile Arg 110 Lys Gin Ser Pro Lys 190 Ser Ser Val Thr Giu Arg Asp Gly 110 Ala Gly Tyr Al a Pro Ser Gin Leu Gin Ile Ala 175 Thr Ser Thr Asn Arg Pro Lys Lys Glu WO 99/55865 WO 9955865PCT/NZ99/00051 Giu Giu Phe 145 Gly Asp Giu Met Met 225 Ser Lys Gin Pro Met 1 Phe Phe Gly Ile Val Lys 130 Asp Ser Tyr Ile Giu 210 Giy Gly Gly Arg Thr 290 Phe Gin Gly Ile Ile Aila 195 Giu Met Leu Lys Cys 275 Gly Met Pro Lys Phe Phe 180 Phe Phe Arg Cys Leu 260 Leu His Pro His Ile 150 Thr Thr Met Gin Arg 230 Aia Ile Gly Leu Gin Leu 135 Aia Leu Thr Phe Vai 215 Asp Leu Lys Leu Arg 295 Asp 120 Giy Gin Gly Val Asp 200 Gin Arg Thr Asn Pro 280 Giu Vali Asp Arg Cys 170 Ser Asn Ile Thr Tyr 250 Leu Trp, Trp Arg Gin Giu Gly Thr Gly Ile Thr 235 Phe Glu Giu Ser Ile 125 Ile Phe Ile Gin Gly 205 Ser Asn Gly Gin Ser 285 Leu Thr Ile Ala Ser Arg 190 Glu Gin Thr Al a Arg 270 Pro <210> <211> <212> <213> <400> Lys Leu Leu Thr Gin Asp Ser Asp Val Lys 150

PRT

Human 150 Ser Gly 5 Gly Val Thr Lys Gly Gin Ser Gly 151 27

PRT

mouse 151 Ala Ser 5 Asp Thr 152 86

PRT

mouse Met Phe Leu. Leu Leu 10 Phe Ser Gin Gly Gly 25 Vai Tyr Cys Thr Arg 40 Thr Tyr Gly Asn Lys 55 Gly Lys Ile Ser Leu 70 Ser Leu Ala Leu Phe Gin Vai Asp Cys Giy Giu Ser Asn Pro His Cys Ala Phe Cys Lys Lys His Pro Gly Lys <210> <211> <212> <213> <400> Met Leu Lys 1 Pro Ile Val <210> <211> <212> <213> Leu His Ile Leu Phe Leu Gly Ile Leu Asn Val 10 Ser Thr Lys Thr Gly Vai <400> 152 Met Leu Gin 1 Gly Pro Ala Pro Ser Cys Phe Trp Val Phe Ser Gly Ile S 10 WO 99/55865 CYS Vai Phe Trp Asp Phe Ile Phe Ile Ile Phe Phe Asn Vai Leu Ser PCT/NZ99/00051 Leu Giy Leu Leu Met 1 Leu Asp Ile Ala Met 1 Ser Pro Ala Giu Ala Ser Asn Giy Phe 145 Gly Gly Asn Ala Gin Ala Pro Leu Ser <210> <211> <212> <213> <400> Ser Ala Ile Cys Arg Asn Gly Glu Phe Ser <210> <211> <212> <213> <400> Ser Giy Arg Leu Ile Trp Ala Val Leu Phe Gly Leu Met Ser Asn Gly 115 Tyr Gin 130 Thr Gly Glu Met Arg Gly Gly Phe 153 72

PRT

mouE 153 Ile Thr Lys Arg Ile 154 169

PRT

mous 154 Leu Pro Trp Lys Asn Ser Lys 100 Gly Pro Leu Pro Giu Met Ala Pro Phe 5 Cys Thr Lys Leu Arg Arg Gly Tyr Giu Cys Ser Asp Thr Val Pro 165 25 Ile Ser Ala Lys Asp Phe Ala Asp Gin Pro Ala 40 Trp Gly Ile Trp Gly His Thr Ile Thr Cys Gly 55 Lys Pro Cys Ser Leu Lys Arg Giu Gly Pro Asp 70 75 Pro Asn Phe Gin Ser Leu Leu Thr Val Ile Leu Leu 10 Ala Tyr Ile Arg Ser Leu Ala Pro Ser Ile Leu 25 Gly Leu Leu Gly Ile Phe Trp Lys Cys Ala Arg 40 Ser Pro Tyr Val Ala Ile Cys Cys Ile Val Met 55 Phe Ile Gin Leu 10 Gin Gly Giu Val1 Al a 90 Leu Ala Lys Lys Leu Cys Thr Al a Leu Tyr Cys Leu 125 Asn Ile Val Arg Met Val Met Pro Gly 110 Lys Lys Pro Al a Ala Al a Asp Glu Pro Pro Leu Pro Phe Gly Arg Gly Gin Leu Thr Gly Phe Leu Leu Glu Asp Gly Met <210> 155 <211> 61 <212> PRT <213> mouse WO 99/55865 PCT/NZ99/00051 <400> 155 Met Glu Lys Gin Met Asp Ala Ser Val Ser Val Ile Phe Gly Ser Ile 1 5 10 Val Ile Ser Ala Phe Leu Tyr Leu Ser Leu Ala Gly Pro Trp Ala Val 25 Thr Val Thr Gin Met Arg Thr Ile Ile Ile Thr Met Asp Gln Leu Arg 40 Asp Ala Leu Ile Leu Asp Gin Leu Lys Val Ala Val Ser 55 <210> 156 <211> 131 <212> PRT <213> mouse <400> 156 Met Ala Pro Ser Leu Trp Lys Gly Leu Val Gly Val Gly Leu Phe Ala 1 5 10 Leu Ala His Ala Ala Phe Ser Ala Ala Gin His Arg Ser Tyr Met Arg 25 Leu Thr Glu Lys Glu Asp Glu Ser Leu Pro Ile Asp Ile Val Leu Gin 40 Thr Leu Leu Ala Phe Ala Val Thr Cys Tyr Gly Ile Val His Ile Ala 55 Gly Glu Phe Lys Asp Met Asp Ala Thr Ser Glu Leu Lys Asn Lys Thr 70 75 Phe Asp Thr Leu Arg Asn His Pro Ser Phe Tyr Val Phe Asn His Arg 90 Gly Arg Val Leu Phe Arg Pro Ser Asp Ala Thr Asn Ser Ser Asn Leu 100 105 110 Asp Ala Leu Ser Ser Asn Thr Ser Leu Lys Leu Arg Lys Phe Asp Ser 115 120 125 Leu Arg Arg 130 <210> 157 <211> 133 <212> PRT <213> mouse <400> 157 Met Arg Leu Leu Ala Ala Ala Leu Leu Leu Leu Leu Leu Ala Leu Cys 1 5 10 Ala Ser Arg Val Asp Gly Ser Lys Cys Lys Cys Ser Arg Lys Gly Pro 25 Lys Ile Arg Tyr Ser Asp Val Lys Lys Leu Glu Met Lys Pro Lys Tyr 40 Pro His Cys Glu Glu Lys Met Val Ile Val Thr Thr Lys Glu His Val 55 Gin Gly Thr Gly Ala Arg Ser Thr Ala Cys Thr Leu Ser Cys Arg Ala 70 75 Pro Asn Ala Ser Ser Ser Gly Thr Met Pro Gly Thr Arg Ser Ala Gly 90 Ser Thr Lys Asn Arg Val Asp Asp His Gly Lys Lys Asn Ser Arg Pro 100 105 110 Val Glu Arg Leu Gin Gin Arg Thr Leu Gin Ile Lys Ile Lys Ala Leu 115 120 125 Ser Phe Ser Gin Ala 130 WO 99/55865 <210> 158 PCT/NZ99/00051 Gly Al a Val1 Leu Met <211> <212> <213> <400> Thr Arg Ser Gly Trp Trp Phe Ser so Leu Pro 78

PRT

mouse 158 Lys P: Leu A: Met C, Leu Vi Cys L( Leu Pro Met Glu Ala Leu Ala Trp His Tyr 25 Val Leu Gly Trp Leu 40 Cys Ser Phe Pro Ser 55 Phe Leu Arg Gly Gly 70 His Ser Arg Arg Glu Lys Giu Cys Ser Gly Val Ser Ser Phe Leu Val Phe Leu Pro Ile Asn His Ser His Gly Ser Asn Val <210> <211> <212> <2 13> <400> Met Leu Pro 1 Leu Met Arg Tyr Ser His Leu Asp Arg Thr Lys Tyr Glu Leu Val Trp Ile Gly 115 Gin Giu Trp 130 Leu Gin Cys 145 Thr Ala Cys His Asn Phe Glu Arg Lys 195 <210> <211> <212> <213> <400> Met Ser Gly 1 Ser Arg Leu Pro Ile Trp 159 206

PRT

mouse 159 Pro Ala Asn Cys Val Val n l Asn Ser Ile Ser Cys Ala 100 Gly Gly Arg Cys Gin Asp Lys Cys 165 Glu Ser 180 Arg Ala Leu Phe Val1 40 Gin Gin Cys Thr 120 Asp Thr Tyr Pro Ser 200 Ser Lys 25 Pro Val Cys Leu 105 Lys Lys Arg Thr Ala 185 Ser Leu Thr Ser Se Giu Ser Val1 Arg 125 Gin Ile Asn Gin Leu 205 Leu Giu Ser Leu Pro Leu 110 Arg Arg Thr Giu His 190 Ser 160 169

PRT

mouse 160 Leu Arg Thr Leu Leu Gly Leu Gly Leu Leu Val Ala Gly 5 10 Pro Arg Val Ile Ser Gin Gin Ser Val Cys Arg Ala Arg 25 Trp Gly Thr Gin Arg Arg Gly Ser Giu Thr Met Ala Gly Ala Glu Al a Ser Asn Gly Phe 145 Gly WO 99/55865 Ala Val Lys Leu Phe Asn Gly Leu Ser Met Ser Lys 100 Asn Gly Gly 115 Tyr Gin Pro 130 Thr Gly Leu Glu Met Pro Tyr Glu Cys Ser Asp Thr Val Pro 165 <210> <211> <2 12> <213> <400> Met Ser Val 1 Leu Cys Pro Thr Cys Ser Gly Gln Ser His Ala Cys Pro Arg Gly Leu Phe Met Ser Leu <210> <211> <212> <213> <400> Met His Tyr 1 Phe Ala Trp, Glu Leu Glu <210> <211> <212> <213> <400> Met Phe Thr PCT/NZ99/00051 161 114

PRT

mouse 161 Thr Ile 5 Val Ala Leu Phe Leu Glu Glu Cys Ser Ser Tyr Glu 100 40 Gln Phe Ala Thr Val1 120 Tyr Cys Gly Leu Leu His 40 Leu Cys Arg Gly Glu Ser Ile Val 105 Cys Pro Gln Met Al a Thr 25 Ser Ser Cys Trp Trp 105 Glu Val1 Al a 90 Leu Ala Lys Lys Leu 10 Arg Leu Val Arg Val1 90 Thr Ala Asp 75 Lys Val Arg Arg Met 155 Phe Ser Ser Cys Val 75 Leu Gln Gln Gin Ala Ile His Pro 140 Asp Leu Trp Leu Phe Leu Gly Gly Al a Leu Tyr Cys Leu 125 Asn I le Ile Pro Ser His Trp Ser Gly Val1 Met Pro Gly 110 Lys Lys Pro Gly Gly Leu Val1 Asp Ile Leu 110 Asp Glu Pro Pro Leu Pro Phe Ile Pro Arg Cys Pro Thr Ile Gln Leu Thr Gly Phe Leu Leu 160 Leu Asp Leu Ile Lys Cys Val 162 46

PRT

mouse 162 Pro Cys 5 Met Cys Thr Met 163 122

PRT

mouse 163 Phe Val Leu Ala Cys Leu Phe Val Asn Val His Trp Cys 10 Ile Leu Val Lys Met Ser Glu Leu Leu Giu Leu 25 Val Ser Cys Leu Val Asp Val Gly Asn 40 Val Leu Val Ile Thr Ile Val Ile Cys Leu Cy s WO 99/55865 WO 9955865PCT/NZ99/00051 1 His Ile Pro Val1 Ser Leu Asp Met 1 Phe Ile Leu Met 1 Phe Ser His Val Cys Giu His Pro Thr Leu Gin Ser Giy Met Pro Ser Leu 115 <210> <211> <212> <213> <400> Ser Phe Ser Val Phe Leu Cys Ser so <210> <211> <212> <213> <400> Gly Ser Vai Ala Leu His His Pro <210> <211> <212> <213> <400> Thr Arg Met Val Pro Leu Trp Glu Ile His .5 Phe Gly Thr Giu Ala Gly Asp Ser Asp Giu Pro Asp 100 Ile Giu 164

PRT

Rat 164 Val Lys 5 Val Pro Val Ile Phe Phe 165 57

PRT

mouse 165 Pro Ile 5 Leu Gly Thr Met Pro Leu 166

PRT

mouse 166 Arg Thr 5 Cys Ile Phe Leu Gly Ser Thr Pro His Thr Al a Glu Pro Gly Asn Ile Gin Phe Asp Ser Trp Ser Arg Leu Ser Ser Asp Ser Thr Gin His Ser Tyr Gly Asp Gin Asn Asn Ile Ala Glu Ser 110 Giu Ala Thr Pro Thr Gin Thr Lys Trp Pro 10 Ser Leu Leu Val Thr Val Tyr Ile Cys Tyr 25 Phe Phe Phe Phe Glu Ala Cys Gin Glu Val 40 Phe Ser Arg Arg Arg Gly 55 Gly Val Cys Pro Val Leu Pro Gly Gly Leu 10 Ile Phe Leu Leu Phe His Arg Asp Ala Phe 25 Ala Gly Phe Pro Lys Ser Pro Ala Asn Pro 40 Leu Ser Pro Lys 1 Phe Phe Gin His Leu Thr Gly Gin Leu 10 Phe Leu Phe Leu Phe 25 Val Arg Lys His Ile 40 Thr Met Thr His Thr 55 Pro Arg Gin Cys Gin Gly Leu Phe Ser Val Asp Phe Cys Phe Leu Phe Pro Leu Leu Ser His Cys Lys His Thr His Thr His Ile Ser WO 99/55865 WO 9955865PCT/NZ99/00051 70 <210> 167 <211> 52 <212> PRT <213> mouse <400> 167 Val Arg Ser Leu Glu Gin Leu Gly Leu Phe Ser Val Asp Phe Met Val 1 5 10 Cys Ile Phe Leu Phe Leu Phe Phe Cys Phe Leu Phe Pro Phe Pro Leu 25 Phe Leu Val Arg Lys His Ile Leu Leu Ser His Cys Lys Gin Trp Glu 40 Gly Ser Thr Met <210> 168 <211> 119 <212> PRT <213> Rat <400> 168 Met Leu Gly Ala Thr Ser Leu Ser Trp Pro Trp Val Leu Trp Ala Val 1 5 10 Ala Gin Arg Asp Ser Val Asp Ala Ile Gly Met Phe Leu Gly Gly Leu 25 Val Ala Thr Ile Phe Leu Asp Ile Ile Tyr Ile Ser Ile Phe Tyr Ser 40 Se ValL la. al y Asp Thr cGiy Arg Ph-e Ser Ala Gly Met Ala Ile s0 55 Phe Ser Leu Leu Leu Gin Ala Leu Leu Leu Leu Pro Arg Leu Pro His 70 75 Ala Pro Giy Ser Giu Gly Val Ser Ser Arg Ser Ala Arg Ile Ser Ser 90 Asp Leu Leu Arg Asn Ile Vai Pro Thr Arg Gin Leu Thr Arg Gin Thr 100 105 110 His Leu Gin Thr Pro Leu Gin 115 <210> 169 <211> 104 <212> PRT <213> Rat <220> <400> 169 Leu Val Pro Lys Ser Ala Arg Ala Ser Leu Leu Cys Cys Gly Pro Lys 1 5 10 Leu Ala Ala Cys Gly Ile Val Leu Ser Ala Trp Gly Val Ile Met Leu 25 Ile Met Leu Gly Ile Phe Phe Asn Val His Ser Ala Val Xaa Ile Xaa 40 Asp Val Pro Phe Thr Giu Lys Asp Phe Giu Asn Gly Pro Gin Asn Ile 55 Tyr Asn Leu Tyr Glu Gin Val Ser Tyr Asn Cys Phe Ile Ala Ala Gly 70 75 Leu Tyr Leu Leu Xaa Gly Gly Phe Ser Phe Cys Gin Val Arg Leu Asn 90 WO 99/55865 Lys Arg Lys Glu Tyr Met Val Arg S100 PCT/NZ99/00051 Met Trp Giu Thr Phe CLr Gin Thr Ser Ala Pro Ser Asp <210> <211> <212> <213> <220> <221> <222> <22 1> <222> <221> <222> <400> Arg Pro Arg Pro Leu Trp Gly Pro Phe Ala LeuL Pro~ His His Glu Cys 115 <210> <211> <212> <213> <400> Ala Gly Phe Gly Leu Arg Leu Leu Asn Arg <210> <211> <212> <213> <400> Thr Ser

UNSURE

(27) .(27)

UNSURE

(104) (104)

UNSURE

(118) (118) 170 Gly Ala Asp T Ser Cys Ser L Leu Tyr Arg A Met Phe Val I 5.

Lys Phe Leu A.

Arg Cys Gin P: Lys Thr Asp S, 100 Ser Pro Xaa G.

170 123

PRT

Rat Al a Pro Pro 40 Ala Lys Cys Xaa Ile 120 Al a Ser 25 Tyr Phe Al a Pro Gin 105 Al a Val Ser Val Leu Asp Ser Gly His Ala Arg Ala Pro Asp Lys Ala Leu Ile Giu Leu Arg Trp Gin Trp Gin Tyr Ser Gin Cys Ile 110 171

PRT

Rat 171 Val Pro Vai Leu Asp Thr Ala Ala Val Phe Leu Ser Leu Tyr Val .25 Phe Leu Ile Ala Gly 40 Ser Val Phe Trp Phe 55 Pro Val Gin Asn Tyr 70 Phe Gly Cys Ala Phe Ile Phe Thr Ile Ala Thr Asp Ala Phe Phe Trp Leu Val Leu Val Arg Val Ile Thr Leu 172 79

PRT

Human 172 Tyr His 5 Lys 1 Tyr His Thr Asn Val Giu Glu Leu Thr Ile Pro 10 WO 99/55865 Giu Thr Arg Asn Val Leu Val Leu Lys Ala Asn Ala Tyr Leu Lys Leu PCT/NZ99/00051 Leu Tyr Ile Ser Ile Ser Trp Leu Trp Cys Leu 25 Ser Thr Met Ile Leu Asn Lys His Gly Trp, Met 40 Ser Leu Val Pro Ser Ile Ile Tyr Ser Pro Ser 55 Leu Arg Leu Tyr Lys Leu Gin Ile Cys Cys 70 <210> <211> <212> <213> <220> <400> 173 Leu Arg Gly 1 Cys Cys Val Arg Lys Leu Ala Leu Gly Pro Giu Asn Ser Pro Arg Val Cys Tyr Phe Leu Pro 115 Gly Thr Tyr 130 173 134

PRT

Human Arg Ser Leu Ser Asn Val Asn 100 Thr Thr Ala 1e Leu Gly Ile Gly Ile Al a Ile <210> 174 <211> 137 <212> PRT <213> Hum <400> 174 Trp Ser Arg Gin Ala Thr 20 Ala Met Phe Asp Asp Lys Phe Ile Val His Gin Ile Lys Tyr Giu 100 Leu Val Ile 115 Arg Ala Gly 130 <210> 175 an Cys Met 25 Leu Ser Ser Asp Al a 105 Lys Ser Val1 25 Gly Arg Ala Tyr Ile 105 Leu Pro Gin Thr Ile Giu Ala Gly Tyr Val Leu Ser Lys Ala Val1 Pro Ile Pro Phe Gin Cys Val1 Gly Thr Arg 110 Giu Ser Leu Arg Gly Ser Pro Al a 110 Val1 Gly Val Ser Arg Phe Arg Val Asp Al a Gly Cys Gly Trp, Thr Gly Leu Pro Arg Val Val Al a Val Phe Leu Leu Met

I

Phe Ser Pro 1 Val Phe Leu Met 1 Cys Leu Gly Val 1 Phe Giu Al a WO 99/55865 <211> 43 <212> PRT <213> Human <400> 175 Lys Leu Ser G-.

Leu Thr Gly Vi Arg Thr Pro A: <210> 176 <211> 63 <212> PRT <213> Rat <400> 176 Asn Thr Arg Pi Phe Tyr Met L( Cys Phe Ser L( Pro Arg Phe A, PCT/NZ99/00051 <210> <211> <212> <213> <400> Leu Gin Val Phe Gly Asn Ala Gin <210> <211> <212> <213> <400> Ser Pro Leu Val Pro Arg Lys Pro <210> <211> <212> <213> 177 52

PRT

mouse 177 Gly Pi Trp, A., Arg G' Gly 178 62

PRT

mouse 178 Arg Pi Thr G' Ala L( Thr S( 179 123

PRT

mouse Met Phe Leu Leu Leu Ser Leu Ala Leu Phe Cys 10 Phe Ser Gin Gly Gly Gin Val Asp Cys Gly Giu 25 Pro Thr Ala Leu Gly Asn Arg Arg His Thr Ala Cys Arg Val Ser Ile Ser 10 His Thr Giu Leu Lys Lys Cys Trp Phe Phe Leu 25 Phe Leu Trp Phe Cys Phe Trp Phe Cys Phe Leu 40 Tyr Leu Pro Met Pro Ser Thr Arg Pro Arg 55 Ala Pro Ser Cys Phe Trp Val Phe Ser Gly Ile 10 Phe Ile Phe Ile Ile Phe Phe Asn Val Leu Ser 25 Ile Ser Ala Lys Asp Phe Aia Asp Gin Pro Aia 40 Thr Tyr Pro Ser Thr Ala Ser Ser Met Aia Ala 10 Phe Phe Phe Ser Leu Phe Val Val Leu Gly Met 25 Phe Arg Pro Asp Lys Ala Leu Pro Leu Ser Cys 40 Leu Cys Val Gin Ser Ser Phe Leu Gly 55 WO 99/55865 WO 9955865PCT/NZ99/00051 Ala Arg Gly Leu Tyr His Pro Al a Thr Ser Leu Val Leu Ser Phe Lys 1 Asn Trp Asp <400> Ser Arg Ser Arg Thr Leu Pro Ser Gly Met Ser Phe Gly Phe Ser Arg 115 <210> <211> <212> <213> <220> <221> <222> <400> Arg Arg Gly Leu Leu Val Gin Ala Val Thr Ile Leu Glu Asp Tyr Trp 115 <210> <211> <212> <213> <400> Gly Pro Val Ile Ala Trp Leu Gly 179 Thr Met Ala Al a Gin Arg Ser 100 Lys Al a Asp Ile Leu Val Gly Ala Asn Leu Val1 Al a Tyr His His His 105 Gly Cys Asn Phe Tyr His Lys Val Cys Cys Phe Ala Tyr Asp Ser Gin Ser Giy Leu Thr Cys Leu Val 180 120

PRT

mouse

UNSURE

180 Arg Xaa A Ary Ala A Vai Ala A Leu Thr M Vai Ile V Giy Cys T Giu Giu S 100 Cys Ser T Arg Ti-p Thr Ile Leu Tyr Val1 Leu 120 Arg Thr Lys Met Ile Leu Gly 105 Gly 10 Val Ser Asp Ala Arg 90 Asp Cys Cys Pro Ser Al a Gin Glu Ile Asn Lys Thr Gly Ser Giu Gly Ser Pro Gly Gly Gin Pro 181

PRT

mouse 181 Glu Val Ser Cys 5 Phe Trp Phe Leu Asn Glu Lys Gly Gly Phe Asp Pro 55 Cys Ile Lys Tyr Phe Ile Phe Gly Phe 10 Gly Ile Thi- Phe Leu Gly Ile Gly Leu 25 Val Leu Ser Asn Ile Ser Ser Ile Thr 40 Val Ti-p Leu Phe Leu WO 99/55865 PCT/NZ99/00051 <210> 182 <211> 72 <212> PRT <213> mouse <220> <400> 182 Lys Pro Thr Val Gly Ser Ala Glu Val Ala Ile Ala Val Phe Leu Val 1 5 10 Ile Cys Ile Ile Val Val Leu Thr Ile Leu Gly Tyr Cys Phe Phe Lys 25 Asn Gin Arg Lys Glu Phe His Ser Pro Leu His His Pro Pro Pro Thr 40 Pro Ala Ser Ser Thr Val Ser Thr Thr Glu Asp Thr Glu His Leu Val 55 Tyr Asn His Thr Thr Gin Pro Leu <210> 183 <211> 771 <212> PRT <213> Rat <220> <400> 183 Glu Leu Tyr Leu Asp Gly Asn Gin Phe Thr Leu Val Pro Lys Glu Leu 1 5 10 Ser Asn Tyr Lys His Leu Thr Leu Ile Asp Leu Ser Asn Asn Arg Ile 25 Ser Thr Leu Ser Asn Gin Ser Phe Ser Asn Met Thr Gin Leu Leu Thr 40 Leu Ile Leu Ser Tyr Asn Arg Leu Arg Cys Ile Pro Pro Arg Thr Phe 55 Asp Gly Leu Lys Ser Leu Arg Leu Leu Ser Leu His Gly Asn Asp Ile 70 75 Ser Val Val Pro Glu Gly Ala Phe Gly Asp Leu Ser Ala Leu Ser His 90 Leu Ala Ile Gly Ala Asn Pro Leu Tyr Cys Asp Cys Asn Met Gin Trp 100 105 110 Leu Ser Asp Trp Val Lys Ser Glu Tyr Lys Glu Pro Gly Ile Ala Arg 115 120 125 Cys Ala Gly Pro Gly Glu Met Ala Asp Lys Leu Leu Leu Thr Thr Pro 130 135 140 Ser Lys Asn Phe Thr Cys Gin Gly Pro Val Asp Val Thr Ile Gin Ala 145 150 155 160 Lys Cys Asn Pro Cys Leu Ser Asn Pro Cys Lys Asn Asp Gly Thr Cys 165 170 175 Asn Asn Asp Pro Val Asp Phe Tyr Arg Cys Thr Cys Pro Tyr Gly Phe 180 185 190 Lys Gly Gin Asp Cys Asp Val Pro Ile His Ala Cys Thr Ser Asn Pro 195 200 205 Cys Lys His Gly Gly Thr Cys His Leu Lys Pro Arg Arg Glu Thr Trp 210 215 220 Ile Trp Cys Thr Cys Ala Asp Gly Phe Glu Gly Glu Ser Cys Asp Ile 225 230 235 240 Asn Ile Asp Asp Cys Glu Asp Asn Asp Cys Glu Asn Asn Ser Thr Cys 245 250 255 WO 99/55865 Val Asp Gly Ile Asn Asn Tyr Thr Cys Leu Cys Pro Pro Glu Tyr Thr 260 265 270 Gly Glu Leu Cys Glu Glu Lys Leu Asp Phe Cys Ala Gin Asp Leu Asn 275 280 285 Pro Cys Gin His Asp Ser Lys Cys Ile Leu Thr Pro Lys Gly Phe Lys 290 295 300 Cys Asp Cys Thr Pro Gly Tyr Ile Gly Glu His Cys Asp Ile Asp Phe 305 310 315 320 Asp Asp Cys Gin Asp Asn Lys Cys Lys Asn Gly Ala His Cys Thr Asp 325 330 335 Ala Val Asn Gly Tyr Thr Cys Val Cys Pro Glu Gly Tyr Ser Gly Leu 340 345 350 Phe Cys Glu Phe Ser Pro Pro Met Val Phe Leu Arg Thr Ser Pro Cys 355 360 365 Asp Asn Phe Asp Cys Gin Asn Gly Ala Gin Cys Ile Ile Arg Val Asn 370 375 380 Glu Pro Ile Cys Gin Cys Leu Pro Gly Tyr Leu Gly Glu Lys Cys Glu 385 390 395 400 Lys Leu Val Ser Val Ser Ile Leu Val Asn Lys Glu Ser Tyr Leu Gin 405 410 415 Ile Pro Ser Ala Lys Val Arg Pro Gin Thr Asn Ile Thr Leu Gin Ile 420 425 430 Ala Thr Asp Glu Asp Ser Gly Ile Leu Leu Tyr Lys Gly Asp Lys Asp 435 440 445 His Ile Ala Val Glu Ser Ile Glu Gly Ile Arg Ala Ser Tyr Asp Thr 450 455 460 Gly Ser His Pro Ala Ser Ala Ile Tyr Ser Val Glu Thr Ile Asn Asp 465 470 475 480 Gly Asn Phe His Ile Val Glu Leu Leu Thr Leu Asp Ser Ser Leu Ser 485 490 495 Leu Ser Val Asp Gly Gly Ser Pro Lys Ile Ile Thr Asn Leu Ser Lys 500 505 510 Gin Ser Thr Leu Asn Phe Asp Ser Pro Leu Tyr Val Gly Gly Met Pro 515 520 525 Gly Lys Asn Asn Val Ala Ser Leu Arg Gin Ala Pro Gly Gin Asn Gly 530 535 540 Thr Ser Phe His Gly Cys Ile Arg Asn Leu Tyr Ile Asn Ser Glu Leu 545 550 555 560 Gin Asp Phe Arg Lys Val Pro Met Gin Thr Gly Ile Leu Pro Gly Cys 565 570 575 Glu Pro Cys His Lys Lys Val Cys Ala His Gly Thr Cys Gin Pro Ser 580 585 590 Ser Gin Ser Gly Phe Thr Cys Glu Cys Glu Glu Gly Trp Met Gly Pro 595 600 605 Leu Cys Asp Gin Arg Thr Asn Asp Pro Cys Leu Gly Asn Lys Cys Val 610 615 620 His Gly Thr Cys Leu Pro Ile Asn Ala Phe Ser Tyr Ser Cys Lys Cys 625 630 635 640 Leu Glu Gly His Gly Gly Val Leu Cys Asp Glu Glu Glu Asp Leu Phe 645 650 655 Asn Pro Leu Pro Gly Asp Gin Val Gin Ala Arg Glu Val Gin Ala Leu 660 665 670 Trp Ala Arg Ala Ala Leu Leu Trp Met Gin Gin Trp Ile His Arg Gly 675 680 685 Gin Leu Thr Gin Arg Ile Ser Cys Arg Gly Glu Arg Ile Arg Asp Tyr 690 695 700 Tyr Gin Ser Ser Arg Val Arg Cys Leu Ser Asn Asp <210> 184 <211> 340 <212> PRT PCT/NZ99/00051 WO 99/55865 <213> mouse PCT/NZ99/00051 Asp 1 Tyr Ala Glu Arg Ala Ser Cys Arg Glu 145 Arg Leu Pro Ala Ser 225 Ala Phe His Val Gin 305 Pro Arg Lys 1 Thr Gly Leu <400> Gly Ser Thr Cys Tyr Leu Thr Pro Ala Asn Leu Gin Leu Ile Thr Pro 115 Val Leu 130 Tyr Phe Gly Asp Gin Gly Leu Thr 195 Val Ala 210 Pro His Asn Val Ser Val Asp Trp 275 Pro Gly 290 Asn Lys Glu Gly Ser Arg <210> <211> <212> <213> <400> Val Glu Phe Asp Phe Gly Ala Ile 184 Leu T Val P: Thr V Leu P: Pro P: Leu A 8! Ile A 100 Tyr Al Leu L Gin G Pro P 1i Gin A: 180 Lys G: Arg V; Val Vi Ser T 2 Trp T 260 Val Si Leu G Leu G Leu P: 3: Val 340 185 536

PRT

mouse 185 rp (5 Lu al ro ro sp la sn y'S lu ro in lu al rp 45 yr ln ly ro 25 Leu Ser Leu Thr Leu 70 Lys Leu Ser Ala Val 150 Pro Gin Ala Thr Thr 230 Glu Thr Leu Ala Ser 310 Thr Gin Asn Tyr Gly 55 Leu Phe Gly Leu Pro 135 Gly Ile Va1 Gin Thr 215 Asn Pro Pro Ala His 295 Gly Thr Ala Gly Pro 40 Met Phe Pro Asn Gly 120 Pro Arg Val Asp Gly 200 Ser Val Gly Leu Val 280 Ala Pro Pro Thr Phe 25 Ala Arg Val Gly Glu 105 Thr Ala Glu Ser Ser 185 Arg Thr Ser Phe Ala 265 Pro Gin Phe Ala Gin 10.

Leu Gin Gly Thr Trp 90 Asp Ala Phe Leu Trp 170 Asn Trp Asn Val Asp 250 Lys Ile Tyr Ser Ala 330 Asp Pro Thr Ile Thr Leu Leu Pro Asp 140 Ile Lys Ser Cys Tyr 220 Pro Gly Pro Ala Phe 300 Ile Gly Asp Pro Vai Arg Lys Gly Gly Ser 125 Gln Pro Vai Leu Ser 205 Va1 Leu Tyr Asp Thr 285 Ser Val Leu Ala Ser Met Cys Asp Pro Glu 110 Pro Pro Cys Gly Val 190 Ala Leu Pro Leu Arg 270 His Val Leu Pro Gly is Ala Pro Pro Gly Glu Tyr Va1 Lys Ser Arg 175 Leu Ser Gly Lys Gin 255 Ala Leu Leu Ser Ala 335 His Ser Pro Vai Gin Gly Ser Thr Glu Ala 160 Gly Arg Asn Thr Gly 240 Arg His Leu Ala Ile 320 Thr Gly Ala Gin Lys Glu Gly Arg Gly Arg Trp Ala Leu Gly Leu Leu Arg 5 10 Gly Giu Phe Ala Gly Trp Glu Lys Val Giy Ser Gly 25 Val Tyr Lys Val Arg His Vai His Trp Lys Thr Trp 40 Cys Ser Pro Ser Leu His Val Asp Asp Arg Glu Arg WO 99/55865 PCT/NZ99/00051 Met Tyr Met Pro Gly Leu 145 Phe Asp Glu Tyr Phe 225 Gly Cys Gin Cys Glu 305 Arg Ser Lys Ser Ala 385 Ser Asp Pro Leu Asn 465 His Ala Leu Ala Glu Ile Glu Leu Met 130 Lys Leu Leu Arg Ser 210 Ala His Ala Val Glu 290 Lys Leu Glu Gly Ser 370 Phe Thr Ala Gin Ala 450 Asn Met Arg His Arg 530 Leu Pro Met 100 Trp Phe Ala Phe Met 180 Arg Ala Glu Pro Leu 260 Pro Pro Ser Arg Leu 340 Glu Ser Ser Asp.

Ile 420 Val Glu Asn Val Thr 500 Ala Glu Glu Val Glu Asp Leu Asn Gly 165 Asp Glu Ile Lys Glu 245 Ile Thr Asp Leu Ala 325 Ser Glu Gly Arg Leu 405 Ser Asp Ala Pro Glu 485 Ser Ala Cys 55 Ala Gly Gly Arg Cys 135 Leu Ala Leu Ser Ile 215 Ile Pro Leu Gin Glu 295 Ser Ala Leu Ser Arg 375 Ser Pro Asp Val Gin 455 Leu Lys Asn Asn Cys 535 Lys Lys Ile Cys Ser Leu 105 Phe Arg 120 Met Ser Leu Asp Lys Cys Phe Gly 185 Arg Leu 200 Trp Gly Leu His Pro Ile Met Gin 265 Glu Ile 280 Val Lys Lys Ser Pro Pro Asp Ser 345 Arg Ser 360 Leu Ser Leu Ser Thr Asp Thr Ser 425 Leu Asp 440 Glu Glu Thr Asn Gly Arg Ala Lys 505 Gly Asp 520 Gin Met Gin 90 Glu Ile Pro Ala Asn 170 Thr Phe Val Ile Cys 250 Arg Thr Asp Glu Phe 330 Gly Ser Gly Leu Ile 410 Arg Ser Cys Arg Gly 490 Asp Glu Glu Glu Lys Val Pro His 155 Gly Ile Asp Leu Met 235 Arg Cys Ser Leu Ala 315 Asp Ile Ser Val Ser 395 Gin Leu Ser Val Lys 475 Ile Glu Gly Met Pro Leu His Leu 140 Tyr Met Gly Thr Thr 220 Met Pro Trp Glu Ala 300 Arg Asn Phe Glu Ser 380 Phe Lys Met Ala Lys 460 Gly Val Asp Gin Ala Val Leu Glu 125 Leu Gin Ser Tyr Lys 205 Gin Lys Arg His Thr 285 His Pro Asp Pro Cys 365 Ser Glu Lys Lys Ser 445 Trp Ser Glu Gin His 525 Lys Gly Ala 110 Thr His Met His Leu 190 His Asn Val Pro Ala 270 Glu Glu Glu Cys Arg 350 Lys Val Arg Lys Ile 430 Leu Leu Thr Leu Trp 510 Lys Phe Leu Ser Ala Leu Ser Ser 175 Pro Asp Asn Val Arg 255 Asp Asp Pro Ser Ser 335 Leu Leu Asp Glu Leu 415 Leu Leu Leu Pro Leu 495 Thr Ala WO 99/55865 <210> 186 <211> 337 <212> PRT <213> Rat <220> PCT/NZ99/00051 <400> 186 Arg Phe Giy Tyr Gin Met Asp Giu Gly Asn Gin Cys Val Asp 1 5 10 Vai Asp Glu Cys Ala Thr Asp Ser His Gin Cys Asn Pro Thr Gin Ile Cys Ile Trp Leu Tyr Cys Cys Asn Val Asn Thr Tyr Giu Asp 130 Phe Leu 145 Ser Cys Asp Ile Thr Cys Cys Giu 210 Ala Giu 225 Asp Met Met Gin Lys Ser Ile Ser 290 Ile Gin 305 Arg Gly Phe Asn Leu Gin Pro Giu Gly 115 Giy Cys Pro As n Tyr 195 Glu Asn Asp Ala Gly 275 Ala Leu Ser Thr Giu Gin Gly Cys 100 Ser Ile Gin Pro Giu 180 Asn Pro Thr Val Thr 260 Asn Thr Asp Ser Giu Gly Leu Phe Giu Phe His His Giy 165 Cys Leu Tyr Gly Val 245 Thr Giu Leu Leu Val1 325 Giy Gin Cys 70 Thr Thr Ile Cys Giu 150 Tyr Giu Gin Leu Cys 230 Ser Arg Giy Val1 Giu 310 Giy Cys 55 Al a Leu Giu Cys Ser 135 Cyvs Val1 His Gly Leu 215 Arg Gly Tyr Arg Met 295 Met 25 Thr Asp Val1 Asp Pro 105 Cys Met Asn Leu Asn 185 Phe Giy Gin Ser Giy 265 Phe Arg Thr Cys Ile Pro Asp 90 Cys Asp Asp Gin Giu 170 His Lys Asp Pro Val1 250 Ala Tyr Pro Val Ser Asp Gly 75 Gly Val1 Pro Giu Pro 155 Asp Thr Cys As n Phe 235 Pro Tyr Met Ile Asn 315 Cys Thr Giu Cys Ser Tyr Arg Ser Gin Thr Gly Tyr 125 Cys Ser 140 Gly Ser Asn Arg Cys Thr Ile Asp 205 Arg Cys 220 Thr Ile Ala Asp Tyr Ile Arg Gin 285 Lys Gly 300 Thr Val Asp Arg Ser Cys Cys 110 Giu Phe Tvr Ser Pro 190 Pro Met Leu Ile Phe 270 Thr Pro Ile Gly Tyr Tyr Giy Cys Thr Gin Asp Val Asn Leu Giu Ser Glu Phe Cys 160 Cys Gin 175 Leu Gin Ile Val Cys Pro Phe Arg 240 Phe Gin 255 Gin Ile Gly Pro Arg Asp Asn Phe 320 Ile Arg Leu Arg Ile Tyr Val Ser Gin Tyr Pro 330 33-c <210> <211> <212> <213> 187 152

PRT

mouse <400> 187 WO 99/55865 PCT/NZ99/00051 Met Ala Leu Gly Val Leu Ile Ala Val Cys Leu Leu Phe Lys Ala Met 1 5 10 Lys Ala Ala Leu Ser Glu Glu Ala Glu Val Ile Pro Pro Ser Thr Ala 25 Gin Gin Ser Asn Trp Thr Phe Asn Asn Thr Glu Ala Asp Tyr Ile Glu 40 Glu Pro Val Ala Leu Lys Phe Ser His Pro Cys Leu Glu Asp His Asn 55 Ser Tyr Cys Ile Asn Gly Ala Cys Ala Phe His His Glu Leu Lys Gin 70 75 Ala Ile Cys Arg Cys Phe Thr Gly Tyr Thr Gly Gin Arg Cys Glu His 90 Leu Thr Leu Thr Ser Tyr Ala Val Asp Ser Tyr Glu Lys Tyr Ile Ala 100 105 110 Ile Gly Ile Gly Val Gly Leu Leu Ile Ser Ala Phe Leu Ala Val Phe 115 120 125 Tyr Cys Tyr Ile Arg Lys Arg Cys Ile Asn Leu Lys Ser Pro Tyr Ile 130 135 140 Ile Cys Ser Gly Gly Ser Pro Leu 145 150 <210> 188 <211> 118 <212> PRT <213> Rat <220> <400> 188 Leu Val Pro Gin Phe Gly Thr Arg Ile Arg Tyr ThrAla Tyr Asp Arg 1 5 10 Ala Tyr Asn Arg Ala Ser Cys Lys Phe Ile Val Lys Val Gin Val Arg 25 Arg Cys Pro Ile Leu Lys Pro Pro Gin His Gly Tyr Leu Thr Cys Ser 40 Ser Ala Gly Asp Asn Tyr Gly Ala Ile Cys Glu Tyr His Cys Asp Gly 55 Gly Tyr Glu Arg Gin Gly Thr Pro Ser Arg Val Cys Gin Ser Ser Arg 70 75 Gin Trp Ser Gly Ser Pro Pro Val Cys Thr Pro Met Lys Ile Asn Val 90 Asn Val Asn Ser Ala Ala Gly Leu Leu Asp Gin Phe Tyr Glu Lys Gin 100 105 110 Arg Leu Leu Ile Val Ser 115 <210> 189 <211> 299 <212> PRT <213> Human <220> <400> 189 Met Gly Thr Lys Ala Gin Val Glu Arg Lys Leu Leu Cys Leu Phe Ile 1 5 10 Leu Ala Ile Leu Leu Cys Ser Leu Ala Leu Gly Ser Val Thr Val His 25 Ser Ser Glu Pro Glu Val Arg Ile Pro Glu Asn Asn Pro Val Lys Leu 40 Ser Cys Ala Tyr Ser Gly Phe Ser Ser Pro Arg Val Glu Trp Lys Phe WO 99/55865 WO 9955865PCT/NZ99/00051 Asp Ala Lys Glu Leu Ile 145 Pro Pro Thr Giu Asn 225 Al a Ile Thr Gin Val Asn Thr Lys Val1 s0 Gin Ser Se r Giu Val 130 Gly Ser Lys Thr Tyr 210 Ala Al a Trp Ser !1 290 Gly Tyr Val Gly 115 Pro Asn Giu Ser Gly 195 Ser Val1 Val1 Phe Ser 275 Asp Giu Thr 100 Gly Pro Arg Tyr Thr 180 Giu Cys Arg Leu Al a 260 Lys T.y Val Phe Gly 105 Glu Val1 Cys Asp Asn 185 Pro Gly Glu Leu His 265 Ser Thr Pro 25 Giu Gly Ala Pro Cys Leu Thr Val1 Asn Ser Gly 170 Ser Leu Tyr Arg Leu 250 Phe Gin Ser Asp Ile Cys Arg Gly Tyr 75 Pro Tyr Lys Ile Giu 155 Ile Ser Ser Gly Asn 235 Gly Asp Pro Val Asn Thr Thr Val Pro 140 Gin Val Tyr Ala Thr 220 Val Ile Arg Ser Asn Gly Cys Lys 125 Ser Asp Met Val1 Ser 205 Pro Gly Leu Thr Al a 285 Lys Ile Met 110 Leu Ser Gly Pro Leu 190 Asp Met Vai Val1 Lys 270 Arg Ile Thr Val1 Ile Ala Ser Thr 175 Asn Thr Thr Ile Phe 255 Lys Ser Thr Phe Ser Val Thr Pro 160 Asn Pro Gly Ser Val 240 Gly Giy Giu Trp Asn Leu Thr Giu <210> <211> <212> <213> <400> Pro Thr Leu Arg Trp Phe Arg Tyr Pro Gin Thr Gin 190 91

PRT

Human 190 Val PI Leu G' Leu Pi Pro A: Thr C, Al a TI Ala Lys Lys Gly Asn 1s Arg Pro Ala Arg Gin Pro Giu His Ser Ala Trp, Pro His Arg Leu Ser Tyr Leu Ser His 75 Gly <210> <211> <212> <213> <400> Gly Ala Trp 1 Leu Gly Gin 191 89

PRT

mouse 191 Ala Met 5 Pro Ser Leu Tyr Gly Vai Ser Met Leu Cys Val Leu Asp 10 Val Val Giu Giu Pro Giy Cys Gly Pro Gly Lys 25 WO 99/55865 PCT/NZ99/00051 Val Gin Asn Gly Ser Gly Asn Asn Thr Arg Cys Cys Ser Leu Tyr Ala 40 Pro Gly Lys Glu Asp Cys Pro Lys Glu Arg Cys Ile Cys Val Thr Pro 55 Glu Tyr His Cys Gly Asp Pro Gin Cys Lys Ile Cys Lys His Tyr Pro 70 75 Cys Gin Pro Gly Gin Arg Val Glu Val <210> 192 <211> 299 <212> PRT <213> mouse <220> <400> 192 Ala Arg Ala Gly Ala Cys Tyr Cys Pro Ala Gly 'Phe Leu Gly Ala Asp 1 5 10 Cys Ser Leu Ala Cys Pro Gin Gly Arg Phe Gly Pro Ser Cys Ala His 25 Val Cys Thr Cys Gly Gin Gly Ala Ala Cys Asp Pro Val Ser Gly Thr 40 Cys Ile Cys Pro Pro Gly Lys Thr Gly Gly His Cys Glu Arg Gly Cys 55 Pro Gin Asp Arg Phe Gly Lys Gly Cys Glu His Lys Cys Ala Cys Arg 70 75 Asn Gly Gly Leu Cys His Ala Thr Asn Gly Ser Cys Ser Cys Pro Leu 90 Gly Trp Met Gly Pro His Cys Glu His Ala Cys Pro Ala Gly Arg Tyr 100 105 110 Gly Ala Ala Cys Leu Leu Glu Cys Ser Cys Gin Asn Asn Gly Ser Cys 115 120 125 Glu Pro Thr Ser Gly Ala Cys Leu Cys Gly Pro Gly Phe Tyr Gly Gin 130 135 140 Ala Cys Glu Asp Thr Cys Pro Ala Gly Phe His Gly Ser Gly Cys Gin 145 150 155 160 Arg Val Cys Glu Cys Gin Gin Gly Ala Pro Cys Asp Pro Val Ser Gly 165 170 175 Arg Cys Leu Cys Pro Ala Gly Phe Arg Gly Gin Phe Cys Glu Arg Gly 180 185 190 Cys Lys Pro Gly Phe Phe Gly Asp Gly Cys Leu Gin Gin Cys Asn Cys 195 200 205 Pro Thr Gly Val Pro Cys Asp Pro Ile Ser Gly Leu Cys Leu Cys Pro 210 215 220 Pro Gly Arg Ala Gly Thr Thr Cys Asp Leu Asp Cys Arg Arg Gly Arg 225 230 235 240 Phe Gly Pro Gly Cys Ala Leu Arg Cys Asp Cys Gly Gly Gly Ala Asp 245 250 255 Cys Asp Pro Ile Ser Gly Gin Cys His Cys Val Asp Ser Tyr Thr Gly 260 265 270 Pro Thr Cys Arg Glu Val Pro Thr Gin Leu Ser Ser Ile Arg Pro Ala 275 280 285 Pro Gin His Ser Ser Ser Lys Ala Met Lys His 290 295 <210> 193 <211> 314 <212> PRT <213> mouse WO 99/55865 PCT/NZ99/00051 <220> <400> 193 Glu Glu Pro Cys Asn Asn Gly Ser Glu Ile Leu Ala Tyr Asn Ile Asp 1 5 10 Leu Gly Asp Ser Cys Ile Thr Val Gly Asn Thr Thr Thr His Val Met 25 Lys Asn Leu Leu Pro Glu Thr Thr Tyr Arg Ile Arg Ile Gin Ala Ile 40 Asn Glu Ile Gly Val Gly Pro Phe Ser Gin Phe Ile Lys Ala Lys Thr 55 Arg Pro Leu Pro Pro Ser Pro Pro Arg Leu Glu Cys Ala Ala Ser Gly 70 75 Pro Gin Ser Leu Lys Leu Lys Trp Gly Asp Ser Asn Ser Lys Thr His 90 Ala Ala Gly Asp Met Val Tyr Thr Leu Gin Leu Glu Asp Arg Asn Lys 100 105 110 Arg Phe Ile Ser Ile Tyr Arg Gly Pro Ser His Thr Tyr Lys Val Gin 115 120 125 Arg Leu Thr Glu Phe Thr Cys Tyr Ser Phe Arg Ile Gin Ala Met Ser 130 135 140 Glu Ala Gly Glu Gly Pro Tyr Ser Glu Thr Tyr Thr Phe Ser Thr Thr 145 150 155 160 Lys Ser Val Pro Pro Thr Leu Lys Ala Pro Arg Val Thr Gin Leu Glu 165 170 175 Gly Asn Ser Cys Glu Ile Phe Trp Glu Thr Val Pro Pro Met Arg Gly 180 185 190 Asp Pro Val Ser Tyr Val Leu Gin Val Leu Val Gly Arg Asp Ser Glu 195 200 205 Tyr Lys Gin Vai Tyr Lys Giy Giu Giu Ala Thr Phe Gin Ile Ser Gly 210 215 220 Leu Gin Ser Asn Thr Asp Tyr Arg Phe Arg Val Cys Ala Cys Arg Arg 225 230 235 240 Cys Val Asp Thr SerGln Glu Leu Ser Gly Ala Phe Ser Pro Ser Ala 245 250 255 Ala Phe Met Leu Gin Gin Arg Glu Val Met Leu Thr Gly Asp Leu Gly 260 265 270 Gly Met Glu Glu Ala Lys Met Lys Gly Met Met Pro Thr Asp Glu Gin 275 280 285 Phe Ala Ala Leu Ile Val Leu Gly Phe Ala Thr Leu Ser Ile Leu Phe 290 295 300 Ala Phe Ile Leu Gin Tyr Phe Leu Met Lys 305 310 <210> 194 <211> 109 <212> PRT <213> mouse <400> 194 Gly Thr Arg Val Gly Thr Pro Tyr Tyr Met Ser Pro Glu Arg Ile His 1 5 10 Glu Asn Gly Tyr Asn Phe Lys Ser Asp Ile Trp Ser Leu Gly Cys Leu 25 Leu Tyr Glu Met Ala Ala Leu Gin Ser Pro Phe Tyr Gly Asp Lys Met 40 Asn Leu Tyr Ser Leu Cys Lys Lys Ile Glu Gin Cys Asp Tyr Pro Pro 55 Leu Pro Ser Asp His Tyr Ser Glu Glu Leu Arg Gin Leu Val Asn Ile 70 75 Cys Ile Asn Pro Asp Pro Glu Lys Arg Pro Asp Ile Ala Tyr Val Tyr WO 99/55865 WO 9955865PCT/NZ99/00051 Asp Val Ala Met Leu Cys Thr Pro Asp Asp Gin Leu Lys 145 Ser Lys Asn Lys His 225 Met 1 Thr Ala Giu Asn Lys His <210> <211> <212> <213> <400> Leu Ser Ala Leu Val Val Met Ala Val Asn Asp Ser Ser Ser Thr Asn 115 Gin Val 130 Met Giu Giu Thr Thr Thr Thr Thr 195 Ser Leu 210 Ile Leu <210> <211> <2 12> <213> <400> Ala Leu Ala Leu Gin Gin Gly Pro Ser Tyr Ala Ile Leu Thr Lys Arg Met His Ala Cys Thr Ala Ser Thr 100 105 195 237

PRT

mouse 195 Leu Arg Ser Leu Leu Pro His Leu Gly Leu Phe Leu Cys 10 is His Leu Ser Pro Ser Leu Ser Ala Ser Asp Asn Gly Ser 25 Leu Asp Asn Ile Tyr Thr Ser Asp Ile Leu Giu Ile Ser 40 Asn Val Ser Gly Gly Asp Val Thr Tyr Thr Val Thr Vai 55 Asp Ser Val Ser Ala Val Ile Leu Lys Ala Val Lys Giu 70 75 Pro Val Gly Thr Trp Ser Gly Thr Tyr Giu Lys Cys Asn 90 Val Tyr Tyr Asn Leu Thr Ser Gin Ser Gin Ser Val Phe 100 105 110 Trp Thr Val Pro Thr Ser Giu Asp Val Thr Lys Val Asn 120 125 Leu Ile Val Val Asn Arg Thr Ala Ser Lys Ser Ser Val 135 140 Gin Val Gin Pro Ser Ala Ser Thr Pro Ile Pro Giu Ser 150 155 160 Ser Gin Thr Ile Asn Thr Thr Pro Thr Val Asn Thr Ala 165 170 175 Ala Lys Asp Thr Ala Asn Thr Thr Ala Val Thr Thr Ala 180 185 190 Ala Asn Thr Thr Ala Val Thr Thr Ala Lys Thr Thr Ala 200 205 Ala Ile Arg Thr Leu Gly Ser Pro Leu Ala Gly Ala Leu 215 220 Leu Val Phe Leu Ile Ser Lys Leu Leu Phe 230 235 196 154

PRT

Human 196 Gly Val

S

Thr Giu Gly Asn Ile Ala Cys Ile Cys Arg Leu Thr 100 Pro Giu Trp Leu Asn 70 Cys Ser Ile Al a Thr Lys 55 Gly Phe Tyr Ser Ala Val1 40 Phe Ala Thr Ala Leu Val Thr Leu Phe 75 Thr Ser Leu Thr Giu Cys His Gly Tyr Phe Pro Ala Leu His Giu Glu Asn Pro His Giu Giu Arg Lys 110 Ala Ile Asn Asp Leu Cys Tyr Met Thr Ile His Giu Giu Ile WO 99/55865 WO 9955865PCT/NZ99/00051 Ala Ile Gly Ile Gly Val Gly 115 Phe Tyr Cys 130 Asn Val Cys 145 <210> <211> <212> <213> Tyr Ile Arg Ser Gly Glu 150 Leu Leu Leu Ser Gly Phe Leu Val Ile 120 125 Arg Cys Leu Lys Leu Lys Ser Pro Tyr 140 Arg Pro Leu <400> 197 Ala Arg Pro Leu Ala Leu Pro Arar Pro Pro Trp Trp Trp Arg Pro Leu Ala Ala Leu Leu Val Arg Ser Ala Arg Met Ala Glu Arg Glu Glu Leu Gly 40 Gly Pro Val Arg Leu Gin Ala Gly Gin Phe Thr Glu Pro Ile Tyr Ala Arg Tyr so Leu Ala Ser Val Glu Glu Glu Val Lys Gly Phe Asp Val Thr Al a Gly Lys Glu Gly Arg Gly Tyr Asn Ala Gly Lys Asp Ser Ser Arg Gly Val Ile Ser Gly 115 Met Ser Leu Ala Asp Leu Thr Ala Lys Glu 120 Tyr Glu Ala Leu Thr His Asp 110 Asp Ile Phe Thr Ala Arg Tyr Lys Ala 130 Arg Ile Lys 135 Gly Pro le Val Leu Asn Glu Ser Pro Asn 145 Asp Leu 155 Phe Phe Lys Pro Gin Pro His Ile Lys Asp <210> <211> <212> <213> 198 1399

DNA

Mouse <400> 198 ggcaaagact tcgggcgggc ggagaccaca agcaggggaa cttggagccc ccctcccaca ctgcttcttg gagggccttg cacagatttc agtggacttg ggcagtgacc gaaagcacat ggtgatgaag acctctgagt ccaaaccctg accagacctg ggtgtacagc tgaggagcta tgaggggacc tcggcacgag gtgccacaga ggtgctaagt ctgtggagaa agctggtatc gcgcccacca gtgacagaag cttgtgctga caggggagca gtacagattc tgcgagatct tggttcatca actctaagag gcccagggca aaccacctgc gacctcactg tggaagacag ctcagggctg tacatctgcc asaacagcaa ggcagttgaa gagggtgctc ggcagccagc tgctgCtctg cagcagaaag ac aggca ccg agcaggtacc ctgagaccaa cccaggcaga ccaagtattt gcaacatgca atgctgaagt cagtgaagac tggggtcctc gcgtggagtg ggcaggggca gaaacgcctc agatctccac agcagagctg gtgaaagtga acagaacccc aaggaagagc tttggctgtc acagcggcag cggggctttt agtgctggat acaggattca ggcgttgctc cctccaggcc ggtttctaga tggagctgtc tcaagtggag tgtctccctg gcggctgcag ggccaagcgc tctcacctta ctctctgtat gctgcagcca aagagaaacg ctcttcagcc ctgagagtag tctggggcag cccacggaca gccagcagtg gatggctccc cctgttatct catgctgact agacaagagg ggtggcccca cggcacccta ttccaggtga cactgcagtt cataaaggca aagggcgcta cccaacctca caagctcaac t t cactggc c ataagagaac agagatcact cctccatggg cagggactga tcatcttaga gggacaggga tggaaggcat ttgaggcctc gcagcgggaa ccacttttga gtgtctccat cactgaacct catcagagac tctccatggc gcggccagct cactggagcc ctctaaagga agatcatgcc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 WO 99/55865 WO 9955865PCT/NZ99/00051 acttaacatc ctggctcccc ccaaagtaca actgcacttg gcaaacaagg atcctctgcc ttccctcgtc tgcagcattg ccggctacta tcctctggat gtgggagtga cgtggattcg agaggagctg ggtggaattc cagcccaagt ctctggtgcc tccttctcca gcctcaggca gagcacgatg ggaacctaca gcatttcttc cacggtgatg gctgacccag gccccacagg tgccacttat acctgccaa 1200 1260 1320 1380 1399 <210> 199 <211> 469 <212> DNA <213> Rat <400> 199 ggggcgctgg cacggtgctc agatatgcga catccagctg gaaatggcag gggtctccag accccttagg ggtgagcctc ccagtcatgg ggagcgctgg gtgactctct gcgtgggggt caaatgaagc agatatcgct caactgcaga cactgccctc cggagccttg gcaccctggg tcaagcttct tctacgggaa tctcaaaact gggtctgctg gggcttgggt agccttgcct ggctgggcag cagcgagttt cctgctttgg cacagtgacc cacagagaat gctcctgtgc tgggggactg ccaacagcgt tttctgcaag ctgcgggagt ttggtgttaa gggttgtatc aaaggaaggc tgtaccttgc gagtaccatg caggtactg ctttgcccgc gggagacaca gtctcctggg accgtccagg agcaggagaa tgctatccag atgctcccag <210> 200 <211> 529 <212> DNA <213> Rat <400> 200 aaagcttcca tacacggagt ccagadcga gatgtcgacg attggcttcc caggaatatg aagtgccatg gcatacagga agcagctcgc tcctcaacat ccgaggggac agLdayLtgUL ccttgttcac atdgagttgt tcaatctggt atgttgtcat gcaaagtaga aaattcgatg gccactagtg cttcagcagt gacagccttg cacaaagaac ggaaattttg ggaagatgtg tgatacttgc taaaggatct gaagaactaa acgacactct ccagtcaacc gctgcgcggg tggttgggtt cacaagaaca gacacaaagt cgagacctga gctgaggaag ggttcttttg tctacgcctg tgaagaaaac ccaagcttag acaccaagaa gtgcCcctgt tgaacttagc aggatcgtca agaaaatcga ctacccaga cttctatcac attcaagatc agcctggaat gagagcaccc ccagatattg cactaagttc acagttgctt tgtcatcctc <210> 201 <211> 1230 <212> DNA <213> Rat <400> 201 aagaattcgg gctgcgtgcg ggcgcccgcc gaccaagcag gtacttttct gtctcagtct tcttggggtc aggcgagctg gagactcttc gtactgtttc catgaatgac ccacatcttg cattctcagc cccctttgga Ctacatctcc Ctatgtcttc atttgtgtcc tatggtgaag cacgaggcca ctgtggctgt aggctgctac tccggCtcgc cacttctacg c tgtt cc tgg acgcagttcc gc tctgt cta gagtgcttct gggctggtct aagaacgtgt ggaatgatga aatctcagga gactggttcg atggctgtc a ttcagccaag tacccaaagc agcgcagccc tggctggttg tgctggccgc cgagctgcgc ggcgccccgc tcgtctcagt gagcgccgtt aagccctggg Ccttcttagt acgtcagcgt actatgtcct acgctctggg tgttcttctg gaaataagaa agtatgtgtc ccttcgggct Ccttgtctgc at aggaaagc aggtgacagg ggcgggggcc cgccttcctg gctcttccag cgtctgcagg gttatggaat tccaagctgg gatggagtcc gttggtgttc cttctctaac tgttggcctg gaagaatcta gtcCtctgcc aggtgtggtc ttctgctaac ccacaacgta gttcttcaac tttcctcccg ttCccttcct gagctctcgg ctcgcactgc gacctcatcc gccttcgacg ggctccctgc ctttgggctt aaggcttctc ctctgggtcc acggccattc accgtactga ctgctacaag catcagtata atccactgcc tacctagcag acctggtggc cacaggttct ttcttgtttt cgagacgc tg tcctgaaccc tgctgcagct gctacgggaa t ccc caagag tctggttcct tgctcagaac ggatacaagc atagtcttcg acgtcgtgca gccaagtgcc Ctcggtggtt agtgccacgt agcacagaat agctgatgat tggtggtgac acaaaagcac gaacaggctt agacaggctg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 WO 99/55865 WO 9955865PCTINZ99/00051 aagtacactt tctgcagctg gcgcccgcca ggctgctacc gagctgcgcg ctcttccagg acctcatccg ctacgggaag accaagcagt ccggctcgcg gcgccccgcc gtctgcagcc cgggggatcc actagttcta gagcgccgcc <210> 202 <211> 778 <212> DNA <213> Rat 1140 1200 1230 <400.

ctgcaggtcg aaaataaaaa aaatgaaatg aaatcagatg acctcctgga cactgttgta tttgcgcagg tgccttcCtc aatcaatgtg gcttggtggc aagttcaagg aacaactcct agtgacttga 202 acactagtgg aaaaggaaat gaaaacattt gagctcaatc ttcgcccgcg aagaacagcg tgcctccctt gcacagtaag ttttgggttt acttgccttt ccagcctggt attgaatcca gctcctgtca atccaaagat ttacttagcc attacacaaa tgcaggcgct accaggcagt tcacatttag cccccacccg tgacctctcc gtttgtttgt aatagtagcg ctacacagtg ctacaggaag cagcctttcc tcggcacgag gcatgtcagt tttaattaca gatcctctcc cagaggcctg cgcatctggc cgctttgtta atgacaaagg t tgt t ttgt t cttggtagac agaccgggtc ggggggcgcg agcaagggca ataaggcaca cacccaaatt attctaggga ccctggtttg gctcttgcag gtagtagcag ggtctacctc gcccccagac ttaaagaaaa agaggcaagc tcaaaaacaa gatcactgtc agcttcttta tttgcttcat ttgagtgtac ataaacatgc cagtctgtgc gcaggaggat tttttaacac tctaaatctc agcagttata a cc cggc cat ggttctctgt aacaacaaaa tgcaaactaa ttagttat 120 180 240 300 360 420 480 540 600 660 720 778 <210> 203 <211> 1123 <212> DNA <213> Rat <400> 203 gggccccccc ctagtggatc cgggtgccta tgctcaggag tgtgt caaga agtgttgcca ctcctggcat gggccaaggg atggccccaa tggcttctct agaccaacat gcgtgtattt accttatgca cagatacatc gaatgggcaa tgctttttga ggtgagctag taactgttac tttaggggct <210- <211.

<212; <213.

tcgagtcgac caaagaattc cagcccccat gcagctcgtc tgaatacatg tggagattat t cc aggaaa c tgagaaagga aggatagaag agcgactcac tggaaactt c cttcaccttc caatggtaac cagcaaccat cggtgccctc aactaagtga ggttgttagg attggtcaca aggaagaata gktatcgata ggcacgagc c cagcttcccc tggtggcacc gagtctccac ggattccgtg catggaaaca gacaaaggcg ggatacccag ttcagcaatc ttcgatgtca agcatgatga acggtgttca gcagtgctga catggggacc tgaggaagtc atctgagggg ctgctactca gaccacaagg agcttgatat tgaggcgact ggggagattc tgctggcttt aagctggagg gttaccaagg atggaaataa acctggggcc gggtgccacc agaacagtgg tgactggtag agcatgagga gcatgtacag agttggc caa accagcgctt aggatagctc tgttggagtt ttctaatggc taatattccc cgaattcctg acggtgcggg tgccgatttg gcttttcCtc actgccccca gccccctgga cggagccact tcgaggggaa agagctgcag cattatcttc atttggggcc cgtggaggaa ctatgaaaca aggagatgaa ctctaccttc catgctaagg gggcttctct ataccaatta aga caggtcgaca tgccgggtgc t ca cgag cc a ccattttgcc gactgcagca cccccaggtc ggccacgaag cgggggcagc attgcgttca agcagtgttg cccgtatcag gtgtatgtgt aagggaaaat gtctggctaa gcaggctttc gcgatttgta atggagtatt tgttggatac 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1123 204 434

DNIA

Mouse <400> 204 accaccaagc agatggaatg ctggcacacc catgcacctg catggcgtca caggtggaag attgttaaaa aattgacatc agaaatattt acagaaatag atacctgttt gaataaagtt agagatgaaa tttttgctaa acttcaaccg aagcttagat gcacattagg tgacatggaa agtcctgtgt ttgcacttcc tgtactgtta aagcttgaac cccatgttga aagcctcttt acatattctt tttcttggaa ttttgaatgt tcccattgtg gacaccagta ccaaaacagg WO 99/55865 p tgtgtgaaga gtctggtcac ctttaccaat attgttcctg agtggcatcc actcaatgct gcccattttg gtccatgtaa cagctgcaac agtaaatcac aaataagaaa aatggtgttg gaaagagcgt cgcc <210> 205 <211> 783 <212> DNA <213> Mouse <400> 205 CT/NZ99/00051 360 420 434 aattcggcac ggttgcgggc catctggtgg cttaagtcag cgtggatcaa tccccccacg taacggaggg tatctattac gaaaatggac aaccctagcg actcacttta aagaagtacc taagggaggt aaa gaggctagtc tcgcgcctgc ggaacacagc gaggaggctc ctcatggagc tctatgtcca gatgggctgg cccaaaagac attcctttcc gaatccaacc ctggccgata agctgaacct gggtaggcag gaatgtccgg cacgggtcat gccggggctc aggccgtgga tggccgggtt agagtccccc tctgtgcgcg ctaacaagcc ttggtgaaat agacttactc tcattacctt gccatcttac gattctcaat gctgcggacg cagccagcag ggagaccatg ccaagagctt gagctgtgcc gactgtcttg acacctcaaa cctettcact gcccccagag atctcactga gggggtcgct cctgacacag aaagacttgg ctgctggggc agtgtgtgtc gcgggcgctg tttaacgagt acggctattg gtcatctgtg ott t ttggt t gggctagtga gatgggatgt cggcacccaa ttgtaccacc agtgtgtcta tactttctgt tggggctgct gtgcaaggcc cggtgaagta atcagttcag ccaaggctta gccccggaaa accagccaac ctcagtgtca agagaaggga gaagtctgca tgctctagag ccgtctacag cttgaaaaaa <210> 206 <211> 480 <212> DNA <213> Mouse <400> 206 aaatgaaaac tcttggarct ggcacgagtt aaggttttca tagtaacaag ataccatgca agactgcccc catcccagat gggaatggag aagcagatgg tgccttcctg tacctgtcct gatcatcatt acaatggacc tgtgagttaa accaggaatg cgcgcgcctg gactttattt gctccctcta ttgcttagtt atgcttcagt tggctggacc aactgaggga accgcacttc caggtcgaca catggtattt gcctcggatc tgtctcccaa ttcagtcatt ctgggcagta tgccctcata cacatcagaa ctagtggatc gacattgaca accgaagcag tgtgctggac tttggctcta actgtcactc t taga cc aat atcaaacaaa caaagaattc catactgagt gaagaaggt c tttaaagaca tagtgatctc agatgaggac taaaagttgc atcaatggtt <210> 207 <211> 501 <212> DNA <213> Mouse <400> 207 ctgcaggtcg acactagtgg atccaaagaa tggaaggggc ttgtaggtgt cgggcttttt cagcatcgtt cttatatgcg actaacagaa gttcttcaga cacttctggc ctttgcagtt gagttcaaag acatggatgc cacttcagaa aatcacccat ctttttatgt gtttaaccat gcaacaaatt cttcaaacct agatgcattg tttgactcac tgcgccgtta agctttttac agtattggag tttggggtgt a ttcggcacga gccctagccc aaggaagatg acctgttatg ttaaagaata cgtggtcgag tcctctaata aaattaaata gaatcatggc acgctgcctt aatcattacc gcatagttca agacatttga tgctgttccg catcgttgaa acaggacaga gccgtcgctg ttcagctgcg aatagatata tatcgcaggg taccttaagg gccttcagat gttacgaaag cacagaattg <210> 208 <211> 480 <212> DNA <213> Mouse WO 99/55865 <400> 208 ggcacgagga agcctcttcc cgcctggcct ggcattatga tggctttcct ttttagtttt aatcattctc acatgcttcc gtaggcccca gtccataagg caggaacgcc caggagggga ctgttgcttt tgcatgttta cagatatgca cacgaccttt PCT/NZ99/00051 catggaagca atgcagtggg tttacttttt atgtttgttt aggtgtgaac gggggagggg atatagacgt gaattgtgcc c actCt agga gtcagtgtgt agtttagttt ctgagaggtg acaccccctt aagaggtgag t cc tgt cga t tactaattat gagagaaggc ggtggatgtg gttcttttcc ggggctcaaa actgcttatc ttctgcacag ccttgggaga agcaggggac ctctgggctc tgtactgggt ttccccaata tgtatagaaa acccatttga tcggacattt tcatggcctt ttgggtaccc 120 180 240 300 360 420 480 <210> 209 <211> 962 <212> DNA <213> Mouse <400> 209 ggcacgagat tagcggctcc cattcatctc tctctcattc aaatgatgcc acagaaatcc cagcaacagc accctgaatc ggatcgaaac agtcgagttc ggacggccag tgcaccagca gcccctgccg gtgcttccca gaggagctct caggagtggc gcagtgtcag gacggcagca caagaggtac acccgtcagc caagcccgcc cagcaccaca gagctagacc tggactgact ctctctcgag cctgccattg aagcccagca gqtcctt aatgagtggt ttgcagtgaa gtcatttctt taaaagcacc aa tcagcccagc ccctgctctg tttattcaca aagccaggaa aagtgggctg tcagccctct actggatcgg ggtgtgtcaa cgcgcaccta acaacgagtc gagagcggaa aggaagcatc Ctctttcctc ctctaaaact agccaggcat tgatgctgca aaatcctcca catcctgatg tgtggttaaa tggaggcagg cagggaactg gaaggagctg aggaggctac cgacaagacg caaaatcacc cagccacaac gagagccagc tgctacccag acttgaaagt agct t ttcc t cctgtagttt ttctgttaca ctcatcatgc agaaactgtt cctgtcccgg catttcagta c ggt cc acc a gtgtgcgcgg ggaacaaagt cgcacccaga gtggtcacgg tttgaaagcg aaatccagca atttgattgc atatgctttc ttacaaatgt ccatcccctc gtttaaaaaa ttcctcctgc tggcttttaa cacaccccag gcactggact aatacatttc gcgagtgctt actggagccg ggatccagct cgtgcaagtg tgtcgccagc agcacagtct ttggaagact tgctttgatc ctcaagatgt ccccatccca aaaaaaaaaa <210> 210 <211> 778 <212> DNA <213> Mouse <400> 210 ggcacgaggc tagtcgaatg cgggctcgcg cctgccacgg ggtggggaac acagcgccgg gtcaggagga ggctcaggcc atcaactcat ggagctggcc ccacgtCtat gtccaagagt gaggggatgg gctggtctgt attaccccaa aagacctaac tggacattcc tttccttggt tagcggaatc caaccagact ctttactggc cgatatcatt gtaccagctg aacctgccat gaggtgggta ggcaggattc tccgggctgc gtcatcagcc ggctcggaga gtggaccaag gggttgagct cccccgactg gcgcgacacc aagcccctct gaaatgcccc tactcatctc accttggggg cttaccctga tcaataaaga ggacgctgct agcagagtgt ccatggcggg agctttttaa gtgccacggc tcttggtcat tcaaactttt tc actgggct cagaggatgg actgacggca tcgctttgta cacagagtgt c ttggt act t ggggctgggg gtgtcgtgca cgctgcggtg cgagtatcag tattgccaag ctgtggcccc tggttaccag agtgactcag gatgtagaga cccaagaagt ccacctgctc gtctaccgtc tctgtcttga ctgctggttg aggcccatct aagtacttaa ttcagcgtgg gcttatcccc ggaaataacg ccaactatct tgtcagaaaa agggaaaccc ctgcaactca tagagaagaa tacagtaagg aaaaaaaa 120 180 240 300 360 420 480 540 600 660 720 778 <210> 211 <211> 1152 <212> DNA <213> Mouse <400> 211 ggcacgagct tctcagggcc tgccacccaa ataagtctgg ccctagcctc aactctctct WO 99/55865 WO 9955865PCT/NZ99/00051 caggctgggc tctgtgacta ccatccctca ctttccctga gtatgcattc cgcgggtctt gt tggggggt tgacacgagg magactgcag aaa caaaaca gtccctagac aattttttgg tttggctgcc gagaagctcc ccagggactc accctgtctc tctcagccta acacaggtga gcctgcccag <210- <211- <212.

<213cacaggaagc tagggaggtt cccgctcttg gcctgaggtt atgcctgtga ccctctgtag ggacccaggg ctaagcccga agggagctgc aaaataactc ttcagcaact agtccgtgcc ctcacctcgc tgcaccagaa ccaggtggga ctggcattgg gcaccacctg cagtcccaag cc tgctgactgg agcacttttt gcctggacca agggcagagt gtgtgtggct atgggtcctg tgggttgatt gaaaccccgg acttttgttt tgaagggcgg ccgctgcgtg tgtggtgggc actacttgac agcaccaaar actgctgtgg gctccggctc tccccgagtc tagataacct ccacttgaca c taat tggaa gatacatgca ttagagggtg tgctgtcgtg ggttctatca gtctctttgt gagacagcac tgaccaaaaa gaggataccc gcctgagccc agtcctgagc cttgaggctc sccmtggcac cagtgagctc tacctcccca tt ct cagct t ccatgggaca ccctccccct ttcttctctg gcct cttt ct ggctaagtgt tcctctggga cctgcttatt aaggaagtat tgcataagaa caaaaaacaa aagcctgatg agcgggaggg cttcagctga tgagtatctc cccatcttac agcccggaca agcagggcga gcccatcatt agttgggtgt aaagctaatg tcctgtggcc ccagcacagc atgttttcat tcccaagcca tatgtacgag gtgtcggggg actggtitcc aacaaaacaa cctgagagga atggggagag agcagtgctt ctgtgcacag tccactctcc gacactgcca ggccccgcct ctcggcgccc tgccttaccc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1152 212 446

DNA

Mouse <400> 212 ggcacgagct tgagtctgga tttgtttgtt aatgtgcact actcctggag ctggagttag attatttttt taataagttg ctaatataga ttatttatga aacaagaact agggccagca gttcagtctc caggaaccac gtgctgcaaa ggtgttttgc agacaatggt cctcggtcat attcaggtgg agtggcttaa acagtg taatagtatg ctggatgtgt gagctgcctt ttaaccacta gttgtcttaa cttaatggta gggtgcctgc cactatccct atacttgtga gtggatgttg agccatctca tcagagcgat tatgcatgaa taaccatctc gcctggcatg agatgtcaga ggaattgaac acagccccaa agaaaagtaa ttagtagtaa agccacctga <210> <211> <212> <213> 213 2728

DNA

Mouse <400> 213 ggggagggag ggccctgttt gagagggagg cgcttcgccg tcgcggctcc ctcaggatcg agatggtgtt gccgacagtg agacacgacc ccgggcggcg ccgggccgcg cgtgtcaggt accccgagcg acgctccccg ggcggccctg cctgcccggc agccgccctc gcgcactccg cgcagactcg cagcaacttg gcgagcggac ccgggccggg ctccgcctcg tgctcttttc gtgtgtctgt cgttctgtct gaggagaagg gcaagccgtt ccacagagaa gcaagaccga ctcaggtgga gcagacgtac tgcaaattgg agttcactgt atttcattcc caggctttcc gctttaccat aggtaagcta cattgaattg gaaacaaccc tggcggagca ggtgccactg atgcaccgcg ttaattctgc acggagcggc ctcctcggct cgcgctattg ttctcgcgcc cagccacctc cgaggttggc tgtcggacgc ggagtgtttg gtctgtcttc ttaggatgct Cccttcctgg tgcttagtca tgcttcaagt taggacaggt atttgccgcc ccagaacttc gggcgcgcgg c cggggaggc gttaacccgt tcctctcctg ggtcggtcgg tctgtcagct tcCtcgcgc gctttccccg agccctgccg agcgcggcgg cggtgtgcgt tagccagcgc tgtctccccg cttcgatcca gcgaaccaac gaggattgtc ttcctgatgc tgcatgatta caagtgtctg caggggtgct c tgggc ccc t tcgtcgggac gaggaggcgg ggcggcgggg gccgagcgca ctctcagctc gccccgaccg ggagcggcgg gggtccgagc gagcattgtt gtcccacccg gccggaggtt gggcaagact tctgtctttt ttgcagagtt agggctgtgc ttcgggtttg ttttgttcct gagagaggtt tcggatggtt gaagtggagc ccagcgccgg cggccgggga ctgggaggtg cgtcgcggag gcctcagccg cgctcccgcc agcccaggcc cccgggaccg ctgcaagcga agtgccttcc gtgtgtgtgt ttagttgact tgagttgagt ttcttaaact tccctccccc agacagcggt atgagaaagt agcttaaaag gtcagcagcc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 WO 99/55865 WO 9955865PCT/NZ99/00051 taatttgata ctttgtctca tctgaagttg acacatttta tt t ttttaag ttctgtaaca aattagacac acgtagtgat ggggaaaaaa ggagtttctt aaacttaaaa agtatgtagg caaggccatg tttatttgta atatagctaa tagatattgg aaatacagaa tcatcttgcc tgtgaggggt tagttttccc atgatagttt gcttctaaaa gaaagcctga ctgaaaatta atgtacacta tggcactatc <210- <211- <213.

ctttagaaaa ttgacttaaa gttttgtgta gatgacagcc aaccagattg cggcttatag tgttctctat acaaaatgcc gtaaattaac tctgcactaa aaaaaaataa tatatttata caaggctttg actcattata gtttatatat ctgtagtgca ctttaaggta tgtttgtgtt gggaagctgg ttctatgttg ttgagtttat agttatttgt ctatctgatt tcttttgacc cacacaatta ctgattagcc tatcctagtg ctgcaggacc ctcagtttct actaatagat cagaccgttt tcctggctgg gaggtaataa t tttat taag agcataagca gtaatgattc aagttttcac atttggggct gattcaacat ctatatgctg ttttgtgatg ttggaaagtt taagccatgt aatcactgtt aaggaggcaa gtggatgt cc gaagtgtctg tgcctagcaa tctagtcccc ttcacatgca taagataata acaatttt t tt t ctgtag c agc ctatt t gttgttgtgt gcttattttt gtaaagagcc c tgt tt tcac aatctaagtt gaaaactaaa ttgtgggtga aaaggccagg ttaagtatta gtggaatgta ctctgtttaa ggt t ttt tt t ttttgtaggc gaaatgtttg tcaggtgaaa gtgtgtgaat taaagtgctt tgcccagtgt tatggaagta aatggctcag atc cc tttag caccatggtt aagttatttg tgtattgtct ttgtctggca gtactattca gttttgtttt tctttattta tttttgtgat aaatgtgata accaatgtgg agagttttat ttttgttgtg tgtcaaattt gcccagtggc ggcccaaaac ttttatctga tagtgtgcat taaggttagg ctaaactctg gtttttctta aaatactaaa tgtatttgta ttcatatatc taggtgggag t tgaaggaga cctcgtgccc gagacgtgtt gtgttcatcc ttctgcttac tttattaagt tgttttttgt.

acatttgtat tatggtcagg cactttgata cctgttgttt.

tcagatcttt cttctgctaa.

gtaatacttg aattgcctag tcctcctatg actgaatcgc tcaaacttag gtagttgtag ttggttgctt ctgcacataa acaacttttc gaaagatacc tgtacaaaat cacttgcttt gaaccaactc ttactcacac aggaacttat 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2728 214 2046 D h,.TA Rat <400> 214 cggtatcgat aagcttgata cggcacgaga aaataaccaa tttaaggatg gagctgctct gacccagaag ctgcccacca attgtttcac gattcatccg agatacacct agaaggtatt agtgacacct tgtgatgcgc gtccagtgca gatgggtcag tgatgtggag ggcacagaac ttcaagttcc ccatctggtt tttcaaagta tatgccacca tgaccccaga gttgatgtga aagccccaca gcttctatgc gcacaatttc aaaagccttt ggtggcgccc aaacctggcc aacagataat ttgggtaagg ccatgtctac tggaggccta tttcacagtc tccgacctga taccaacact aacatgaaca aaaacagaag acagtggagc agggaaaaag tttctacggt tcactcttgt atggacactg acagaatgtg gaaggcattc cattcgactg aaaggcaaca gcccagtaag cacgcattcc gctacgcact tgctcttcag ttgtatctac agaaaggaag aaaccagtgc ctaggaccag tcgaattcct ccaaacaaac actggtgttt gagatgagga tgattccaga tcttcatggt ctttggaatg gtgacccaga tgttctccta tgtatcagtt ccactccaga cctctattgg tgaaacaacc gtgcagcaga tagactttag atcgcagctt aggttgacat agcccaatac cagcttttgt tcaaagatgg ttgctccagt ttcaagtcca ggcagttcca agaaaggagc cctctcttcc tcacggtggc tgggtggaaa acaccagaaa gcaggt cgac tttcCtcttc gctgtgcctc actttttcag tggagctgaa tgaggaagat.

gaagcttagc accacttgac caagggcaat ggagcttctt atctgatcaa acgtaccaca catagagtac aacaaaaatg cccctttgac cctggcaaag aaaaaaaatc ccagtactac gggtgccttt gagggtcaca ctcctctcac agtgagaaga gttaagagga atcaatgttg tgatgacaca ttggcttggc ctacagtgaa gaagtcagag actagtggat ccgctagaaa ctgttaccac atgcagatcc atcagcagtt aacaccccac ctccaggagc cagcagaagc gatgtagagt tcaacagaga ccataccctg gtcactttgg tgtgtggtca agtgcagatg tttgcccatt ccttctccca tgcataggaa tttgatgtct gccaggacca gatgtggtcg caaaaagtca gatgggaagc aaacccaaag aaaatactag agaatcaaag acccaagaga gagcagaaga aaggttcttt ccaaagaatt aaacaaattc tcacctccag gggataaggc acctatttag tgtcagtcac tgcctgagga agcagatgac attttctgtc aagacacaca acttaccata cctggaagca tcaacaagga atgccttcat tcggatttcc aagtggggcg gtaaaaatat tcatggtcaa aggaggaggc ttaaaaggaa ccctctttat tgcttctgtc gaaagtacct ccaccaccag cctttgacaa ggagaaagt t gaagagagag gcaagtactt 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 WO 99/55865 WO 9955865PCT/NZ99/00051 ccacagccaa caagtcttac gagtaaactt tcccggagag tgtacttgaa gacttgtatt caaagg aacctgcaga ctactggacg gtgaaaacaa atatggaatc agaaaggata cacgcacacc aagcagtgac tttatgttgt ggaaggtctg acactgcctg acaacatgtg tgtggtactt gacagagaca aggacatggg ttagttacct ttactgacta tacattgatg agggtccatc atcagagatc ggacactctg taagtgaaga ctctcatgac cctgtgtaat tgtctaatgc tgcaacctgg tgaagtatca tcagtagaac aaacagaagt gtaacgtgga tggctaatgt 1740 1800 1860 1920 1980 2040 2046 <210> 215 <211> 493 <212> DNA <213> Mouse <400> 215 cccacccagc agaagatcct cacaagaaga accagccacc ggagcactgg ccctttcttc agcctaatcc ttcttctttg gggtcttgcc aagtgacagg aagaacactg tgcaaactca ctgcggaatg tctcggtaat tgggagtcgt tcccttctgc tggtctctgt ctg ctaccaatga ttcacacagc aacacagatg gaaccaagtg ggtggtt ct C ggatgacatc cagatgggaa tctgatccct atgctgactg agcctccggc agttggggac ccagggcttg ccagaactgt acaagcatcc ggggatagct atacaggaca agcctgccca t tcac ttt ag tacagattct agggtcaaga gggaggcctt ggctgttgaa agctctctaa aggctgagca actttttgtg gaccctagca cccctgcctg gttccgattt ctggactgtg gccgcaggtt gaggggc tga tgaggcaaag 120 180 240 300 360 420 480 493 <210> 216 <211> 511 <212> DNA <213> Mouse <400> 216 gggcatagtg ctggagtaga attgtcttcc aggtagcttg tccaacaggg ctatttccct gtggatggat gtctggtctg gccttggctg ctgatggggc ctttgttaat gtcccaggct attgctgccc gaagcactgt tgtccctacc tcttgcctgg gtgaactggc tccctccttc tgagaattct gagaagggt C ggccaagcat ggttgccact aggggcatgc tatgttacca gctagccctg gcagcacaat atctactgta atgtcatgtt tcagagtgat attcaaacca ggagaccttg Ctgggtctgt ccaaaagcca cctcttgctg agagctgacc g cccaaggcaa gcatttcctc ccacagtgac tggatatatg ggtcctattg ttcagatgcc accaccacac ctgatqaaqt ccaggagaag caatgcccac taaaggccaa aggctgtgct cactctgggt cctggtctgg tcagaagagc qgaaqcactq <210> 217 <211> 1107 <212> DNA <213> Rat <400> 217 cggcatctca agctgctgca agcaggactg agcactacca gagcagcaac ctcggatggc cctggacgtg acccatatcc C ctggatgct ctcgcaggga gc ccac Ctgg ctggtaagga cacctggcag ggagagcggg cgggcaagaa gcggcagtag agcgactgcc ccagtggcaa tggccaacaa ttgacgccaa gcacgcgcgg agaaagaacg cttggcctgt cttccagaag ccctccagga tggccaagac gacaggcaac tcctcgagga gggacctaag ccgagccaag catcaagttt gttcgtctgc acacctggcc caccggcaac ggcacagagg at ttagatga gcccttccgt ggtggtcCtc gcaccaggat ggccaggacg cgaggaaaac cccaaggggg ggcaagaaag tcggcctttt gacaagattc agcgtgccag atcggcctag cacgacgtgg caagaagact cagtttttag gtgctgctga aactggtgtg cc t caggaat gagaccgagg aaggaccaaa tcagtggtac gggaacctgg cggtggcggt tgatgaatga ggatctatta tgcacaatgg cctcgggctc tgatgaagcc aaaggtgacc cccaatgctt cagtctgcct ggtgggaaga ggacagtgga gggcaaagct ccccgggaaa gctcccaggc aaccaagagt gggaggccac ctttacctat ccagtaccgc caccatccta tctcttccca accatgatct ggtgcctttg ggtccccaag atgggttttc gaagaaggtc ggggccattg catggtatac ccctgtagct tacccacgtg tacaatgcat gacattacgc attcggactt gctctcaagg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 WO 99/55865 WO 9955865PCT/NZ99/00051 agggtgatga agtctggtta cagattttct actoggagca gaatggacto ttctacgacc cttattggac cgacagcctg ttcaccggct toctcatcta cgctgatcaa ggagacccca atgaggtata gacaagctgg ggttgagccg tccaggcagg gactaagatt ccgcaagggt gctgatagaa gaggatotot gaactga <210> 218 <211> 1001 <212> DNA <213> Rat 960 1020 1080 1107 <400> 218 ggagcaagaa gcaacocgaa ggtaggagtg ggagcagggc gggagagctg gggagccggg octcctgggt gctctcctcc caggcacacc gcgacggtgc ggccacgtgg cgggggagtg tacctccgcc attacgatgc tccatgccac tagcttcttt cgatggtgag ttggcatcta actggcacag ctagtggagg catcaccatg tctggacgac aggccaccac acccggagct ggagcccggg ctcggtgcco agccgaoaca cactaccggc tgtctaccgg cttccagttt gctagaacct tgccagcatc ctccccagtc gtgtgacatt gctaggagtc cagcaggagg aagggcctac aggccacttc aacaagatcc ggcagocaag ccgggagaga ccgcgtggag ccacgatcag cctaccct aagttcacct gccagcctac tttggggggt gaggaccagg aaaacagaca ttcgcttaaa ggtccagcgc tgtcagcgag gtctgaggaa agactacaag ttgccctgct ccagcctgtg gcctgcctgg aaggcgaggg aggcaggacc ccttcagtgc tcgaccgtgt gccaagtgoc agtttgatct ggccaaagoc tatgggttca gtaccttctc atacagtgaa gcataccagg ggcaggggct gccattcaaa agaggatcct gotto tggg~t tcccgggcag ccgtgacggc ogggagaccg tgtgggggot caagcgatca gctgctcaat tggtgtctac tgtcaaaaat ago c tcgoto ggtgggtgtg tggatttctc cccggagctg gcctggttgg gogagoagot ggcgtctggg ctggcat cag cccggcctcc cgtgatggcc ggactacctg at cggg0cct g gagagccggg gagcagggac tactttgctg ggccaatcca tcagggggtg ggtgattaca gtctattctg gcacttgctc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1001 <210> 219 <211> 2206 <212> DNA <213> Rat <400-.

gtttcgtctt tggaacatct atccgcggtg gagcgtcaac agtgtccagc gaagaagaag agootactoc acctggtgaa tgagaagcag gaaaattgcc agagtgtgga tcagagaaa t catggaggag toacagagat gacctacttt tcagcgtaaa cgggagaat c caagaagctg gactttccag tgcgttaagc ggccaggaca ctttgactgc gcggctgatg catgtggaaa ct cc tgc ac c agtagtgccc 219 aacgccctct cagcccacao act goaagt a agcaagaaga oatgaaggaa ogttctggat acacoagaca aotgaagtgt ocagaaoaot caggaacgag ctcatotoot ttcgaaattg tttgagoagg ogtccaaota tttggagotg ctgoagoatg tctgagaggo accgooatgo gaggtggaga ttttacoaoa gtggcgaaag gacggcaatg agaggootgg tgtgoocaag ttagcacoco acatccccat otgogttggo agactaagog ooggtotoot otgaogctgg gcgctgcaga toagagacag aaatottoog toatgacccc tgggootgga aaaagtttgc tctctgacta cottcaagat ttcaaagcat ctgggaacac atctcaaagg acgttctaaa agttcggtgg agaggcagct aottcttcac tggotggagc togagotgtc gggagotgag agaagoccaa aaacogcctg goaatcctgg ctttctggaa agaaotggo o gagactgatg gtggaagaag agataagggg oactgoggoo aaaagtaatg gtattttgoo aoaggaottt tcagtaoata tgacgaaggo catcttocto gtttgacttg cattogotoo cotcaagtot gaaactgaoo gotggagttt catgctgctg gaagaagcao tttcctgaag atcotcgat ggaccacgtg oaataaggag ggacatgggo ggactttgct agtggcottc gtgacototg gtgggotooo ttggtggcgt gotcaogoag aagagcaagg gagocttaoo gagtatgaga aoottgaaag gtgogotcoa ataaagcgot agoatottot aoaaoggtgo aatggagatg cagaccagca ggottatgtt attaaaaaot gaaogcoatg gootaoagtg ttoaaggatg aaoattaatg aaagtgacoa tgtgacgtgg tttgtctooa tttacoogto ctaoccaaat atgotgotga gcctcagotg gotggtacca tootoggago aatctccacc acacccggga cagaggagaa ataggatoog taatoaacga taacaoccaa tcgatggaaa atacccttgg totocactoc gagaagtaga tgggcatgcg cggccctcao tcctggaatt acooggtaga gagtgoagto ggaagggcct aogtggacao tgcagoaagt tgtttgcact tcatgaagca toatgcaggc agtaccccac tgcttctggg gctgacctct 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 WO 99/55865 WO 9955865PCT/NZ99/00051 ccatcctccc gtctaagaca gggtaaatgc actgtggat t aagtttggaa cctggtaccc ggcaccagga ggctctccag gggactctgc tatagacctg atcaCtttaa ctgacccagt ggaacaagtc ggggagccct taagtaacac atactctggc tgatctzggca aggctctttg aacctcctgc ttcactagag cagagcgcag ttatagcact cagtgttccg ttcaaagcag cccacactgg aaacgtccct aggcaaaggg gggcacctgg ccaccagcac tctttttttt ccagggctga c t cagag cc t ttgcaggaaa ctaggctctg agaccatagc cagccccagg gccatcttcc aagtctgtga tcaggggaag agctcccgat ttcctcccgg gcccctgttc atctgccctc taccccaaaa aatctgcagt tcccttaacc aggcatctct tcccactgtt tgaacggtaa ggtctgcgtc tcaaagtcgc ctccctgcga cttgtgtctt tgtctaatac aaaaaa cagatcaaag agtgccccgt gcagtctctc ttaaagctgc tgcagatgac agacaccagc tgctttgagc tgcctcctct gtcccctctc actcgtaaat 1620 1680 1740 1800 1860 192 0 1980 2040 2100 2160 2206 <210> 220 <211> 376 <212> DNA <213> Human <400> 220 atcggcatca ccttctacaa acgatgctgc acctggccgt tgctccagcc acagggcccg cccacagctc tggcgacggc accgtctcgc tgtgagtact tctgtccagc ggggtgtctg ccagcccttg ctctct caagtggctg gatcttcctc tgtggtgctg gcttgacgtg ggccatgccc cacacccggc acaaagagct ttctccgccc agctgggccg ggcttgtcca tgctgcctcc tgctaggcca tccatttccc tgtccagggc actacctcag actggagctt cttcaggctg gccactccac Cctcttcatg gctggttcag aagagtggct cctgtatgtc aagctgtctg cactctggga 120 180 240 300 360 376 <210> 221 <211> 433 <212> DNA <213> Human <400> 221 agcttcttct cagagcaaac gcattagaga aacatgaaaa ctttctcaga cctgtactag attttacata ttgctattcg acattgacaa gtatgcatgt caaattctca gatttgaagg ttacagcagt gctctgtctt caattttatt ttt agtaagcaac taaatataat tttaccggtt ggtaattcaa gccagggacc ataatatgta gcttcacatt agaaaatata tcaaggaagt caagaagctc ataaaatgca aaattagagg ccaataaaaa agaaatcgaa catttgatga ataatgattc tcatcacatt ggtcttgtaa gttctttggt aaaaatctgc aacagctgtt aacattcttt tctaatatgt tttcacttgt aagaataaaa gcagttagtc tgctagacat ctcaacaagc <210> 222 <211> 530 <212> DNA <213> Human <400> 222 gtttcaagcc tgtaatcata gcctgagtta gatagagaaa atattgactt tgtaagaagt cctctaagct tatgtgaccg gactggtgaa aagttgcagt tccttaatgt taggactcta ttctgatcat gtgaaaatgg ttacttacat actaactgaa gcgttgggaa cactgccaaa atactcttgg gagttttact gtaagttaga tttttttttt tataccttca cactagttgt gagaaaatca tgctaaggca ctcaaaaata aaataggtgc Cttttgtcct atttggctcg ttgagcactt gaggcatgtg tagaggaagt cgtctcctag gaatcccata ttcagtctga taagcaaata taattttctc aagcctgctt caaaaagtat tgttgggat t ctctccttca ttctttgtaa gttgagggca ggatgactta gtgtttggga attttctttt ccttagttga gatatatagt gaaattcaaa atctcagcat 120 180 240 300 360 420 480 530 <210> 223 <211> 550 <212> DNA <213> Mouse WO 99/55865 <400> 223 PCT/NZ99/00051 aagctgctgg aagagggctg tactgaacat ggttttgctg ctccttgtgt gccacgatgt ggggcctgag gggaaaggaa ttctgcgggg tccttgcccc ttttaaatat tcacaggtga tgtcccaaca cagcccctgg ggacagagtg gactatttgt agcttgcagg caggtcagag t tgaggtggg t tactt tccc atggtttggg gaaagttcct agccaacatt gtgaagacgt tgaggtttcc cacttaaagc gcgttgctct ctcccttctt aggaggtggg gaacccttct atcgttctcc ttggttgtgg attcctcacc agcctcttcc ttcctggcaa ggcagaggcg tgtagatgcc tttcttcagg tggcagagtt ttccttcttg gaggctgacc tccttgcctt aagaccttgc aggggccggc gCtcgggctg tttcCtctcg tgtttgttta ttagctgcct gcaggcttca tcttgcctgc tcagtaaatg caggctgagt cacaggcaga cccatcgtgt taataacaac <210> 224 <211> 470 <212> DNA <213> Mouse <400> 224 aggcctgttc accaccactc ttttttgtta ctgttattca ttatgtttgg gctgtgccac tgggctcagt ccttacctcc taccttcagc cagcagtctt tgcttcctca tcttcactca atctgggtgt gtatttatat cttcttagga tgggtgagtg ctgttCtccg acagttcagc tgaactgttt tgcttctgtg ttcccctgct accttaagca gtgaataatg cacggggctc ctaagctttt ctaattatac actgtagcgt taggaggctc gtatagcaac gagttcaaag atatcagatc gggctctttg ctttggcttt catggcagag gtgggtgaag agccgaggct ccttctaccc actcaacttc cagagtaaca ctgaatactt tggtggtttg aacgagcctt gtggaactaa tggaactggc ttgcttttct aacattggtc cctttgctgt <210> 225 <211> 1752 <212> DNA <213> Rat <400> 225 ggcacgagct gacatgaagc ccatgtggcc acttcttcat ccctgtcaaa gtcagatgcc tttcggataa acctgtccaa tggttcttga acatcgtagc aggtcctagg ctatgtcact ggagcaagtt cacacagatc tgtttgaaat cacaggcctc atgccaaagg cgtgcgcata tccgaagcgt cctagacagt tggcaaagaa ccagcatttt agaaacatgt aggcctcatt ggctgctggt cattctggtc tgtttacaca caaggagttt catacgacta ctccacatca cctgtgttca ggtcctagac acttctatgg catggattat gggcagtttt gaaggtggct gaagaggagg gtccaccagt gtacaaagag cgaggagjgtt gagagccagg agcactgtgt cgcaggcctg cacatgcctg cactgctttc tttgattagc gaacctcttg agcagatcca cctgtgacac cgtctcactc agggataccc taaggagatg gggcagatca gggcagtgga cccctagacc gtcctctggc aaaaaagctg gaccggggt c tactgctcag ccatggaaca tcaccagtct catgatgtgg gtgcCtcggc gaggatgaga gacggctttg cacatgctta atcccacctg gagcagctgg cagcagcctg cccaagtcac gcagcctcca ctgccattgg gccctactcc ccaaagaaga agaggtcgtc tttcagtgat tttggccatg accaaaggct aaggccttct atggggctcc cagagattgg ttgCtctggt cctcaaagac tggtggtgac caagggctcg gccatggcta ggttgcagct accaagggtg t tc tgt ttga t agaagagc t tggtggaggt ctcacttggc ctgtcacccc cccccatact gccctaatgc agtggcgtag aggatgcccg ctgtctcatc tggcaggctt gcctcttaga ttcacacctg ggcctcacga ggagacacag ttttgtcact ggagttggcc CtCttgcctg ttcctgctgt ctgtggctct gctgctggaa ggacatcaaa ggagagaaac tgatgttgcc gaagagacgt gatzgcgagct agactggact cagcaagact ctggagccag tgaggcgctg tgggactgac agatggcttc tccattgtca caagatcctc tgagcctgtc ccagcagatc ggggctggcc tacagtttgg gatcctagtg ggcagcaccg gtagcagcat tgccagctct c tcagc tcag agcttgcagg tacatacaga gacatgccta gttcacacca aagactcagt gctgaggatg tttgctggag aaggtctttg ggtcgggaga gtcaagaagc tacgatgatt gtggtacagg ttgctgagcc caccaggcca cagctgggca agcctcatga tggatccgag ctgggattga attggagcca tggacattgg tcagagccct cactggcagg agcgcggtcc gctctagctg agcgggtcag gcatggtcag atgtcatgtg attggatctt cgctgaagga 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 aacgtcagac cttctacccg WO 99/55865 WO 9955865PCT/NZ99/00051 ccacaggccc cgtgtggtat gggacagcca ggctgcggaa cacttctttg agtacaagaa gaatcgcggc gggaggcacg ttgtcttcta cccaacgctg aagtctctgc aggtgcggct ggagctagcc ag 1680 1740 1752 <210> 226 <211> 2165 <212> DNA <213> Mouse <400> 226 ggcacgagcc cagaagctca atcggcctcg tgtctcctgg Ctcttggtga ccagcatcct atttccatcc tcagctgcag gaattctcct cccaaggcca ccttttgata Cttctgccct aagtgtccct ttcactgact aaactggagg aacgccacag cagctctgct ggct ctc tcc ttttcttcga gataccccca ctagacctca gtccattttg ttgctccggt tcagaggcac ggtggacgcg ctgccgtggc ctgtggaact cgcaccttgt gccaaaggtg ctgccgcgcc caccttgggg gaggctgcca tagcctcagc ttgggggtgc cctccctcac tcctcagccc aaaaa tgctgccctc tggggagccc ctgtgtctgc cctaccgtgt ggaaatctaa tccagaggaa cctcctcagc aaggaagaga ttgatttgct gtgtgcgcct cccagaaaat gcatgtgcat tccagagctg acagccagca cctccctctg cacaggagtc ttaagttctc catcctggac ggacatatgc LLL.ctcctLt tcatcccctt cctggaagca ccc taggct c agcgacgcct acgtgatcgt tttgggcagc gtgcgggtcc tgtgcgctgc acatcccccg tgctgagagc ctaagcggtg aagatgacta ctgtgtagca ttcttgtccc atttgctccc tttctgagaa ttgcagacag cagactggca tcgggttgcc ggataaacgt aagtcctcct gctgctaggc catctcccac acatctccct gcccgaggtg ttgttatcag tgtgtctgga agaggcctcc gcctgaagct caatcagatg ctggaggcag agaaggatgg atttgaaaac tgtgagcatg caccttcagt g tae agcat c cctgaggcag cgtcttgtgt cggtcgaaca ggtgggagct ggatctctgg gcgggagcgc cagcaccgcc tccacgtccg gccgctgcgc actggatgct cttgaaaaac Ccaaggctca acagcaggaa ccaaaccgta tcttagagtt ggagggacga gaaagacatg gccttgctcc tgcccctgcc tttgctggcc aaatttgaag agcccttccc agaggccaac gaagcagggt caggctgttc tgggcactgg ggccacactg tacctgcaag tatggctcag gtcatggct c gacccactca tatatcctgg agcagccacg gatacccagg gctgcctgga agccagaccc gagaattgca cctgatgacg aggccagtt t ttggccgaac gaagggacgc gtggcgcggg tgcagcggtg ctgctgctcg gctctgccac c agcct g cc a cgtctggagc accaatagtc Ct ccagaa tg agactcacct cctgagagga tttttccatt gtctctgcgc tgtctctccc tgcggagttg ttcagtgggg actattggag tgtctgagga gcaccaaaag cacaaaagtg gggtgactat aatgtgaaga tagacctgcc aggacactgt acttctggca tgacactccg caccctgcga agaatgtgga ttgaatgtcc cccagcagct gtgacccagg agggctcagt tcctggtgtg ccccttaccc tactcctaca tgctgcggac acgtagcacg agcagggcac acccgcaggc cctacttcag gctaccgcct ccctagcctc agtgtcacct cctgtggttt aggcctcaca taagtcccac acttgggctt tcttttcaaa ccggatccta gctactgctc gaccagccac ctggttccct gcacaggaca aagccatcga ggcccagcct tggaggacct tcctgcaggc cttgagtagc ttatgaattc gaggcgcaaa gtcaatacgc ctgcccactg aacccttccc cttgcacccc ccaccagagt gacgcttcac tttggggccg cccagtgacg gaggtcagat tactcagctg tgcagcggac ggcgctggga cattggacca agtgctgctc tgcgtccctt tcgcctctgc gcttcgtgac cagctggagt gctggaact t cagctgtctg catgtactct acttgaccaa tcctgatagg actgaaaaaa 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2165 <210> 227 <211> 1348 <212> DNA <213> Mouse <220> <221> unsure <222> (644) (644) <400> 227 caaagaattc ggcacgagac cggcctcact atgtctgcca ttttcaattt tcagagtctg ttgactgtaa tcttgctgct tatatgtaca tgtgcttata tccgatccct ggcacccagc atcctggaca gaaataaaac tggactattg ggaatatttt ggaagtgtgc ccgaattggg WO 99/55865 WO 9955865PCT/NZ99/00051 gaacgcaaga atacagtagc cctccagaaa aacttcaaga aagatgtaac tccagtatta, ttcgggcacg aataatgtct ttgttctatt gattgctaac agt att t taa aagatacagc gtgagcaagt tgtagtcttg gttcttaatg ttgtaacttt aagtacat tt tttgtatcca gaattaaatc gctcttttta <210- <212-, <213-, gtccttatgt tttggaaact ataatgggaa tgctgttctc agttcalatac cattctgcaa aagtagaaac tcacagaatg tttgttgttg cagagtacct acaaaactct tgccacactg aagcaccgtg tcttccaaat cagtgcttta gtaggttata cagctttgac acatttcttc ctagctgaaa aaagtttgaa cgccatatgc accagcatgt gaatggttaa tatttttatg acaggaatgt atgtcattct ccagtggcaa gtacctctag ttactgttct ctattcttgg gaatttcttt tgacgaagag cagtcttcgt agaacgtcca agtctagtgt aacatatctc acagaatgtg aggttcagct actatacata aaaaaaaa tgtatagtga gcttgctatc gccatttgtc ctattggacc gattgtatcc gttgtgtcag attccaaggc cgactgtcct tatggattgc caaattccgc agttagccta caccttagaa gcaagt aagc tcgtagttac atgttctgtc atatctgctt aatagacgaa gaaaatcagt gcatttatta tggcct tcag agactgtaaa tctgaacatg aatgagctga atcaacctca gactgctttt tcctttgact attnttattg attcatattt agtttattac agagttggct agaaaagcag accgtgcagt ccaaaggtgg agcttgaact tagtctgggt tatcaaagga tactgtttca attaattact catcctcttc caaggacttg gaatgagata atgaataatt gttctctcac cataaggttc agggcttcaa agaaaaaaac aaaccctttg aggtgtttaa tctagtcaca caagtgagcg cttcgttctc tatttgtggt ggaatctctc actatgctct tacttacaag aaacaaagag gggtttaact 240P 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1348 228 2296

DNA

Mouse <220> <221> unsure <222> (2255) (2255) <400> 228 ctggagctcg cgcgcctgca ccactccagt agaccgggga aatagctatt tcacagcagt gaccatgatc agcccagcct ccaagtggca cctctgtcag aggcttcatt tactgtaacg tgctacaaca ctctaccttc gaagaacttg ctgaaagtac taccaacctt ccaaagtatg cacctatgat tcactttcga agtctcggct gttagcatcg ttttctgtcc cgtaaccacc attacgcctg gatgacaatc aagcctgaaa cgcctggttt agttttcttc aacttagtaa agcgccagtg aaccttcccg caaccgggta cccccaaatg taataataac ctaagcaatt actgattctt cgcaacaatc gttacagtcg ctaccggtga ggtccgtgga atggctatca gattgtgagc accattcaga acagtggcca gctcctgtga tcagcgaact acaggcagcc Ccctgacaca atccacatat ctggcttaaa ctgggccata agaacgcagt gaatacttgg ggttcccatg gaaaccagta ccaaactgcc cctcttcgaa agaaccttac aaaaatccaa ggtcgacact ctaaaacaga aacagaagct ggagcctctt ttgtggctaa atcgctctct agaacaacca aaagaatata tcaaagagtt aaattccgta aagagggagc ttagcacaat gcatatcaac tagatggaaa acttaacaga gcacaagcct ctttttctta tacctcaggg cttggtattg aggtcaatgt aggacctcag taaccactgc ccaaacaacc cc tcac gga a cctggagact gcccagcctt tcaccgccct acctttacct tgtacaaccc atttaccttt agtggatcca aattctgaga acctgctata cctcatcggg atcctgtcca gacatccatt aataaacaat cctataccac acatttgcaa tctggaagag atttcgagac cccggggggc gatctcttcc cttgttgaac gctgtccctg gaggaagctt ttt aaggcag tatctttgat tggatgcaag gcgtgggctc tgcagaactg aatacccaac agatattaaa aacaatttta tgctctgcct tggatctata agaacctgaa gtttgatgaa cacaaccacc ggctgccatc aagcttaaaa aagcagcaag ataaagacct actaaaattg tctgtatgtc ccagtgggaa gttgggattc aacagtttag gagaataaca ttacacttgg agtaactatc ttgcccagga ccatcacttc aaccatggtt gtgaggaatt taccttcaag ctgtatcgac gatttggaca atgaaatggg atgtgccaag tttgattgta acagcatatc aaccccaagc attactgtga atgactgctc acagaaacaa tcaccctata acacctgttt ctcaatcgag attggtgggg gagactccac aagcagaaga caacactgct ggc tgt tct t gctgtgacgc ttccggagga cttccgattt atgaattccc taaggactat atgataactc tgcggctgct Ctattgagga atggtctcac tgggtgacaa ccttgacagc acaaccatat tcgatatgtc atataaccca tacgagactg ccccagaaaa aagacagtgg Ctgctcaagg tcattaagga aatctgtcac tgcgactcag tcgtaacagg gagtatgcat gtattgagac agcaagagaa ctgtggccct 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 WO 99/55865 WO 9955865PCT/NZ99/00051 ggtaagcatc ttcacggaac tactaagaaa aagcaatgaa gatgaatctg tggcatccca tCcgggtttt aacactggaa ttaagaactt gccctccttg tgtgcgtaca gacaactcca cccatctcca tacaagaaca gactcggacc tttttaaaaa aagagactga tttatt ct ttggtgtg gcaaagggcg tcctggaaat aggaggagt t acctcagtga actcacactc acctaagaaa gagaagcaat ttggtatgtg gaggagaaag cagggaaact tgtaatacac gagcagtagt atgatgcaag ggtgatggta gtacntgtac cataggaacg gatgactatg tctttccaga accatatttc aaccggagct gaggtcccac ggaactctgt atttgccata ggtcactgtt cagaagccgg tgctaccgat ctccgaatgg acagagacag accagactgt tctactgcaa taatttatat 1860 1920 1980 2040 2100 2160 2220 2280 2296 <210> 229 <211> 1704 <212> DNA <213> Rat <220> <400> 229 ccaaagaatt gccgggcagc tgagcggcct agccgccggc tggagtacgg agactgggtg ctgcaggcct cactggatga gagaagctca agcccggact cctggaggac aataagacca tgctgcccgg tgttacgcat taccccctga ggtgatgact caaagaaccc cgaaacattg gcggttcaat ccccaatggg ggtggtggtg aaccctcgag gtccggctca agcccgaagc ntggctccta tgaccagcgt accagttgcc aagcctgatc <210: <211: <212: <213: cggcacgagg ccgggcgctg ggcgggtgct ctcccgcacc cttccacccc ggcc tat ctg atgcagctgg acacggtggt agagcttcct cgccatactg agctatgaag acgaccaagc cagccatgat catcatggag ttgccggcaa tctacatcct aagcgctgtg tggccaaccc agtggcacgt cc cagc cct g gcatcccccg ccaagatctt tgaggtacaa ccaacgcaga cccatttcag tgcactggct accgttccag tttggatgtt cggctcggga cggcgggctc ctccccaccc cgctcgctgc .gatgcggtgg gacctgggca tgtggtggag caattactgc ggaggccaac gcaccaggtg gccgtttaac aggaatctct gcttccgtgg ctcctggtgg tcccccgggc caacttgatt gggcagtggg gaagtacgtg gCC tggcct t ataataacca gaagccgggt ggctgcagga ccagagggac tgacttcctt gaacgccatc gccctgcgtc aagtacatga tggagtaaat ctca tggcggcccc tggcgctggc tcgggcccgg tgctggacgc cctgggctaa caaatggcag gcctctgtgt ggccccttcg ctggagtgga cggctgaccc cttcccaact ggagatctgg gCtccggttc ctcacaacac tgcagttccg ttttcgtctt ctggtcaccc caaccccagg ggatggggc c gtggatgatt gctcaccatc attcgatatc cagtcactag catgaccctc tctgccccgc agcgcgccca gcatgctggc caccattcca catggaccgg ctcgctggcc ctggcggcgc cgcttcgggc cctcaccaac ctacaagtgg ccgaggagct agtacgaagt tgcagaggga tcgggctgca gggaggttca ddydacctaga gtgctctgcc ttggaactcc ggaggggc cg acccgggcac tggagaccac gctgtgtgct acctgggcag gtggactaca ctagaacaga aagcttatcg tagaggacgt tgtcgttgtg tctgatctca tggcggcatt agccagtggc caacatgctg acccatggtg gggctattgc caaaaccccg cagctgcgcc gccatccgcg at ccc ccggg catctacatg cggctactgt aatggagctt gctgaagagg acatcaaacc gacagccctg ctcatcaagc taccagaaca caagaaggag catcttctcc c aa tcggc aa ggagtggatt atgtcttcag aggcattcat tcccgggcat atacacgtcg agacaccatg tgaggcctgc accctgctaa gatgtgaagg cccacgtggg cacatgggcc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1704 230 2004

DNA

Rat <400> 230 Ctcgaggtcg acggtatcga tggagctcgc gsgctgcagg gcagccgcag gtatggcggc gtggggcagg gctgctgtgg gttatcactc cgctgccttc gattccgatc tgcagcggga cagttgatct ccaagtactc taagcttgat tcgacactag tgccatgccg ccgcgtggag cggcgacgtg aggagtgtcc tctgcgggag taattaaccc tggatccaaa ctgggtttat ggcccacgcg g ccgc ca cat cattacaggc ctacacctgt tcactaaagg gaattcggca cgttgctgtt acagcctgcg tccagttccg tcttccctaa cattcacgca gaacaaaagc cgaggcggaa gctggtgcta agaggaactc cacgcgttgg agccctggga aggcttttgg WO 99/55865 WO 9955865PCT/NZ99/OO51 aggacccgat tggttccaag* tcagggatct gcctccttca gtgctgcccc tgtagctcca taccactccc tcctgggagc aagaaagac t gcatctcaga gaggtgagcc tatgccgtct cagctcaaat cagcggtacg tctcatcctt ctgtatgtgc cactaccagc ccggccaact gaatacacgc gtgcccagca ttgttcccgg gtgaacctgc gtggtggccg gagcccaaat gttccccctc ggggagcagt ctaactcccc actgggggcc acactgtcac tctgcgcgtc aacctctggg gggaggtcgt aggcagggct aggcagtgca tgaggcagac ggtctctctt gcctagttta ctcccccaac atgacttgtt ggaagagacc tgagtggtta accgggcctt acaccctcac ctgcccagga ccgtcaccaa cagaccccaa tggtggcagc tgtctgatgg ccacccccga tgtgctatgg ccggcggcct tctaagattc ggcagggctt ctggatctgg acccttcctg agatgtggat cctcaacttc gctggccaat ctgcaccgag gtccgtgcta tatccggcca cctttcagtt ccgcatgttc tgtggacatc ttccacatac tgacacagcc cccagataat tgggctacag ccctgtgctg catcacctcc ccggcagcag ggtctccatc ccatggcttc caaaccagtg ctccagctac cttcagcatg ctccttctac ggccaagcgg cctttcttca tttctgccat tctg caggctccat aagtcttgga atcgactcca gacactgacc aatctcacgc ctgaaagcag atctgcagaa gtctttgatg tcccggactc acaggctaca caggatgtca atgatcaata gaagccctgc aagggcgagc ctactggatg aagggcaagg ccccacctcc cagtttgaac tatgtcagcc gactgggaag tttgtccgac ccctacaatg aatctcctca ctggctaacc gcaactacag gc cct ctt tC caggtgcaga aggagctcag ccaataccgt actacttcct cgtggaagaa atcgattgtt atgctcactg ccttcatcac tcacagaggc gc caggacaa ttttgggcac actcccgaaa ccgtgccctt tgagcaccct ctgtgccctg ataataaacc tggagatgct gagccctgct catctgtcct agagccctct tctacacaga tgatctgcct cccgaacctt tcatccggcg cttcatactc cccagagtta gctctgggtc taatgtcctc cactcccaca gcgctatgct gctcctgccc ccacaccagt caccagtatc cggacagggg ctgtccattg cgaaacactg caggaagacc cctcaacatc cctgcatgca gttgtacaac gtacctgcgg aagttatatc cattcagctg caagtggaca cagtgccctt cttcaacacc gcccttgcta tacatgcact ccacattgaa tgCtcgtggt acctgcccca gcttctgaag 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2004 <210> 231 <211> 1397 <212> DNA <213> Rat <400> 231 cgggcccccc ctcgaggtcg gaacaaaagc tggagctcgc acgagcggca cgagcggccc gctccggcgg cgacgacggt tgggcccggc ggtgatccga ggctgtgcct gagcctggcg cgctctcccg ctctctgtac cgggcggcgg gaaggacacg cacttcagtc tgtctttgtt acagcattga gaaatctggc tttttagcct gtttatgtct ttgtgttctc accagatcag atagacttct tgatttaggt ttgaagaaat ttatgccact aatacagagt gcttggtata gctgcttaaa tctgctggat gtgtcttgga gcccacccaa atgtggaaaa cgtaggtggc agaattggga agagcaagtg tcgaagcttt cactagactg ttctggacga cgctgtcttt agagtcaccc ctggaatctg cctctgggga ctgtcattct tttctttgta gtgtgta acggtatcga gcgcctgcag cgaagggggc ggccggaggc gctggcggcc tccgtgtggc gtgaacatga caccagtggt cagagttatc tggct attt a agaacatcta tttcagagac gctggagatg gaactttctg aatgaatggc cgctgtgatc ggcagggtca aagtgggaga aatagcctgc ccatacctgt gttctcagac ccctccagaa cagtatcatg taagcttgat gtcgacacta tgcacgggcg ggcggctcct gcggcccccc tggcgcggag ctagcggccc atgtgtgcaa ttgaccaagg tccaactcta ttaacgggtt tgcttaaaat gagaagtcac aaacaatgat agaatacagg agcctctgac tCCtggcctt aaccatcaga ctgaggtgtt gtgaaggtga cagtgtaaac gaggaggtgc taggaattta taattaaccc gtggatccaa acttggcggc ctccttctc gatgagactg gatgtggacg tggcgggcca cagagagaaa aacacagatc tcattctttt gctaggaaga taatccggac gaaaatcatg ctggcagctc gttccagtat attgttaaaa ggttttgccc aattctggaa caggaaagct catgtacaat atgtggaggc atccagtgat aaaagccaaa tcactaaagg agaattcggc gatggctcga ctcctgggct ttggcgggct ctgcggagcc gcggcggcca ttatgcgaat t tct taaac a gtatcatctg ggctccatgt tggaaaaccc agccctcatt cagaagaaga gatgtcatca gatatcagaa tttcatccct atcaagggac ggctttgtca gactactatg ccaagtcttc gtgaggggga atactaattc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1397 <210> 232 <211> 861 WO 99/55865 <212> DNA <213> Rat PCTINZ99/00051 <400> 232 gaattcggca cgagaggaga ttagcaccta gcttgtttgt gaagaaaaaa aaaaaacaaa tgagagaaca gacccagttc agcaagatgg tgttgctctg ggttttggtt caggctccca ggttcttctg tccctcaccc ggctctggaa gaaatatcca gcgctgggtg tcctggttgg tgatagactc cctggcctta aaaaaagatt tagaggaagg tctactcagg atcccgagtg gccagtgaga gacatcccca atcactcaaa aggggtttcc ttcttgaagt catcgaacct gaaagagaag gtctgataca aaaaccaaac tcgacccttg atccagtcag tattcatacc ccttactctc ccatttgcag cagaatcact gtcatggggt agctgaggaa tttctgtaga aggacctgcc tagaaagaaa a tgtgcacaaa ccaccaagta agtgggtact cttctcaagg tattcttttg ctggctcatt cccactgata agctgatgtt cctgtattac gttttctaga agaaagacag tgtagattgg aggctttcct gacaagtgac gaaacttgta gtaattgttg caaataagat tcctcccacc actttttttt tagctttccc ttcttcccag ctgtagatcg tctggtacat ggcagactaa ttgtgggagg aatgtgtcca tcgctccagg ttaaaaaatc ttattattaa aaaaaacgaa aggagaaaaa aggctgccaa ttaatctcca tcatgttgtg tcaagactgt taatgttgaa aggtgtctcc gacaggagtc aaaatcaagt taacagagag aagacgcacc tgccagtggg 120 180 240 300 360 420 480 540 600 660 720 780 840 861 <210> 233 <211> 445 <212> DNA <213> Mouse <400> 233 ggaagtagaa gggcccggcg gctggtggcc gcactgtggg ggagcaagtg cgtgagcgga cgggaataet yaggtgcgtc cggccgtatt cccagcccat cttacctgat gccctttctc catcaacaga tctgacgtta tgattgttgg gaaggtcctt ttttcatggc gtggcacgca cgtgggcctg tagctctcac ctcttactca ctcaatcaga gctgtgccca ggaga ggcgtcctgg gccgctgctg gcagctgttg ggacgagccc ctagaagttc gt gga t c cct tctgcaactc gggcaggtgc aagcgagcct caggagataa ctgaaaattt ctggaagagt tctctactac tctggccatc ttgctctggt cctCcggcct aggctctctt caccataggt catttatcct ttgactttgg gtctttacac 120 180 240 300 360 420 445 <210> <211> <212> <213> 234 565

DNA

Human <400> 234 cagcatcctc aatcaatcca gttaggttgc ctgcggacac tctcgctggt tctgtctacc tgtttgtatc accacctatg ccaagaaccc cagggcaagg ctgctttgct ttggcatgtg ctagatgtgg ggcttctaga caaatgtgcc acacgctcgc ctggtctcca aagctctttc tagatcaatc aaaaaaaaaa acagcatatt gctgggcctc tggcctggat ctatcaacgt ctaagaggca agccttgcct ttaccccctc tcttttttac cattgcccag aaaaa cggttgcatc tgtcctgatg cctgttcttc gagcctgatg ctgagccctc aagggggcat ctcctgccat acccagtgcc ggagggaagg ttctacacac ctgctgagct gtgctctatg tggctcagtt aacccaagcc atctgggtcc acccgcacat tctgactctg ttctgagcaa tacagctatt ccctggtgtc atttctgcat tccggaaggt aggctgacct ctagaaggcc gacaatggac tccccatggg taaagtttct <210> 235 <211> 476 <212> DNA <213> Human <400> 235 ggtggctttc attggtgctg tccccggcat aggtccatct ctgcagaagc catttcagga gtacctggag gctcaacggc agaagcttca ccacaaaagc gaaatgggca caccacaggg agaaaactgg ttgtcctgga tgtttgaaaa gttggtcgtt gtcatggtgt gttacttcat WO 99/55865 WO 9955865PCT/NZ99/00051 cctatctatc attaactcca tggcacaaag ttatgccaaa cgaatccagc ctcagaggag aaaactaaat aagtagagaa agttttaaac tgcagaaatt ggttctgcct taaattggga ggactccaag ccgggaagga aaattccctt tatcaatttt tacaactttt ttcctgaaag cagtttagtc catactttgc tttttccttc tgtgctaagg taaggtatcc accctcgatg caatccacct agcggttgaa ggagtggatg ttccaacctg actgacatac tgtttt 240 300 360 420 476 <210> <211> <212> <213> 236 607

DNA

Human <400> 236 tatgtccact aacaatatgt CCcgccgagc gaatgtaacc ggcatgatct tcagcatgtg gtctactgct ccttcatcag atgagtagct tcatgctgtc cCcatgacgc ccccatggtg cactaggcct gggctttggc tgaatgaggc cgtctcggtg acaccctagg cttacccctc ccatgtttct aggggtattc cactctg cggacccacg cggccttgga cggcctcatg ctttgccaac catctctgcc ataccagcct tgctaaacct cccccagctg ctgcctccct atttgctttc gaggccgaac cgacccgacg cttaagctga tctcggagct gtggtgatgt agaagggtca gctgccttca gatagaggga tcccctgcct tcgttgaaac aaagtgctga cggactacat agtggtgtgc cggaggacac cctatctgca cattttggac gctgccatcc ac c tggc cc t gctgctgggg ctgttgttaa ggtacaagcc gaacctgctg ttgggtcgct gaagcaaatg gaatcctcag cctgtctatc tggacttccc ttcctaggga gagatgctgt taaagttttt <210> <211> <212> <213> 237 513

DNA

Mouse ttctccatta ttgattcaac ctgtgccttt atcactccct atcacctcat gtactgtggt ttacagtttc ataataactt tagtaggcgt cctctatgcc agattcaaac ctcatgctat tcaaagcctt gcgatgacct ccatgtactt atatttgtat ttacatttgt ttaataaatg taatattcat ttcctacagc tctttttgct tcttccttta ccctcattct actaatatgt ttatttccaa atctctgcac cttgttgaag cagccttcat cttctactga tagattgctc tatcttctga gtgctgcCtc tgctttgtaa aattaaattg ccccgagtgc tat tact c tctag tgtcttacaa tttggtccca ctgagctctc agcacttatc ttattttcta taagctcctt ctagtatagt catattcacc gctcttgcct gctcatgttc cctgattgac ttttgagttt gcactctgtg gagggcagga gctgagcaca <210> 238 <211> 944 <212> DNA <213> Rat <400> 238 ggcacgaggg tcgtgggtgc cgggtctgac aggtcaaagt aaaaatccaa cagaatttga tgaaaatcag taactggagt ttgatctttt tgaaacctat tatgtagaaa gcaaagagaa atgttctaaa cgtgggtgga gtcctgtggg gccgccgagt cgtgttcggc gcgccacagc gctgctggaa gattgagacg taatgaaaag taattatgga tcatcaggtt ggtaaaaaac ctctgtggaa gaaagcagaa agaaaagcct gaaaatttat atcccgagag aaccgtcatg cccgccgggt ttttcctgtc atggcttccg aagtccacta gaactaagga ccagctgctg tgggatcagt cctgctgaga ctcaatggca agcagttcaa aacacacgat tcctacgaca gaagatggag aagcaagcca tggagtgctc cggtgtagct tacttcagtg ctt tggagga ggaaaagact acaagatgca tggttgc tc c cagataagtt atgtgcaagt agaattactc aaaaagtcaa gggactactt ctgaggcaga atgatgacat gggaagacac gtgtttccag cgctgccgac caccgctgca gttgcagaaa acgtgatact gcagaagtca tcttacaaca tgtgaaaatc acacttcaca catgattgtg gactgataca aactcaggtg tcctagtgag gaagcgaacc agaattctga tagggactgz gctgcgacgc gctccggcct gacctagaag cttacaaatg cagaagaaac gggtacactg tacattactt gagaggtcat aacaatcttt gt tat tat cc gaaaaagaat ggattaatga attaataaag ggctttaaaa tggtgaactg WO 99/55865 WO 9955865PCTINZ99/00051 cacacatgtg ttcatgtggg tatgtagttt tggacagatg acta <210> 239 <211> 386 <212> DNA <213> Rat <400> 239 ctcgtgccga attcggcacg gcgtgcgggt cctgctcttt ggcggattca gcccgaggag tccccaccgg ccccatgttt ccaagtttct gaggaaagct ttgccctagc tctgaatggt gcccagattt cttctaccga agtggcgaga gtggccttcc ctgtggcttt gtcattgcct gacgccaccg gtctttacca tgcttc tggggaatgc tggcgaccga a ccggaac cc ttctcacccc acagcaagca acatcataaa ggccctggga gctgctccct gtacgtggag actgtccctg agcctgcctc actgatagtg gcggagctgg cccttccagc gcggaatact atcttcttcg gctgccagcc ggcaggccac <210> 240 <211> 228 <212> DNA <213> Rat <400> 240 ttccgcgggc gtcatgacgg ctgcggtgtt ctttggttgc gccttcatcg ccttcgggcc cgcgctctcc ctttacgtct tcaccatcgc cactgatcct ttgcgagtca tcttcctcat cgccggtgcc ttcttctggt tggtgtctct gctgctttcg tctgttttct ggttcctagt gagagtcatc actgacaaca gagatggacc agtacagaat tacctgct <210> 241 <211> 452 <212> DNA <213> Human <400> 242.

ttcgagcggc cgcccgggca ttgttaggaa aatgtaggct tgcgacacac ataattgtcc atgtgttggc aggccccatt ttttagggct ttctgggaat tctgagtgag ctaactgaca tcttttctgc tttttaacag caggacacca aggcctactg ggttgaaac t accagtagaa caatttttaa aaatgcataa tgtcttgaca caatgaaact gtgtcttcag cactcgggaa ttagaaagaa aatgacattc gattgatggg actgcatagg gagaacctca gtcaggcatg tcagggagga cc gagccgggag tctattaata gagcatgaag actcatgtgg gctggacaaa tttctgctcc caggttgact gatgtattgg agatctgagg cattttttta tctgaatgta gcagccttga tctctctggc gtggtgagtc <210> 242 <211> 1311 <212> DNA <213> Mouse <400> 242 ctgcaacaag gctgttggtt ccctgggccc aatggtcaca tttttcccac ctgctgccct ctcccagggc ctcggcggcc aggggtcgac accagagatg gtatttgtgt tttctgggat atagagaaat ctctgcaaaa gtatctgggg ccacaccatt agagagaggg gcctgacctg cgtcactcct gtgttctggc cagagacagt ccccgttttt attatttttt aaaacaacca ccccaaattg attccttcag cctctccaat gtcacctgct cacctgagcc actacgcgga ctccaagggc tttattttta gactttgctg acctgtgggc ctctctttcc ctcttgagtg aaacttcgac ggatgattat ggtctggcct gggctccagt gaagacccca cagcccagag ctcctacctg ctgcaccaag ttattttttt accaaccagc ttgctcctgg ctccctagct cctttggagg aattgacttt cacatctact gcccaggctc gaagggctcc ctgggtggcc ggcagctacg aagcggaaga ttgcttttgg taatgtcctt tggagctcaa agccaaaccc ccaggcctcc tgtctctgac tatttccttt cccccatccg tattccacat tgggcctggg agaaacgcag tgggccagca ggattttcta gttttttctg tctttgggta ggaatgtggg tgcagcctta tctcctgcct ctgtgaggat tctaattttt tccagaaaag gtgcaggttc 120 180 240 300 360 420 480 540 600 660 720 780 WO 99/55865 WO 9955865PCT/NZ99/00051 caacagctta ctgcctgcct ccttgccttc tgcggagctc tccaggtgtc tgcccaaagc gtctgtgaaa caggtcatta ggggacctag accctattct attctggcca tgatgcctta caaaagctcc tgccctgtgg ctggatgcag ggtgaccatt ccatccccag gggctctgcc cttcccagtc gtaccctaag aagttgggcc gctcaggacc acagaaggct agaccagtat gtacccaggc gctggatcac cttagccagc atctgctgca ccccaagatc acaggtcctg aaagagctct aaagccttga tttctgctgg cactgggcct tggagcaggc tgagccacca ggtatagctg tccagcccct ctgggtcaga ggcctagggt tcttggcaaa cttcaacagt ctaccatgtt ctcctctctg ccagcctccc tctcatgccc gccccagtat gcctcacaga tcatcctttc ccaccccttt ctcccctgct ctttcaaacc tccatgtgag t 840 900 960 1020 1080 1140 1200 1260 1311 <210> 243 <211> 399 <212> DNA <213> Mouse <400> 243 aagggtcctg aagtcagttg tggtttttgg gaataacgtt ctctccaaca tctcgtccat tgagtggcca gcccgagcct gagagacatt aattaaacac tattctggaa tactctgggc ggtctttttt tttcttcttc ttgcatcaaa tcttggaatc caccgacctc gagctctgtc tccctcaccc tatgttttat tttttctttt tacttcattt ggactgtggg ggtggctttg aatgacatcc caccgcacca gtttatttct gctcccaaa ttggcttcaa cgtggaatga acccagtgtg aaggagaaaa aaccagttgg tttttaatcg tgtcatattt aaaaggtgtc gcttttcctc tgaggttaat gttcttctga gttgtatttt 120 180 240 300 360 399 <210> 244 <211> 1421 <212> DNA <213> Mouse <220> <221> unsure <222> (1370) (1370) <221> unsure <222> (1395) (1395) <400> 244 gccgaggcgg gcaggcacca ggaccgagac agtcgaacgg gtccttttcc cagagctggt ctgctacttg tgaggcctgc ctggaggaag tggcgggcag ctgccgcccc ggactccagc gtcggccctg tgccacccac gtgatgctca ttgcggtggt cactcatcac gcgccagaag agaagtatgt ggaccagaga acagggcacc tgacagccgg acattctggc tgctactcag agggaacaaa acaggtgaag tcagtggcca ggaggagccc aggtccctga cgagacagcc aaggggaacc agaagggtct ccgaaaggtc ctgtgcctgc gaggcctgac tcttgggtcc gactgcttct tgacaccctg aaagctgctg gcctctggtg gactctcaca tcctgggggc acacatccca gtttggagcc aggctgactg tgacatacac ggggctgttg atcanatggc gccagagcag tctaacaggg tctgtgggtc gcctgtggtg tggggaagct cttcagtccc caacctcctg gggctcgctg cacaaggcca gaccgggctg caggaagagg aac ct Ccggt ggtgggtcgg cgggaagccc tcagcagagg ttctccttag aacagaatct tcgaaggtca ccttggccat taccccagga ttcaccccga gcaatgaggc agtaaacacc ctgcggtgtc ctggcggcag cctggcttgc aacatggtcc gcctactctg gagggttctt acaccaggga gatgggatcg acctttctca cagcctacta gggggcccca gcctggactc ctccagctag aggaggagga cagtatgtgg ctgaaggggt ccaggaacc ccctaatgt CctCcttggt tgtgggtgcc aacaccaccc agcaccactt agtcctcaga cctgcttgca ctatctgccg acagtcggac ctacctggca cctgcttcct tgtccctccc cagcctcttc ggacccagcc tggac ttctt tcagttcata cccgtcctct tgccttcagc ctcccagcag agccctgcca ggagaaggaa ggtcactgaa tcccgcagcc ccagggagca gtaacaggcc caagaaaggc aatcctgacc caagttccag t tctggaagg acagaagggg ccttggctgn t cgagacagtt gctgcacccg cctgtctctg ggcctccttc cccaagcctg cacagctccg ccgccagtat gtctgcgcgg ttccccgaaa gaggtccctg ctccaggctg ggcagtgggg gaggaggtgt gagaagccgg agcgagggcc gctggtcctt ccagaactgt attcagcttt ctgaatgggc cgcccttaat ggaaggtcag aacaggccag ggagacaaga 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1421 WO 99/55865 <210> 245 <211> 461 <212> DNA <213> Mouse PCT/NZ99/00051 <400> 245 cgcctgcagg tcgacactag tgtgtgtgtg ttttggtttg gctagcccca aactcagaaa ctgccctggt gcagatgact agtctgagaa tcaggcgctt ctatgtgtgc tgggcatgga ggcagccgtg gtcctgtctg caagttctcc tttgcttctt t ggat cca aa ttgttgtttt tctgcctccc cctttaagga tggctacaca cagagcctcc aatattgtct gccctcccag gttctttttc ggttttcctg gagtgctggg gctagagtaa gctcaattta tcatcgccag ctaactgcca atagaccctt ttttcttttt gaactcactc actaagggtg cccttgttcg cacagccaag tgatgatggc cagtttcaga g Cttttttttg tgtagaccag tgcaccacca cctcggtgag cctttagctt cgggtttcca gaaaggggaa <210> 246 <211> 1280 <212> DNA <213> Mouse <400> 246 ttggactcgc gcgcctgcag attcgagaat atgttcggtg gaaaccttca cagacatctt tgggaagggc ctcaccacca cttacacaca ggttcccgtt tcaccttaca ccaagggggc cgccatgaga aggagatcga atgctcagtt ttgggaagcg accaagagtc aaggcgctct tctatccctg acacccctgt ccccgacgta gaccccctat gatgagtgtt ggtcagacaa cctctaggcc gcagccagag acctcacgct ccctgaaggt tagagtctgc agattgaggc caccagctac cggggttctg cctgcacagg gagacattca ttCtctgcc ttttgctttc aaccaaaagt ccaaccagct tttccaaggc ctggtgtgtg tacactagct gcatgtttcg aataaatacc aaacagtgaa gtcgacacta gatgatgtat catttcctgg ccaccacctg ttattacgag cagcctgctt cgcatgtatc gagcctcaac agctggaagg ccccacctac tggataccgg tgagattgtc ccttcgggtg ccgaaccccg caccttacct ctccgtctgg ctgtaccaaa tcagacatgg gtgttcattc tgtgtgtgtg tgttggtgag gtggatccaa tggattgtct tccggcccaa gcctctggct ttcaagatgg taccgaaagt gtgcaggcaa atcgctgcct ctacggagtt caagatcccc cc aggcggc c ccccagccac gtcaagagga aaaaaggcca ctggagccag cttgtgccta gcagcccagg gaccagagcc cttcttgtcc tgtgtgtgtg tgaggtcagg agaattcggc ttgcgatctt ggattggcag cacacaaacc cttttgtgct ttgtccaccc aggagcgcag cagctgctgt tctctatgca tctacctgga tgcagggcag ctgttgggcc agccattgac tgccctcaga caggggacct aatggcacat cctggggcct cc acc agt cc ttcaaaatac tgtgtgtgtg cttatgaata acgagagaac catggcagca gccatggggt cctccccttg gtggctgctc atccctatcc ctatgaaacc gcaggctgct agacctgcgc agaccaggta tgacacagag c cgagagaag t cgagagggc catggacagc ttcgctgcta ggcgtggtac atttattgcc ctaccgacga ttgacagcct tgtgtttacg tttttatata 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1280 <210> 247 <211> 833 <212> DNA <213> Rat <400> 247 gtgccctccg ccgggtcggg ttcactggct gttgacaacc acttcactat cctggccctg ttggcatgtt tcttggtggc tcttctactc aagcgttgcc tcagcttgct gctgaagccc ggggtgagct cccgctccgc agacaattga ctcgtcagac aagctgcccc ccgggggtac tgtcaccttc tttactggac atggagctgc tggggctgct ggtgtgtggg t tggttgcca gttggggaca ttCtcctgct tcggatttct tcacctgcag tgaagctgtc ctacaatggg ctgccgtgaa tggcgttCtc ctgtggccca ccatcttcct ctggccgctt gcctcgtcta tcggaccttc acccccttgc cctggccgtc gtatcctcca cttgaaggtt aggctcctat gcgggactct ggacat tatc cagtgccggc ccacatgcac tcaggaacat aagcctggag ctggggccca ttccctgcca attctcctgg gcttggggca gttgatgcca tacattagca atggccatct cgggagcgag agtgcctacc aacaagggcc gcaggatgct cagaggtggc WO 99/55865 p ctgagtcatg tgccctcgga ggtcccagct gagaagagcc cagtcctaat tctccatgct gcccctccat tcaagacacc tgttaacccc tgggctagaa ctgtggttgg tttcttcccc tcctccccat cactataaca cacaaccgcc gagctgtgca gagtgttcag ggccatccag gccttatggg ccaatgatca ctgcctctca ggctacccca aggtgaccca gcc <210> 248 <211> 1308 <212> DNA <213> Rat CTINZ99/00051 660 720 780 833 <400> 248 gccgaggcgg gcaggcacca ggaccgagac agtcgaacgg gtccttttcc cagagctggt ctgctacttg tgaggcctgc ctggaggaag tggcgggcag ctgccgcccc ggactccagc gtcggccctg tgccacccac gtgatgctca ttgcggtggt gcactcatca cgcgccagaa aagaagtatg tggaccagag gacagggcac ctgacagccg gacattctgg ctgctactca.

gagggaacaa aacaggtgaa ttcagtggcc aggaggagcc gaggtccctg acgagacagc caaggggaac cagaagggtc tccgaaaggt cctgtgcctg tgaggcctga ctcttgggtc tgactgcttc ttLacaccc caaagctgct ggcctctggt tgactctcac catcctgggg agacacatcc cagttggagc gccagagcag tctaacaggg tctgtgggtc gcctgtggtg tggggaagct cttcagtccc caaccttctg gggctcgctg gcacaaggcc agaccgggct gcaggaagag gaacctccgg gggtgggtcg ccgggaagcc ctcagcagag tttctcctta caacagaatc ctcgaaggtc gccttggcca gtaccccagg gcttcacccc cgcaatgagg ctggcggcag cctggcttgc aacatggtcc gcctactctg gagggttctt acaccaggga gatgggatcg acctttctca acagcctact ggggggcccc ggcctggact tctccagcta gaggaggagg ccagtatgtg gctgaagggg gcccaggaac tcccctaatg acctccttgg ttgtgggtgc aaacaccacc gaagcaccac cagtcctcag acagtcggac ct ac ctggc a cctgcttcct tgtccctccc cagcctcttc ggacccagcc tggac ttc tt tcatgttcat acccgtcctc atgccttcag cctcccagca gagccctgcc aggagaagga gggtcactga ttcccgcagc cccagggagc tgtaacaggc tcaagaaagg caatcctgac ccaagttcca ttctctggaa aacagaag cgagacagtt gctgcacccg cctgtCtctg ggcctc ct t c cccaagcctg cacagctccg ccgccagtat agtctgcgcg tttccccgaa cgaggtccct gctccaggct aggcagtggg agaggaggtg agagaagccg cagcgagggc agctggtcct ccagaactg cattcagctt c ctgaatggg gcgcccttaa ggggaaggt c 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1308 <210> 249 <211> 1212 <212> DNA <213> Human <400> 249 tagcgtggtc gcggccgagg tCctagaaac ggtggccaca cgatcctcgt ctgcaaggtg tcttcCtcct gggtgtgttg acgggagcac agggcccaca cctgcctgct ggctcatgct CCctgttggt gattctgggt ttgaatatat tgtcctgacc ctcctcgtcg caatgaagac tgaccttcct catgtcctcc gggCCcacat ctacctcacg tgctcatgct tcctgacttt ctgccaatgg ctgggtgttc agcaacgaaa ccccatggat agaagagcta tggtgtggag aagagacagg ggacacgctc ctcccaaaa ggaattctcc atgaagtaaa gaaagagggc cggcagatct agcgggagct tgtacctgcc cgggcggccg ggcccggtac ac tactacagac gctggggttg c aggac tcc a ggcatctttg cgcttcttcc gtcagtctga ctggccgtgg atgaatagga tttgtcctcc ttcaccttct atgctcctct gaccgcaggt ctgttggctt tatcctgttg aacagagcct tatgccccct atcccacggg agctaactct caaagggatg ctcgaaatca tttgtgataa tgacctcggt acaggcgaaa gcctcacctt tct t tgggat ccaagctcgt gcttcagcct ccaacgtcaa tgctcaccta gtggttcctt ccattgccat gggatgacac atgttagtcc aggatgcttt actctcaaga attccacaca cccacgcttg gtcctgaaga tgggcgaaat agcttatcga ggctgaagct ggccttcatg aatgctgcct cgccttcatc CCtcttttcc ccgggggagg agtccaggat tgtcttttct cgtcCtcttc cacgggctgg ctgggtggcc catcctcagc cgagttttgg ctgtaaacct ggaaatcact ttttcagctg gccgagccct gtgggacaaa cttgagtctt taccgtcgac tggggcatcg ctcactctcc actcagtttc atcggactgg atctgcttct aagccccttt gttatcgcta gagctttccg ttgatggcgc aagagacatg tggatcaccc tccgccttgg ctgctcacaa caactcgtga caaggttttg cagaaccagc tacaaagact tgcagccggg ctgagaaaac ctcgaggggg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1212 WO 99/55865 <210> 250 <211> 453 <212> DNA <213> Human PCT/NZ99/00051 <400> 250 aagaattcca aatgcttact atgtgggaat tcaacttcaa ggaggattgc agcctcccgt tgcctactgc aggtcaccac tttactctgt ttactatcaa ttccaagatt cccctgtcca atcctggacc agtgcacagc ccctgagagc gtagttactg tttctggtgc gttcaaaaaa tcagtacgaa cctcaatttc tgtgagcacg tggtggtcgg gttcggctct cttcccatcc agaaagattg cagtccccta gatgttcata atctttattc gacatgcggc aaactgcgca ttgactggtg ctt ttgggaacag ggttaaagag Ccaatccaga cgattgtcat atcatcgagt gtgaacaggg gcatcctcag acaggaacca caagtgtaca ccaggactgc gggaatgata gagactggtg tgtgcaagtc tacccattct 120 180 240 300 360 420 453 <210> 251 <211> 242 <212> DNA <213> Human <400> 251 gagagagaga actagtctcg acattctggg gggttagggg agaggggcca gggaagtgga taccccctcc ccatccaggg ca agttttttgt atttttattt ttgttcatct gctgctgttt gagtccccct ccctcccttt cccccccaag cacagagggg tgtctcctcc cctcccaccc caccctgttg tagcccctcc gctgtgtatt attgtgagcg aataaacaga gagacgctaa 120 180 240 242 <210> 252 <-211> 358 <212> DNA <213> Human <400> 252 gatggcccca gtcccaagtt acagccctgg gggaggctgg gtggcactcc tggtgccaac tactgcaccc gctgtggccc gtcatccatg ctgggagcaa ggggtgcaga cctgcagaac ggccctgtgg tcttgccgag gtgtgtcttt ccatgcaccc gagcccaaca cagcglzgtga ctgccctcac cacagccaga ttggtggtcc aacaagcgca gaacccatgc tggggtgcag cagctcccac gggatgaccg tgcttgcact tcactgactg cccccagggg acccccctca agcagcccca gtggctgctg gggcat cgtg ctatcgctgg cagcctcaca tggagtat <210> <211> <212> <213> 253 568

DNA

Human <400> 253 catctgtcat ggcggctggg ctgtttggtt cgacgcgagg gctcccggcc gcccgcgtcc tcgccccgtc cgctgtggcg ggaaagcggc acccagaacc cgaggacgaa aacttgtatg aggaccccgt tttggacgtc tggaacatgc tcctggtcct tggcagcacc tttgtggcct cccgccgcga agctgagagg cttgtgaaat aatccaactg cttcgacccc agcaagatcc agtggggctc aagaagcacc gccttcccca gagcacctaa ttaaaggggc tgaaagtc tgagcgctcg gctgggaatc ccccagaacc agaagaaccc gacttgtctt atctgcctga accgagaggc agctgccaga Ccccctgcct ccgtcttttg tagcttctcc gaccacaccg agactcccat cttctttggc ctacaggatg caatggcctt ggatgagtga gccattctga gcggcagcgg aggactgtgg tggcaagagg ggttatgaca gtctccatca aaagagtggt cc cat ca tgg ccagttgcta cctcttctca 120 180 240 300 360 420 480 540 568 <210> 254 <211> 1421 <212> DNA WO 99/55865 <213> Human PCT/NZ99/00051 <400> 254 gattagcgtg gtcgcggccg agtggcctga tcgcgatggg atattggcga tcctgttgtg cctgaagtca gaattcctga tcttctcccc gtgtggagtg aataacaaga tcacagcttc ttcaagtccg tgacacggga ggcaacagct atggggaggt acagttaaca tcccctcctc caagatggtt ccccaccttc aatcccaaaa gcacccgtgc gagctggtct ttgatcccct aatgggtatg ggacacccat gtgggggtca tcgtggcagc ggcatctggt ttgcctatag aagaaggtga tttacagcca tcattcctgg tgtgagcctg tgctaccgga ctctggcccc caccccacag ggccccctac atcctccttc atgccctccc aagtgtttat tccccatttc tcccttctaa gtagacagca cctggctggc agggatcttt gtacctgccc gggcggccgc aggtgtctgt gacaaaggcg ct CCCtggca gaataatcct gaagtttgac ctatgaggac agacactggg caaggtcaag tgccaccatt tgaatacacc cttcagcaac gtcagcctct gacttcaaat cgtccttgta ccgaggccac gcctagtgcc gtcggctcac tgatgtctgt ttcttcggat tccctttcct tttgagggat aaaatggcgg gaataggtat tcgaaatcaa t cccaggagt caagtcgaga ttgggcagtg gtgaagttgt caaggagaca cgggtgacct acatacactt ctcatcgtgc gggaaccggg tggttcaaag tcttcctatg gatactggag gctgtgcgca accctgattc tttgacagaa cgaagtgaaa cgcctatcat agtttcacag gtgtttttaa accactggtg caggaaggaa gggtcgcagg cttgagcttg gcttatcgat CCttcggcgg ggaaactgtt ttacagtgca cctgtgccta ccaccagact tcttgccaac gtatggtctc ttgtgcctcc cagtgctgac atgggatagt tcctgaatcc aatacagctg tggaagctgt tcctgggaat caaagaaagg gagaattcaa ctgcatttgc gatgccttat taatgtcagc agtggcctgg tcctgggtat aatctacact gttctgggct a ctgttgtgtc gtgtctcttc ctcttctgaa ctcgggcttt cgtttgctat tggtatcacc tgaggaaggc atccaagcct atgctcagaa gatgcctacg cacaacagga tgaggcacgg ggagcggaat Cttggt tt tt gacttcgagt acagacctcg cttactcagg ttgtctttta tatgtgcccc aacttgttta gccattgact caactgccca ctttccttgt 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1421 <210> 255 <211> 1464 <212> DNA <213> Mouse <400> 255 ggcacgagcg ggagcctgct Ctgtccacag ggtcgcttcg ggcatgtgac ccagtgtcgg tgagcgcggc tgtccccagg gaatgggggc ctgtgtcatg gccacactgt gagcacgcct ttcctgtcag aacaatggca cttctatggt caagcttgtg gagagtttgc gagtgtcaac ccctgctggc ttccgtggcc tggctgcctg cagcagtgta Ctgcctttgc ccaccagggc Ctttgggccg ggctgtgccc cagtgggcag tgccactgtg acagctgtcc tctatcagac actcagagga acgcccacag tgctggtgac taagatagag attgctgtgg acagctatgg gaagaaggcc tcctttggac ttacatgggg accctgcagg gggaccaagg tgggaataga catggactgc tgcagccagc taaggtattt atgggcatct gaccccagaa cttaggcagt aaaacccagt gagttaaagg actgccctgc gccccagctg ggac ttgcat accggtttgg ctaccaatgg gccctgctgg gctgtgagcc aagacacctg agggcgctcc agttctgcga actgccccac gcgcaggaac tgcgctgtga tggacagcta cagcacccca aggcccacta gtggcacttt atagtcatat acaaggaatc ctgtgctgtg caaggcccca caactgttta ccacctgccg ggcctgtggg caca tgggttcctt tgcccacgtg ctgtcctccc caagggctgt cagctgctcc gcgctatggt cacctccggc ccctgccggc ctgtgaccct gagggggtgc gggtgtgccc cacatgtgac ttgtgggggt cacgggaccc gc act cc agc ctgtgttcca tggatccaca agccacacac caggaagtcg gaatcctggc cctgcctgcc cctggaaatg ttatggtcct gtctccagca ggggccgact tgtacatgcg gggaagacgg gaacacaagt tgccccctgg gctgcctgcc gcttgcctct ttccatggat gtcagtggcc aagccaggct tgtgatccca ctagattgca ggggctgact acttgccggg agcaaggcca gcccaaggga cctcttctgg ccgggctcca gctgggcttc cctcttcagc aggtccttct tagtccagac gggtcagatg agtgggatca gtagccttgc ggcaaggggc gaggccattg gtgcctgcag gctggatggg tcctggagtg gtggccctgg ctggttgcca ggtgcctctg tttttggaga tcagcggcct gaagaggccg gcgaccccat aagtgcccac tgaagcacta cccaggcctc aaagccatgg tggtcatggg gggccactgt gacctgggat ggtgctaggc catatttata gaagctgcct agggttttgt 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1464 <210> 256 WO 99/55865 <211> 2411 <212> DNA <213> Mouse PCT/NZ99/00051 <400> 256 tcggcacgag agtgggtaca acaacttcaa gtctgacatc agagtccttt ctacggcgac gtgactaccc gcctctcccg tatgcatcaa cccagatcca agaggatgca tgcatgtacc aagataactt aaaagtgttt gattactgtc tcagagetaa ttttctacca ggctcaatca agaatgcaag cccaacaaga ctgtgtttat agatagtcag agcgatgcag aacctgagga atggacgttg tagtggacat catgttttag ttcttagcat aaactttttg agaaagattt gtgaaagcat agaggtcaaa aaagcctttt tttgtgtgtg ggacttgttt gcctggcgtg gtacatttga agaatattct aatctaaata cacttaactc atattgaagt tttgatcagt tatattgtgt gtgcatttca tttaaaatat atttggtatg tttgggtcat tctaggtgca tgtgcctgtg aatgtcgata atgttgaaca gcgtgaagac cccgttgaga tgctttggag ggggtgaaaa aaaaaggagg ttcatcttaa taccagccaa tggctgttgc agaacacggt ggtcggtcag acagccctgt tttcttacag agtattcttt atctcatctt ttaattcact tggctcatag gatataccca gktatatccc attgtaatgt gttgttttct ttccatattt ttaatcccag cacccgggag ctacaaagtg agttccagga aaactaaatg aaaatacaag caaaaaaaaa a ccttactaca tggtctcttg aagatgaact tcagatcact gagaagcgac gcaagcacct ttgtgcagat tgcgctttga ccttcccaat gtttttcgtt tgcccgatgg aggacctggg gattgtgaac tagagatctc aaaattttta atgtgagttg tttaaatggt atagtcatgt tggaataatc ataactatac tcctcttcag tccattaaat ccaacacttt tctgttttct ttgtttggca tggcccttac taaagtactg ggtatttagg ttccttcaga gtgccatggt gttggggagc ctacagttat atgtatgctg tttgtcttga gaggcatgaa cacaggactg aaaaacatga gcagaggcag cagccaggac gcttctcccc tgtctccaga gctgtctgct tgtattctct attcggagga ccgacatcgc aaactgtaca catacctccc atccttaacc ccacaacttt tgagaattgt tgaagcacac catttgactt ttctgatttt aaatataatt gtttatacat gacactgaag ataaatgaac ttaacatgca ttgcagtagt actgtaatgc aatctttttt gtttcagatt tttaggattg cttgttagaa gggttataat tgaagacaga tgtatgacga aaaccctgag gaattgtgga agagcattgg ttgtactctg tttcaagtaa tcgtagacaa aggctgaact gaaatggctt attgagatga ggttctgcct gaggatttct tacacagaga ttgtagtgac gagaatacat atatgagatg gtgtaagaag gctacgacag ctatgtttat agatcctgaa cgcttatgtc agttttcata ggg a tgc t ca ttcgagtttc acacataggc gtttgctttt tttcttttaa cttataagac tcaaaatgca tctatgtttt ccattttaaa caaggctttg tatagttcaa a agc at atat atccaagtta ttctgagaat aaaaaaaatt agaaaaggtg tttagagtat actgttccaa tgacagacat gtggaatttt gccaaagaac gaaggctcat gcccacagag ttgtaaattt aggaaatctg gggtacatcc ccggtgacca aacatcccct ggcagtgatg gagttcgagg aatcctgtct tttgctttat gaaaatggat gctgcactgc atagagcagt ctagttaata gatgtggcaa gacggcaacc tgggtgttaa tgagcttcat gatggcacca tgctgataga acatgtccag aagtcactta gtttcaagta atgc agacat actattaaat aatgcctttg acgtggttaa tgtttttatt tttctttaca tgttattcat ctttcttatt gagttccctt tttttaaatg tgtgttaaaa qctctaqaqt gagcagcatt tttagttaag ggtgaatgtc agagtaatcg cctgccggtg ctcggttgat tcaaagtaat ggtttttttt cagatcttag tttgtgttgk tcctacaaga gtacacacct ccagcctggt caaaaaacca gaatttgtct 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2411 <210> 257 <211> 3516 <212> DNA <213> Mouse <400> 257 aaagtggagg gcgagggccg ggcgaattcg caggctggga cgccatgtgc actggaagac gacagggaac gaatggagct tacattctac ctgtgtacgg gagacaggct ccctggagaa cgcatcgtgc acgagacagc ctgcacctag acctgaagcc gggccggtgg gaaggtgggc gtggctcgcg cctggaggaa catatgccag gctgctggcc cgtgggcatg agcgaacatc gctctggggc tcgggcggct atcaagtgct gctaagaaga gaacctgtcg tcagagccat aacttcctgc ctgctggatg tgctgcgcac tcgggcaggt cgcccagtct tggagatggc gcttggtcat tgccttggga attgcatgtc cccactacca cttcgacgcc gtacaaggtg gcacgtcgac caagttccga ggagtacatg cctgcgcttt tccgccactg tgtcaagatt WO 99/55865 WO 9955865PCT/NZ99/00051 tctgactttg ggcctgt ttg tttgacacca aagaagccat caccgcccag gggctcatgc acctctgaaa gagccaggcg ctcaagcgcg cagttggact tctgaatgca gactcagcct ggcgacctgg gacaccagca agtgccagcc ctgcttaaca gctgtggagc aatgccaagg gccagcacaa cgaacaccca cgccgtggtg gcctggcagg aatgcccaga cgtgtggctc cagacacctc catcgtggtg gcccagaatg gctcggggtc gtggtagaag gca ctgcacc ggagcacaca ttgctccgac tggaccatc6 gtggcctgcc ggggcacagt ggtattgatt ctgtccatag ggaagggcag tagtgggttc ctgctggagt gccttgccaa tgtctaggtc agagccatat tgtttagtca ggctttgctg gggcagaggt ttgtaccttc atgctatagc tcatggacag ctcaatttgt ttttatgtca <210>' <211>' <21.2:' <213>' ggctggccaa gtacaatcgc aacatgatgt ttgcagatga agctgccacc aacggtgctg cagaagacct agaaaagctc cctctgctcc ctgggatctc agctcccatc tttcctccag gccccacaga ggctgatgaa tgctgcacct atgccaaccc ggaagggacg atgaagacca ggctgctgct tgcatgtagc tggatgtggg gccaccttcc cactagacgg gcattctcat tgcatgttgc ctggcaagga gacacctggc ccctgaatca agctggtcag tggctgct-a tcaacttgca gcagcaagac ttgtttcctc catacactga agccaaagtg ggctgctgat agcaagccat tgtcctttgt ttaatatatg ctagaaaggg catgaaactg accatgcctc atataaaagt aacagtttgc acttgccctt ggccattgga cccatttctg atggtatgtg gatactcttt Cttcactgct ataaaggact gtgcaatggc ttacctccct atacagcttc aaagaacatc catctgcaga gcatgcagac ttgtgagaag tctagagtcc Ccccttcgat ccagactctt gtccagcagt aggatcgctg catccagaag gatcctacag ggctgtggag caacctgacc tggaattgtg gtggactgcc agagaagaat ctgccagcat cctgcaggga cattgttaag gaggacaccc tgacctgtgc tgcagagac t ggctttgacc tactgtcaag gacagcactg tgctgacctc gagtctcaag ctagcttgcc atggggacag ccaagcagag tctgatgtca gcaggccttt ttctgcttgc cttctcattg agtgacatgg agtgattata ctgtttcatt gttcccccga taccggaaat tctttcaggc tagcaacttc gattgttgta ttctgaacac acacagaatg catgacagga tccctctctt ccgcctaaaa atgtcccact ccagagcgaa gccattgtga ctacacatca ccccggccgc ccacaggtgc cctgatgagg aagagtgagg aacgactgca gaaggccccg ggcaagaggc tcactgtctt aagaagctag ccccaagatg gccggacagg aacaggaagg gagctactgc ctgcactttg gcttctgtca ggacaggaga aaggatgcct ctgctagcca ctgcacctgg tctgatgtta ggacacacta tcagagggct ctgctcatag cacctggctg attgacctgt tccagactg ttccaaggag accacaaaac aatggtcctg gctaatggac gatgggacta tatgacaaag ttggagcatg tgatgggcag tagctttgct aagccacagg tggtattttg tttccctgct ttttttgtaa tctcttggtg tgctatgttc ctctgaggag tgtcactgta atattaatgt agt agtggag gtgtaaaaca aaaaaa ctcatgacct ttcgtgagaa tctggggtgt tgatgaaagt gtgcctgtgc ggcccacctt aggtgaaaga ccaggcccga gtctctccga aagagct cag tctcgggggt ttgagcggga tggatgccat tggacttggt aggagtgtgt gctctacacc tagcccggaa cagcccagaa atgaggtgga acattgtgcg ggttgcctct agcagcctgg ctgctcagag acatctgcag gtactgccag atactgcctt aggagaaggc ctgcccgtgg ctgatgagca gccagagctc cagggctccg ggacactgct aaggcaggag ggttggtgtc cctatacaag acatcttcag agtagctgtc tgagacctgt gt tggt cct a gttttggttt gagttctcag atgggtttta aagtgatggt cagttacagt tcagattcga gagatgacct actgtgtact ctggctatgt cggggaccat cagcatggat gagccgcttg gcttacacag ggtaaagggc cagcctgata ccaagaaatt cctggctcat gtc ct cacgc gttgctgtca ccgaagttcc gtcctcagtg agcttcaaca catatcaggg tctagacagc caagtggctg actgcatatg gaccagtgtc tggggatgag ctttgagggc caccctgctc gcactatgct ggtgagtgtg ggggcattac cctacaggca gctactcttg gcacctggca tgatgtgatg acactcagag gggcctcagc ,-jCtCa -a-a aL tgctgccacg tgtaggcttc caccctgttg tagctgtctt atgtcactgt aatgtctcct tagagatgtg tctgaaggca gaggatctgg acactggaca ttagttttga ctaaaatgtc tactaaaagt ttgggccaag agatgaatgt tagccttttg gtgtgcaaac ttgacatgaa tttaatatgc aggagatctg 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3516 258 946

DNA

Mouse <400> 258 cctggctgca aatcctgcac agcgtagtgt gtgagtgcca gacccctgcc ttggtcacag tgtgtgtcgt catggcctgt gtcgctccgt ggagaaggac cccgggatgg accggtccgc tatgtgatca ggaagctcgg ctgcaggcac gggacatgca tggcgactgg ggactcctac WO 99/55865 WO 9955865PCTINZ99/00051 gtgtgcaagt agtgcctgct ccctattgcc atgggggaga gcgtccaagg attcgaagca gaggtggaga cacccatcct ctttgagatt aagtatattg catcttttat ttttaccaag aaattttaag gtgccgaggg cagccttcaa tatgccagcc tagtccgtga tgcccatcat agcggcggaa gacacttgga ccgcctttcg cagaacgaag taaaataacc tatataaata ttttgttttg acaaagaaaa ctacggaggg gtgccaccat tggcttcagt agccatccgc ggaatgccgc atatgtcttc atgtggctgc gaccccagct gagagaaatc aaaaatagaa tatcacaccg tgttgtgtat aacactaata gctttgtgtg gggc agtgt c ggccatcact cgccagaaag gggggctgCg cagtgcacgg cgcgcgtgtt cattgggctg tggagagcaa cttattttta tctgagtata ttgttgtgtt aaaatgtttt accagaagaa acatctcaga gtgagcaaga actacgcctc ggaccacgtg acggctcctc cctgagcccc ggaacagcca gaggcaaaag ttatggaaag tggactatac tttataaaca aaacac tgactctgcc t cgaggggag gaatccatgt ttgtgccacg ctgccagccg attcgtggaa ctctgccacc catggaacct agagaatatt tgactatttt agtgagttat gctgtttata 240 300 360 420 480 540 600 660 720 780 840 900 946 <210> 259 <211> 1018 <212> DNA <213> Human <400> 259 gctaccgcta ctgccagcac agccgggctt ccagctgggg tgggggcccc atgcgagcag accagggcta tgagctgcat actccagcta cctctgtcag gcccacaggg ttaccagctg ctggtgcgca ccagtgctcc gcgtggacac caaccgctgc gcccggcctc caaccctcta rcacactc n~acoanec accccggtgc ctacaatgcc ttaggcaaat caacaacgtc gggagtacgt gctggacctg gctctgtact gaggctcacc gccaccctcc ctgcagctac gcccaggggc ccccattgac agaggagagg aggtaacgag cgctgcgtga cctaacaacc cgctgcttca cgggatggct taccgctgcg ctggccacac gaggcccaaa gtggagccct tgt cgagagc tttcagatcc agcgccatgc gagatggtca gtctttgtag cctagctgag aggagctggg gagggcggac acctgcctgg gctcctgtgt actcctatgg tctcctgcag tcaacgagcc gcctctgcca cctgtgtcaa acatc caggt agccttcatc gtgctggaaa tggtcctcgc ccatgaattc gggcctacac gagcctgttg agctctgcac tccaggcccc ctccttccgc tgatgtgaac gaccttcctg tgatattgat aggccgtttc agacattgat cttccatggg ctctgagaac cattgtgcac r, rr' tc cag-r ctcgcagggg ccggccggtg cctcatgagc cttctgagga tgaggggcag cacgagcttc ggcccagaga tgccagtgcg gagtgtgaca tgtcgctgcc gagtgtagct tcctgccact gagtgtgagt ggctaccgct cgctgtctct cgctacatga gacttttaca acgggccccc taccgggcca gcaggaggga aatgagaaag agtcaccccg lttggact 120 180 240 300 360 420 480 540 660 720 780 840 900 960 1018 <210> 260 <211> 2800 <212> DNA <213> Mouse <400> 260 ggcacgagga agagccgtgc gagacagctg cattactgtg aaacgacata ccggatcaga agttcattaa agcaaaaact cgtctggtcc tcagagcctg ctggtgacat ggtgtacaca accgaggacc cagccacacc tCaggatcca ggcaatgagc gcacaaccaa aagcgtgcct attcctgtga aatcttctgg ttctacaggt gctggttgga ccacattcca aatctcaggc gccgccgctg tgtggacacg tcatgttaca acagcgtgag agatgaaggg catgatgccc cgaccctgtc cattttgttt aggccagtgg tatgctcgga aataatgggt ggcaacacta attcaggcta c ggc cat tac aagctcaagt ctacagctgg tacaaggtcc gaggcagggg cccaccctca gagacggtac agagactctg ctccagagca tctcaggagc gttatgctta accgacgaac gcctttatat acgccacacg ctgaaatcct ccacacacgt tcaatgaaat cgccttcgcc ggggagacag aagacaggaa agagactgac aggggcctta aagcacctcg caccgatgag agtacaagca acacagatta tcagtggcgc caggggacct agtttgctgc tacagtactt ttttaataca tgcttataac gatgaagaac tggagttgga tcctaggctt taactccaag caagaggtt t agagtttacc ctcagaaacc agtgacgcag aggcgaccct ggtgtacaag caggttccgc gttcagcccc gggaggcatg actcatcgtg cttaatgaag catttactca atcgatctgg ctccttccag ccatttagtc gagtgtgctg acacatgctg atctcaatct tgctactcct tacaccttca t tagaaggga gtgagctacg ggagaagaag gtgtgtgcct tctgcggctt gaagaggcca cttggcttcg taaatccagc gagc c tccc c 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 WO 99/55865 WO 9955865PCT/NZ99/00051 tttttacgct ggaaagagtt ttttttaaac gacaccgaga gtctgttccc atttatattc agttcagggc cttcggagga at ctaagt ca tttaacacta gagcattgta gttagttgtt acataactac tatgtgacga tgaaagactt atatttcagt ccacaaggga gagggagtgg ctctccctgg tgagtaatca cggtgctatg agttctaacc gacacttaag tcccctcttc ttgtgcttgg ccataccaaa ctgcatacag gtacttatta aattttaggt gtttcgttCt tggctgcacc aataataaat gccagtgtgc actgatgtct acagtcattt tgggattccg ggccacctcg aagtgtgtac tgagttgcct gattttcaca tcttgttcgg ttctaatata gagctcatgg gcctttggct gcccatgata accatttaca aaactggctg gtctgtcact aatcaaatgg taagtgcgga caaagtcatt aagttggagg ctgttttttt tctatgttgt gtcatgggga tactttaaat ctaatgtgcc cagtttagtt aaag ata ttgatttata tatttgagat aaaggaataa ccaacgagct ttcgcaagcc cttgatcatc gtgttgtcag accatcctta tttaatctaa gtctaagaag tcggtccata ctactttaaa atcactagag cagttgtgaa attctttggg ctaatgtagc tttgtcctgt tgagcatgag aatttgcttt ggattcaata gaatcactct ggatccctca tgcaactgta gtatattttt ctatgatgca aaccaacatt gccaatgaca ctcctagcat ccttggcaac gcatc taact cgcttctctt gcaaaactag agaagagaag tgccttgtcg tttgatcatc tatacctgtt agtattgcca cgtcactcag aatgttttat tcacataacc gcagtaactt agctgcttta ttattatatt ctgtctcctt gtgtcagtga agtagataga ttctgggggc atgtttgggg gtgacctctc cctgtaagtg cacggattca accaagtcca ttccaaaagg gctccttggt gtaagtaccc attttgtttt gtgcaatctt gttatatttt atctgtagta c a t a a. La gttttacaca gaagaggtta gaagcggcgg ggcttccccg ttgtgtgtta aacagaatca catgagaata ttacgtaact tactctgtat aaatgcgcct taagagggca acttgtctgt ctgttatgtt acatgttggc cgtgaatgaa aatcttactg ttcatctggc gccaaagagc tgtgcctgtt ctaagagacc cttagagtca caatgttcaa gtgcgacaga ttttcttgat tgtactagct gggtttattt tatttattgt gtgtgtttta ttagccttct tttagctagg aactggattt gcaagctcca tgtgcttctg cagttcagta cagtgtatgt ttcagtgtgc gtgttagctc cccttatgat ataaatgata ttgtgcaata ctgtctttgt tgaccggaat ccatcatatt gttgaatacc ataaagccca cgcatggaga ctactagatt ttcccatgca ttggatccac tgaggtaatg gtacctcagg cacagccgat catagctact tatactattc atactc tatt aatgttaaat tactttttgt gacatctttc 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 zouu <210> 261 <211> 1335 <212> DNA <213> Mouse <400> 261 acccaaacag cccgggacca cctgtgcctg gctctgcact ggtccttgat aacatctaca tggtggggat gtaacctata cctgaaagca gtgaaggagg gtgcaacgac agcagtgtct aaactggaca gttcctactt cgtcaatcgc acagcctcaa aacccctatt cctgagagtt cacagccaag actacagcca cacagccaat accacagccg cactctcggc agccccctgg actcctcttc taaagaaaac ctcatttcag gccagtgctt ctccaccacc ttggaccaca cctggatctt tcagggcaca tgtaacctga agttctgact cttgccaaag gtattcccat tttactttca aactgatttc gtgacttatg tgactgtagg tttccactgt gcccagacca agaagccaat gacaggacac caaggaaaaa aaaaa tgctgtcgct tatccccctc cctccgacat cagtgacggt acgacagccc actataactt ccgaggatgt agtcatccgt ctgagaccag aggacacagc tgaccacagc caggtgccct tggggaagca aaacataccc gacctgcaac aattccgctt ctcagtttaa gagcctcctg agatttctgg aaaaagagaa gtcggtaggt atgacttttt ccgctccttg cctctctgcc cttggaaatc ccccgtgaac agtgggcacc gacatcccaa gactaaagtc gaaaatggaa ccagaccata c aac ac cac a caagaccaca ccatatcctg gatctccaac gaatgaaggt actagtgcac cttgtaaata cctgttgaca ggtgtggggg ccaaacctac atgagtgatc tttgaaggaa t t ttc taagt cttccacacc agtgataatg agcactatgg gattcagtca tggagtggaa agccagtcgg aacctgcagg caagtacaac aacacgactc gccgtgacca gccaaaagcc cttgtttttc ctccaggtca tttatgtcct ttgagggat a cttagtccat gccaatctga tggggaggga tcaggttgca atcctgtggc gtatatgaaa caaataaaca tgggactgtt ggtcctgcgt ctaacgtctc gtgccgtgat catatgagaa tct tccagac tcctcatcgt cctCagcctc caactgtgaa cagccaatac t gg cCat ccg tcattagtaa tcctcccgag cagtccgcag caaatgcttg ccatcctgcg acttgtgttt atgatccttc aaggacttat tactagcaga actgtgcctc atatattgaa 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1335 WO 99/55865 <210> 262 <211> 1816 <212> DNA <213> Mouse PCT/NZ99/00051 <400> 262 ggcacgagga cttctgctag catgctctgc ctgtgcctgt ctttgagtcc aaggggcttc cccctctcaa gagttctcca caaggacctt gatgggcaac gaaaaaactg aggctggtgt tcaggagatc atgcagtccc gaagattctt aagagcatgg ggactaccac ctcctgcacc ctcgacgatc ttcgatgtcg gaggcagacg gggatgtggt cagaacctgc actgcccccc cagcaacaac atgtgcatcg gtcactctgg cggggcaacg attcatggca tatgagcaga ccacgaaagg cttgtggcag aatggaggtt ctgaagaccc ggactgtgcc aggaggatct ccccaacatg ctggggatca gaaaaatacc tggctccagc cctggcctgt ggtactatct ggtcaggacc cggatgcagg cagcctcttc aaacagattc gaagatcacc ctgggcgtgc gctgcggccc agggtatgca acccaagctg tgaaacccag ctggttctgc tgacctggca ttggggttca ggggtcagta gtgcctgcca gatagcgagc ggacctcagc cacggg tacttgctcc atgtgcccat ctgccgagct cataccgcca tggact ttga tcaagagtc t tgcgggacct ataagaatgg ctgtggagaa gtgagaatct ggaggcacct tggacagact taggtggatt gcatcaatgt tgaaacggct gctccttggc gaatggccct tggctaaaga tcccctatgc gctacgcagt ccagtacttg cacaagcctc tgcggactga t---gcg agtctcggtg gccacctcat gataccatag gaccttcgtg agatgtaggc ttggatgcca tggcggtggc cgccggggcg gaaatccatc atggaagcag agagtttgta ggacaaaaag gggtgtcaag cacgatgacc catcccggag gacagtccca ggtggcagga gaaggtgac cacacagatg cctcaaaatt tgtcggtagt cggagccatt gcggaaaaca gggtgtagct tggcatcgac aaacagtgca tggccagctg cattgagggc gggggccttt acgggagggt tctgtgaatg gggacgggca tctcttccaa tcctgcacta gcttagttct tgagcaaccg gctzcagactg ttcaaactca aaaattgtgc cattacctcc aatgatggtc atctcggaac atcgactgga atcatcctgt' gatgagttca ggtggggcag atgcaggtcc attcgagaag gcccctgagt gatcaggaga gcccagagta ggacagtact gccttctaca ctagctgtct gaccccggtg gccagctacc gcacctgagg gggct ctacc tactgt.

ggtggacttg tgccaacact gggagctggc ggaagacctg gagacaggac tccatctcgt gtctcaccag agttccagta gtgtctttat aagcaggtga aagatcatga gaatcgatgc agcaggcgga acgagtggag actggaagca cagtggagga gggcagtttc atgcctcccg ggggagccaa cggccatcaa cgctgaggat gcatctaccc ccggcatgct aaggctacat atgagacatt tgttcgtgct cactagccct taaccatgag gggggctggc acaaacct gtgagcctgg aagctgactt aagctctggg tggatgttcc gttttcctca tcactcagcc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1816 <210> 263 <211> 764 <212> DNA <213> Mouse <400> 263 gcagcaccca gcgccaagcg ggcgtactgg agcgagccga cgggcggcat cccccggccg ccaccgcgcc cctccggcca ggcgctgtgc gcctcgcgcg gaiccgctac agcgacgtga gaagatggtt atcgtcacca gcaccctaag ctgcagagca gcgcagggtc tacgaagaat agagacttca gcagaggact aagacaaatt atatattgct gctgtgtgtg aaaggcttcc Caagtggctt tttgctgggc caccaggcac cgcgacagac ggcaggagca cccatcgacg gcagagcaga ccgcacgcac gcatgaggct tggacgggtc agaagctgga ccaagagcat ccaaacgctt agggtggacg ttgcagatta atgaagctct agatgtgaga ggttggcggg gagaggcgtg aggccggcgc cctggcggcc caagtgtaag aatgaagcca gtccaggtac catcaagtgg atcatggaaa aaataaaagc tcttaccagg tccagctcgc 999cgg999g cttgaaaccg cctccttgcc gcgctgctcc tgttcccgga aagtacccac cggggccagg tacaatgcct gaaaaactcc cctttctttc gtcagttttt ctgcgcacca acct agaaccaagc tccctgctcc tgctgctcct aggggcccaa actgcgagga agcactgcct ggaacgagaa aggccagttg tcacaagcat acattttata gacttcatta <210> 264 <211> 1697 <212> DNA WO 99/55865 <213> Mouse PCT/NZ99/00051 <400> 264 gcgcggcccg ggggactcac gacgccagat ggtgggcagt gagtcacccg aagcccctcc aatgtagcgg gctatgccag cggaagaact acctggagac tttggcaatg agcccaaggc gaatccaccc cgtcttggca tcctatctga cttggggcat gccacatcac caggagagca ctggcgctgg ttgtggcagg cccatgtacc ggtactcctt gaagcactta agttcgtcag cctgtcatga tgatgggaaa actgccggcc tcatctccat agaagctctc cagccaccac gacagcttca cctcaaattg atgatgtttg gggtcaattt ggggccctac tggagggggc ctcctcctct ccatctgctc tttggagctg ctgtcttcac tcctgcctcc tctatggcca ttcactgccc tcctactcag gtgcccactg agcccccagt gaggcactgg ctcagtatca tgccttaaaa gcccccactt cagagctcct cccccaatct tttgctcata gcacgcaccc tcctgcagtt cccctagggg cagcccagtt ggggccc attccccggt agtggtactc gcagtcctgg ctttatggta aggcaggggt tcctgatgag ggtcctgaag actgcaggaa tttcacagac cctctactgt tgccagtctg cttccctacc gctggtgtcc tggagtgagc actctctggc gcaggatgcc attctcctgt acgcttcatg cgcctttggg tatcatcatg tactgtcact agtctatgcc acagaaggtg gcatacagca catggaaatg ctgaaatctt ttgaggctac ccagtgagaa cccccctccg gccacactcc acacagctgt cctggctacc ctctgcttcc gttctcctgg ctggtcttct agagtgatga tcccagtttc gtcctgcgca tcaaatgtgc caggtgctgg cggcgcagct atgtttcttc ttggtcctac ctgt ttgcc t cttttcacag gggcggcaca cagctcttca actctacgcc gtggtggggg cggggccgga tgagcagtgc gaggattgga acagctgtgg gctggtggcc caggcaccaq tggtgctgtg ccccacgcgg ct tccttggg ggctcttccg tcctggtgca ccctggtgaa ctccgcggac gtgcctcggg ctggcagcta tgglzgctgat agcagccccg ttagcagctg cgaaggcctc atgaacactg tatccagtgg tggcaggcta ataagatgtc taggctcact gtgagtttgc tcttctacac aggctattgc gactgggagt agcagcgggg agtaaagacc gccctggagg gtgtttggtt aagcaaacca ctqqaaqag ccagaaggga ctgggccatg agcaggtgga Cttcttgttg gtacttaaga agcctgtgtg agagacagcg tctccaggtg cggggccaca gaaccgtgtg tcatggtgca gtgccagtat caaggtgatc ggaatacctg accagagcct tattgctttc atcggtgcag actggaacag gctccatgct cat tggacaa catcctcctc agctgtggtc aaagaaggct ctcatcttct cagcctcttt agaggtgacc gcaccagggc aatttacagg caaaggcccc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1697 <210> <211> <212> <213> <220> 265 159

DNA

Mouse <400> 265 gttttcttct ccaggctgaa gacctgaacg tcaagttgga aggggagcct tccatgcgga aaccaaagca gcggccgcgg ccggagcccc tcatcatccc caccaaggcg ggcactttca tCgcccctcc tgtctactcc aacatcaccc cttaccaga <210> 266 <211> 292 <212> DNA <213> Mouse 120 159 <400> 266 gtggggtccc agacttgcca ctggtggcat ggactatggt aacagtggac ctcaatgatg acaaaaacgg cgctatagtg ttgatataat cccaggtgac accaaagggc atggttggtg gaagggctgc gcccctggta acactgggtg cattcctggt gcaaggaggc catctgtggc agacccgagg gccatacggg atatggttct ggcttcagct tgggaccgag tctcgcttca cacacaagaa gccaccatgc aggttcacca tacaaccagt tcctgctggt ga 120 180 240 292 <210> 267 <211> 339 <212> DNA WO 99/55865 <213> Mouse PCT/NZ99/00051 <400> 267 ccactgacct tcccagaagg ccagcagtgc ctcggtaccc atgagaagtc accacagtga catgatgcag cctggccttt cgtgtcatca agaaccctat tacactagcl cagaagagtt tgacagccgg agaagacggg tctcacattt cctagagcct ggatttttcc tgcagctgat cggcggatgt ct gt ctCCC c tgcgagatta gtgaaccctc accatgcgag gctctgctg tgtcaaggag ccaaaagacg tcctgatgga gcttggtgag aacgcctgct ccgagatagt gcgacattcg gatggagtcc tggataccga ccgtggaggg 120 180 240 300 339 <210> 268 <211> 153 <212> DNA <213> Mouse <400> 268 ctgaagttct ctcatccttg tctggaagac cataatagtt actgcattaa tggagcatgt gcattccacc atgagctgaa gcaagccatt tgcagatgct ttactggtta tacgggacaa cgatgtgagc atttgaccct aacttcgtat gct <210> 269 <211> 153 <212> DNA <213> Human <400> 269 ttgaagttct cacacctttg cctggaagat cataacagtt actgcatcaa cggtgcttgt gcattccacc atgagctaga gaaagccatc tgcaggtgtt ttactggtta tactggagaa aggtgtgagc acttgacttt aacttcatat gct 120 153 <210> <211> <212> <213> 270 288

DNA

Human <400> 270 gcggccgcgc tgctcctgct tgcaagtgct cccggaaggg aagccaaagt acccgcactg aggtaccgag gtcaggagca aagtggtaca acgcctggaa gctgctggcg ctgtacaccg cgcgtgtgga cgggtccaaa acccaagatc cgctacagcg acgtgaagaa gctggaaatg cgaggagaag atggttatca tcaccaccaa gagcgtgtcc ctgcctgcac cccaagctgc agagcaccaa gcgcttcatc cgagaagcgc agggtctacg aagaatag <210> 271 <211> 234 <212> DNA <213> Mouse <400> 271 tccaagtgta agtgttcccg gaaggggccc aagatccgct acagcgacgt gaagaagctg gaaatgaagc caaagtaccc acactgcgag gagaagatgg ttatcgtcac caccaagagc atgtccaggt accggggcca ggagcactgc ctgcacccta agctgcagag caccaaacgc ttcatcaagt ggtacaatgc ctggaacgag aagcgcaggg tctacgaaga atag <210> 272 <211> 234 <212> DNA <213> Human <400> 272 t~Ccaaatgca agtgctcccg gaagggaccc aagatccgct acagcgacgt gaagaagctg gaaatgaagc caaagtaccc gcactgcgag gagaagatgg ttatcatcac caccaagagc gtgtccaggt accgaggtca ggagcactgc ctgcacccca agctgcagag caccaagcgc WO 99/55865 ttcatcaagt ggtacaacgc Ctggaacgag aagcgcaggg tctacgaaga atag <210> 273 <211> 645 <212> DNA <213> Mouse PCT/NZ99/00051 <400> 273 atgctgtcgc tccgctcctt ttatccccct ccctctctgc acctccgaca tcttggaaat acagtgacgg tccccgtgaa gacgacagcc cagtgggcac tactataact tgacatccca tccgaggatg tgactaaagt aagtcatccg tgaaaatgga tctgagacca gccagaccat aaggacacag ccaacaccac gtgaccacag ccaagaccac gcttccacac cagtgataat c agc act at g cgattcagtc ctggagtgga aagccagtcg caacctgcag acaagtacaa aaacacgact agccgtgacc agccaaaagc ctgggactgt gggtcctgcg gctaacgtct agtgccgtga acatatgaga gtcttccaga gtcctcatcg ccctcagcct ccaactgtga acagccaata ctggccatcc tcctgtgcct tggtccttga ctggtgggga tcctgaaagc agtgcaacga caaactggac tcgtcaatcg caacccctat acacagccaa ccacagccaa gcact ggctctgcac taacatctac tgtaacctat agtgaaggag cagcagtgtc agttcctact cacagcctca tcctgagagt gactacagcc taccacagcc 120 180 240 300 360 420 480 540 600 645 <210> 274 <211> 63 <212> DNA <213> Mouse <400> 274 gggtacagtg atggttacca agtgtgtagt aggttcggaa gcaaagtgcc tcagtttctg aac <210> <211> <212> <213> <400> Gly Leu 275 388

PRT

Mouse 275 Giu Pro Ser Trp Tyr Leu Met 1 Gly Gin Leu 10 Al a Leu Cys Leu Ala Val Ser Ala Ala Gly Arg Gin Pro Asp Pro Pro Thr 25 Leu Pro Thr Thr Thr Asp Ile Asp Cys Phe Asp Arg His Leu Arg Ala Glu Arg Val Thr Glu Glu Arg Ala Arg Gly Ala Ser Ser Gly Leu Leu Val Leu Lys Pro Val Leu Gly Asp 75 Thr Gly Ser Leu Glu Ile Thr Asp Gly Ser Thr Lys Gin Asp Ser Pro Val Ile Phe Ala Leu Leu 115 Ser Lys Tyr Glu 100 His Ser Val Asp Leu 105 Gly Gln Ile Pro Gin Ala Giu 110 Cys Glu Ile Glu Lys Ala Ala Asp Cys Ser 120 Arg Lys Ala Val Thr 125 Phe Phe Leu Gin Gin Glu Ala Thr 130 His Trp Phe Ile Ser 145 Ser Asn 150 Thr Gln Val Ser Gly Pro Ser Met Val Met Leu Arg Asp Ala 170 Al a Val Gly Ala Val Arg 175 His Pro Thr Gin Val Glu 195 Leu Gly Ser Leu 180 Phe Leu Pro Leu Ser Gin Gly Thr Gin Val Thr Ser 200 His Thr Gin Thr Leu 205 Met Val Lys Thr 190 Asn His Leu Ala Pro Asp Ser Val Ser Leu Cys Ser Phe Ser WO 99/55865 WO 9955865PCT/NZ99/00051 Leu 225 Gin Gly Leu Gin Ile 305 Leu Gly Ser Ser Tyr 385 210 Asp Leu Aia Thr Ile 290 Leu Pro Val Gly Ile 370 Thr <210> <211> <212> <213> <400> Met Ala Giu 1 Vai Leu Gly Giu Thr Gin Leu Vai Leu so Asn Thr Vai Lys Leu Ser Leu Gin Arg Leu Ser Arg 115 Giu Tyr His 130 Leu Gin Gin 145 <210> <211> <212> <213> <400> Met Pro Leu 1 Giu Ser Giu Thr Tyr Leu 260 Pro Thr Pro Leu Trp 340 Ser Ser Gin 276 151

PRT

Rat 276 Pro Ala Asp Ser Thr Lys Tyr 100 Pro Asp Arg 277 163

PRT

Rat 277 Val Gly Giy Ser 245 Giu Asn Ser Pro Val 325 Ile Phe Thr Trp 5 Leu Met Leu Gly Leu Arg Leu Ala Gin Vai 230 Trp Pro Leu Leu Lys 310 Cys Arg Ser Val1 Ala Giy Arg Leu Leu 70 Thr Trp, Arg Pro Val1 150 215 Giu Lys Glu Thr Tyr 295 Val Ser Giu Ser Met 375 Gly Thr Val1 Gly 55 Tyr Giu Val Gin Arg 135 Leu Trp Thr Glu Leu 280 Gin Gin Ile Giu Leu 360 Ala Gin Leu Thr 40 Ile His Asn Cys Leu 120 Val Arg Leu Gly Gin 250 Leu Leu 265 Lys Asp Ala Gin Leu His Ala Gly 330 Leu Gly 345 Arg Gin Asp Pro Phe Leu 10 Gly Ser 25 Leu Phe Gin Leu Arg Pro Lys Gly 90 Trp Leu 105 Gin Arg Ser Leu Gin 235 Giy Arg Glu Gin Leu 315 Tyr Gly Ser Giy Gin Giu Lys Al a Gly 75 Arg Leu Al a His 220 His Lys Gin Ala Aia Gly Gly Thr 285 Ile Met 300 Ala Asn Tyr Pro Ile Pro Thr Met 365 Pro Thr 380 Ala Leu Phe Leu Leu Leu Trp Gly Lys Trp Gin Gin Cys Cys Trp Vai 125 Cys Pro 140 Gly Ser Lys Arg 255 Asn Ala 270 Tyr Ile Pro Leu Lys Asp Leu Asp 335 .Aia Gin 350 Gly Thr Gly Ala Pro Ala Arg Giu Leu Leu Phe Tyr Gin Gin Giu Lys Thr Leu 110 Gly Gly Gin Pro Giy 240 Lys Se r Cys Asn Pro 320 Vai Val Tyr Thr Thr Trp Trp Gly Met

SO

Gly Leu Leu Cys Thr Thr Leu Phe Tyr Aia Cys Phe Tyr His Tyr Thr 5 10 1s Thr Phe Ser Ser Pro Val Asn Leu Lys Lys Thr Phe 25 WO 99/55865 Lys Lys Trp Val Tyr Lys Asp Ala 145 Trp Met 1 Ala Gin Leu Val Val Ser Arg Ala Leu 145 Tyr Phe Val Leu Ser 225 Arg Gly Met lie Leu Leu Glu Val Phe Arg 130 Glu Lys <210> <211> <212> <213> <400> Ala Gly Leu Trp Leu Ala Ile Arg Cys Arg Val Ser Leu Phe Thr Leu 115 Ser Arg 130 Val Phe Val Ser Gly Leu Pro Met 195 Gin Ala 210 Ser Ala Asn Lys Asp Trp Ile Tyr 275 Asp Ala Tyr Leu Leu 100 Cys Gin Glu 278 330

PRT

Rat 278 Trp Leu Pro Tyr Ala Val Leu 100 Gly Ile Leu Val Val 180 Asn Arg His Lys Phe 260 Ile Arg Trp Thr His Val His Leu Lys Ala 5 Leu Ala Gly Phe Leu Gly Val Gln Trp Phe 165 Tyr Asp Trp Gin Gly 245 Glu Ser Gln Asn Lys 70 Lys Glu Asp Leu Ile 150 Gly Leu Arg Lys Asp 70 Trp Ala Thr Ala Val 150 Ser Tyr Lys Phe Tyr 230 Val Tyr Met Tyr Asp 55 Lys Asn Asp Val Ala 135 Asp Ala Ala Leu Thr 55 Val Asn Pro Gin Gly 135 His Asn Val Asn His 215 Lys Val Val Ala Val Val Arg Ser Val Val 120 Tyr Val Glu Ala Leu 40 Lys Pro Gly Phe Phe 120 Glu Ser Thr Leu Val 200 Ile Cys Ile Ser Val 280 Leu Asp Ala Ala Asp 105 Ile Arg Ile Leu Ala 25 Pro Gln Lys Ser Pro 105 Gin Leu Leu Ala Val 185 Tyr Leu His His Ser 265 Thr Thr Ala Pro Pro 90 Thr Asp Ser Leu Ser 10 Phe Ser Ser Arg Leu 90 Ser Ala Ala Arg Ile 170 Gly Ala Gly Val Cys 250 Ala Phe Ala Leu Ile 75 Val Lys Thr Lys Ser 155 Val Leu Cys Gly Tyr 75 Leu Trp Leu Leu Arg 155 His Leu Leu Met Ile 235 Gin Asn Gly Leu Phe Gly Gin Leu Cys Val 140 Ser Leu Leu Ala Ser Phe Trp Leu Gly Ser 140 Leu Val Thr Gly Met 220 Leu His Tyr Leu Ala Thr Phe Ile Asn Arg 125 Asp Ser Asn Ala Leu Arg Ser Phe Trp Met 125 Thr Phe Val Val Lys 205 Met Ser Arg Leu His 285 Ala Thr His Leu Leu 110 Asp Lys Gin Pro Leu Phe Arg His Leu Ala 110 Glu Phe Glu Gin Leu 190 Asn Phe Asn Ile Ala 270 Asn Arg Lys Arg Gln Ala Leu Gly Ile Leu Leu Gln Pro Phe Ser Leu Ser Leu Cys Tyr 175 Ser Leu Phe Leu Pro 255 Glu Val PCT/NZ99/00051 Ala Asn Val Glu Thr Lys Ser Arg 160 Arg Leu Asp Ala Tyr Gin Leu Lys Val Phe 160 Cys Gin Leu Trp Arg 240 Phe Leu Thr 104 Trp Phe 305 His WO 99/55865 Trp Leu Val 290 Phe Asn His Arg Lys Ala PCTINZ99/00051 Thr Tyr Val Phe Phe Ser Gin Ala Leu Ser Ala 295 300 Phe Tyr Lys Ser Thr Phe Val Ser Tyr Pro Lys 310 315 320 Leu Pro Phe Leu Phe 330 <210> <211> <212> <213> <400> Met Giu Asn 1 His Ala Asn Trp Phe Ala Arg Gly Leu <210> <211> <212> <213> <4 00> Met Leu Arg

I

Leu Pro Phe Gly Gly Leu Phe Arg Gly Pro Gly Asn Gly Ala Lys Glu Arg Gly <210> <211> <212> <213> <400> Met Leu Lys 1 Pro Ile Val <210> <211> <212> <213> <400> Met Ser Gly 279 61

PRT

Rat 279 Ile Gin Val Ala Tyr Thr Asn Leu Ile Thr Ile Leu Gly Asn Lys 10 Glu Leu Asn Leu Gin Ala Leu Ile Leu Ser Pro 25 Ala Pro Pro Gly Phe Ala Arg Asp Gin Ala Val 40 Ala Gly Arg Arg Ile Thr Val Val 55 280 105

PRT

Rat 280 Arg Gin 5 Cys Leu Pro Pro Tyr Gin His Gly Gly Glu Gin His 100 281 27

PRT

Mouse 281 Ala Ser 5 Asp Thr 282 169

PRT

Mouse 282 Leu Arg Trp, Glu 25 Lys Gly Asn Lys Gly 105 Leu Met Cys Pro Gly Asp Leu Glu His Gly Ala Leu Leu Pro Asp Pro Gly Pro Leu Gin Tyr Gly His Arg Leu His Ile Leu Phe Leu Gly Ile Leu Asn Val 10 Ser Thr Lys Thr Gly Val Thr Leu Leu Gly Leu Gly Leu Leu Val Ala Gly WO 99/55865 1 5 10 Ser Arg Leu Pro Arg Val Ile Ser Gin Gin Ser Val Cys Arg Ala Arg 25 Pro Ile Trp Trp Gly Thr Gin Arg Arg Gly Ser Glu Thr Met Ala Gly 40 Ala Ala Val Lys Tyr Leu Ser Gin Glu Glu Ala Gin Ala Val Asp Gin 55 Glu Leu Phe Asn Glu Tyr Gin Phe Ser Val Asp Gin Leu Met Glu Leu 70 75 Ala Gly Leu Ser Cys Ala Thr Ala Ile Ala Lys Ala Tyr Pro Pro Thr 90 Ser Met Ser Lys Ser Pro Pro Thr Val Leu Val Ile Cys Gly Pro Gly 100 105 110 Asn Asn Gly Gly Asp Gly Leu Val Cys Ala Arg His Leu Lys Leu Phe 115 120 125 Gly Tyr Gin Pro Thr Ile Tyr Tyr Pro Lys Arg Pro Asn Lys Pro Leu 130 135 140 Phe Thr Gly Leu Val Thr Gin Cys Gin Lys Met Asp Ile Pro Phe Leu 145 150 155 160 Gly Glu Met Pro Pro Glu Asp Gly Met 165 <210> 283 <211> 61 <212> PRT <213> Mouse <400> 283 Met Glu Lys Gin Met Asp Ala Ser Val Ser Val Ile Phe Gly Ser Ile 1 5 10 Val Ile Ser Ala Phe Leu Tyr Leu Ser Leu Ala Gly Pro Trp Ala Val 25 Thr Val Thr Gin Met Arg Thr Ile Ile Ile Thr Met Asp Gin Leu Arg 40 Asp Ala Leu Ile Leu Asp Gin Leu Lys Val Ala Val Ser 55 <210> 284 <211> 131 <212> PRT <213> Mouse <400> 284 Met Ala Pro Ser Leu Trp Lys Gly Leu Val Gly Val Gly Leu Phe Ala 1 5 10 Leu Ala His Ala Ala Phe Ser Ala Ala Gin His Arg Ser Tyr Met Arg 25 Leu Thr Glu Lys Glu Asp Glu Ser Leu Pro Ile Asp Ile Val Leu Gln 40 Thr Leu Leu Ala Phe Ala Val Thr Cys Tyr Gly Ile Val His Ile Ala 55 Gly Glu Phe Lys Asp Met Asp Ala Thr Ser Glu Leu Lys Asn Lys Thr 70 75 Phe Asp Thr Leu Arg Asn His Pro Ser Phe Tyr Val Phe Asn His Arg 90 Gly Arg Val Leu Phe Arg Pro Ser Asp Ala Thr Asn Ser Ser Asn Leu 100 105 110 Asp Ala Leu Ser Ser Asn Thr Ser Leu Lys Leu Arg Lys Phe Asp Ser 115 120 125 Leu Arg Arg 130 PCT/NZ99/00051 WO 99/55865 WO 9955865PCT/NZ99/00051 Gly Ala Val1 Leu Met <210> <211> <212> <213> <400> Thr Arg Ser Gly Trp Trp Phe Ser Leu Pro 285 78

PRT

Mouse 285 Lys Pro Leu Arg Met Cys Leu Val Cys Leu Leu Pro Met Glu Ala 10 Leu Ala Trp, His Tyr 25 Val Leu Gly Trp Leu 40 Cys Ser Phe Pro Ser 55 Phe Leu Arg Gly Gly 70 His Ser Arg Arg Glu Lys Giu Cys Ser Gly Val Ser Ser Phe Leu Val Phe Leu Pro Ile Asn His Ser His Gly Ser Asn Val <210> <211> <212> <213> <400> Met Leu Pro 1 Leu Met Arg Tyr Ser His Thr Leu Asn so Leu Asp Arg Thr Lys Tyr Giu Leu Val Trp Ile Giy 115 Gin Giu Trp 130 Leu Gin Cys 145 Thr Ala Cys His Asn Phe Giu Arg Lys 195 <210> <211> <212> <213> <400> Met Ser Gly 1 Ser Arg Leu 286 206

PRT

Mouse 286 Pro A' Asn C) Val Vz Gin A' Asn S( Ile S( 8! Cys A" 100 Gly G' Arg Ci Gin A.

Lys C Giu S( 180 Arg A: His Al a Pro As n 55 Vai Giy Glu Gly Asn 135 Ser Arg Ser Lys Leu Phe Val1 Giy Gin Gin Cys Thr 120 Asp Thr Tyr Pro Ser 200 Ile Asp His His Cys 75 Ser Leu Trp Arg Tyr 155 Gin Pro His Pro Aia Pro Phe Arg Ile Pro Ser Thr 140 Lys His Aia Ser Leu Thr Ser Ser Giu Ser Val1 Arg 125 Gin Ile Asn Gin Leu 205 Leu Giu Ser Ser Leu Pro Leu 110 Arg Arg Thr Giu His 190 Ser Ile Leu Ser Giy Ser Lys As n Ser Gin Val1 160 Ser Arg 287 169

PRT

Mouse 287 Leu Arg Thr Leu Leu Gly Leu Gly Leu Leu Val Ala Giy 5 10 Pro Arg Vai Ile Ser Gin Gin Ser Vai Cys Arg Ala Arg 25 Pro Al a Glu Ala Ser As n Gly Phe 145 Gly Met 1 Leu Thr Gly His Pro Leu Ser WO 99/55865 Ile Trp Trp Ala Val Lys Leu Phe Asn Gly Leu Ser Met Ser Lys 100 Asn Gly Gly 115 Tyr Gln Pro 130 Thr Gly Leu Glu Met Pro PCT/NZ99/00051 Gly Tyr Glu Cys Ser Asp Thr Val Pro 165 <210> <211> <2 12> <213> <400> Ser Val Cys Pro Cys Ser Gin Ser Ala Cys Arg Gly Phe Met Leu Arg 40 Gin Phe Al a Thr Val1 120 Tyr Cys Gly Leu Leu His 40 Leu Cys Arg Gly 288 114

PRT

Mouse 288 Thr Ile 5 Val Ala Leu Phe Leu Glu Glu Cys Ser Ser Tyr Glu 100 Arg Glu Ser Ile Val 105 Cys Pro Gin Met Ala Thr 25 Ser Ser Cys Trp Trp 10S Gly Glu Val1 Ala 90 Leu Al a Lys Lys Leu 10 Arg Leu Val Arg Val 90 Thr Ser Ala Asp 75 Lys Val Arg Arg Met 155 Phe Ser Ser Cys Val1 75 Leu Gin Glu Gin Gin Ala Ile His Pro 140 Asp Leu Trp Leu Phe Leu Gly Gay Thr Ala Leu Tyr Cys Leu 125 As n I le Ile Pro Ser His Trp Ser Gly Met Val1 Met Pro Gly 110 Lys Lys Pro Gly Gly Leu Val1 Asp Ile Leu 110 Al a Asp Glu Pro Pro Leu Pro Phe Ile Pro Arg Cys Pro Thr Ile Gly Gln Leu Thr Gly Phe Leu Leu 160 Leu Asp Leu Ile Lys Cys Val1 <210> <211> <212> <213> <400> Met His Tyr 1 Phe Ala Trp Glu Leu Glu <210> <211> <212> <213> <400> 289 46

PRT

Mouse 289 Pro Cys Leu Ala Cys Leu Phe Val Asn Val His Trp Cys 5 10 Met Cys Ile Leu Val Lys Met Ser Glu Leu Leu Giu Leu 25 Thr Met Val Ser Cys Leu Val Asp Val Gly Asn 40 290 199

PRT

Mouse 290 WO 99/55865 Met Leu Gly Gly Ser Arg Ser Arg Trp Ala 145 Pro Val Arg Met 1 Se r Gin Gly Phe Pro Giu Gin Lys Leu 145 Val Pro Thr Ile Vai Leu Gly Gly Pro Ser Phe Cys Pro Arg Pro Cys Pro Gly Gly Pro 115 Gin Arg 130 Giy Cys Pro Arg Cys Val Gly Lys 195 <210> <2 11> <212> <213> <400> Glu Leu Arg Thr Ile Arg Ala Glu Phe Met Cys Asp Glu Ser Lys Gin 115 Gly Asn 130 Tyr Gin Tyr Ala Tyr Asp Leu Ala 195 Giu Tyr 210 Pro Giu Al a Gin Ala Leu Gin 100 Ser Gly Arg Ala Cys 180 Thr 291 568

PRT

Rat 291 Leu Gin Asp Ile Vai Aia Ser 100 Gin Asp Leu Thr Pro 180 Trp Cys Thr Thr Arg Leu Ile Pro Pro Pro Giy Thr Leu 165 Val1 Leu Tyr 5 Lys Lys Ser Glu Pro Al a Met Val1 Giu Thr 165 Arg Lys Val Val Arg Arg Ser Val1 70 Gly Pro Gly Ser Pro 150 Phe Ser Val Trp Leu Al a Ser Giu 70 Leu Asp Thr Glu Leu 150 Thr Val Gin Val1 Leu Pro Gly Gin 55 Pro Phe Ser Thr Ile 135 Val Giy Val Asp Cys Pro Leu Tyr 55 Asp Giu Gly Asp Tyr 135 Leu Pro Asp Ser Ile 215 Ile Arg Ala 40 Leu Arg Ser Arg Ala 120 Val Cys Val Val1 Leu Thr Phe 40 Leu Asn Trp Ser Val1 120 Phe Ser Giu Val Pro 200 Asn Leu Ala 25 Gly Al a Aia Arg Thr 105 Gin Leu Val1 Phe Leu 185 Leu Arg 25 His Phe Thr Lys Giy 105 Glu Leu Thr Ser Thr 185 Thr Lys Leu Al a Pro Ser Pro Arg 90 Pro Thr Gin Ser Val 170 Ser Cys 10 Asp Asp Arg Pro Leu 90 Asp Gly Ser Giu Asp 170 Ser Ala Glu Leu Thr Arg Al a Arg 75 Phe Gin Arg Al a His 155 Aila Val Leu Giu Ser Asp Leu 75 Ser Pro Thr Ser Lys 155 Gin Ile Ser His Ser Giu Val Asp Pro Pro Pro Ser S er 140 Pro Ser Cys Leu Glu Ser Thr Ser Leu Giu Giu Ser 140 Asp Pro Gly Met Asn 220 Trp Arg Ser Pro Arg Arg Pro Asn 125 Glu Ser Ala Leu Leu Leu Val Pro Vai Gin Pro Leu 125 Ser Thr Tyr Arg Leu 205 Phe Aia Arg Gly Giu Ser Giu Gin 110 Leu Arg Al a Pro Leu 190 Pro Phe Ile Arg Thr Giu Leu 110 Phe Pro His Pro Thr 190 Lys Lys Ala Ser Leu Arg Arg Arg Pro Arg Thr Phe Giu 175 Ser Leu Gin Pro Arg Vali Leu Asp Ser Ser Phe Asp 175 Thr Gin Ser PCT/NZ99/00051 Gly Val Leu Arg Arg Arg Cys Gly Arg Pro 160 Val Pro Thr Met Asp Tyr Thr Pro Gin Tyr Gly Lys 160 Leu Val Pro Leu Cys 225 Pro Phe Ser Lys Lys 305 Thr Giu Val1 Ser Val1 385 Val1 Tyr Ile Asp Val 465 Tyr Giu Val Thr Val1 545 Leu WO 99/55865 Ala Ala Giu Lys Pro Gly Pro Thr Asp 260 Pro Lys Val 275 Lys Ile Cys 290 Pro Asn Thr Asn Met Asn Ala Lys Gin 340 Val Val Lys 355 Ser His Gin 370 Gin Val Gin Giu Gly Ile Leu Ile Arg 420 Leu Ala Thr 435 Asp Thr Arg 450 Thr Vai Ala Arg Lys Giu Arg Asn Gin 500 Leu Cys Lys 515 Giu Thr Ile 530 Tyr Val Val Val Lys Thr PCT/NZ99/00051 Thr Leu 245 Asn Gly Ile Gin Thr 325 Lys Arg Lys Val Arg 405 Leu Thr Ile Trp Val 485 Cys Tyr Arg Gly Arg 565 Asp Phe 250 Arg Trp Ile Val1 Al a 330 Lys Phe Ile Lys Arg 410 Lys His Lys Giu Ser 490 Thr Asn Gly Se r Asp 235 Asp Ser Arg Phe Phe 315 Phe Asp Leu His Leu 395 Gly Gly Ala Leu Arg 475 Giu Arg Leu Lys Val 555 Ala Phe Phe Pro Thr 300 Met Ala Gly Arg Ser 380 Leu Lys Ala Phe Arg 460 Arg Giu Lys Gin Ser 540 Lys Phe Ala Leu Lys 285 Val1 Val1 Arg Arg Phe 365 Cys Leu Pro Ser Pro 445 Thr Lys Gin Lys Lys 525 Tyr Tyr Met His Al a 270 Val Ser As n Thr Val1 350 Ala Met Ser Lys Met 430 Ser Cys Phe Lys Ser 510 Al a Leu Gln Met 1 Pro Leu Cys Gly <210> <211> <212> <213> <400> Leu Thr Ser His Ala Leu Leu Ser Gin Giu 292 123

PRT

Mouse 292 Glu Pro 5 Ser Ser Ser Ser Leu Ile Phe Arg Ala Gin Leu Phe Val 10 Leu Arg Leu His Phe 25 Thr Gin Met Ser Trp 40 Leu Leu Leu Trp Asn 55 Phe Giy Ser Cys Gin 70 His Lys Lys Asn Gin Arg Thr Leu Ala Gly Gly Leu Gin Ile Leu Gin Val Pro Gly Leu Val Thr Gly Val Val 75 Pro Al a Pro Glu Leu WO 99/55865 Pro Giu.Leu Trp Glu Ala Phe Trp Thr Val Lys Asn Thr Val Gin Thr PCT/NZ99/00051 Gin Asp Asp Asn Val Ser 115 <210> <211> <212> <213> <400> Met Asp Val 1 Ala Val Leu Gly Pro Ile His Gin Lys Leu Cys 90 Ile Thr Ser Ile Arg Leu Leu Lys Pro Gin Vai Leu Arg 100 105 110 Val Ile Arg Trp Glu Gly Asp Ser 120 293 66

PRT

Mouse 293 Trp Ser Gly Leu Pro Leu Glu Thr Leu Trp Ile Tyr Glu 5 10 Pro Trp Leu Leu Met Giy Gin Gly His Aia Trp Val Cys 25 Aia Leu Trp Val Phe Val Asn Val Pro Gly Leu Cys Tyr 40 Pro Phe Arg Cys Pro Trp Ser Gly Leu Leu Pro Giu Ala 55 Met 1 Ala Arg Gly Met Asp Gly Arg His Giy 145 Phe Lys Ser Asp Gly 225 Val <210> <211> <212> <213> <400> Thr Vai Cys Ala Arg Asp Pro Gin Val Gly Gly Asp Asn Arg Ala Gly 115 Giy Ile 130 Leu Pro Ser Val Phe Asp Gly Lys 195 Ile Thr 210 Gin Tyr Ala Ser 294 294

PRT

Rat 294 Phe Leu Phe Gly Arg Arg Gly 100 Pro Pro Gly Al a Lys 180 Phe Leu Arg Gly Arg 5 Pro Gin Pro Met Giy Lys Arg Gly Pro Val 165 Ile Val1 Ala Ile Ser Lys Cys Lys Pro Gly 70 Asp Gln Gly Lys Cys 150 Thr Leu Cys Asn Arg 230 Thr Met 10 Pro Gin Gly Lys Giu 90 Gly Val1 Lys Ser Pro 170 Gly Gly Ala Ala Leu.

Ile Met Leu Al a Asp 75 Gly Lys Ser Gly Ser 155 Arg Gly Ile Ile Asn 235 Lys Ser Leu Val Pro Gly Pro Al a Gly Lys 140 Arg Glu His Tyr Gly 220 Thr Glu Trp Gly Cys Gly Gin Pro Gly Thr 125 Lys Ala Arg Tyr Tyr 205 Leu Gly Gly Leu Phe Leu Ser Gly Arg Ile Gly Glu Ser Pro 175 Ala Thr His His Glu Leu Ala Pro Gly Gin Thr Giy Lys Pro Al a 160 Ile Ser Tyr Asn Asp 240 Val1 WO 99/55865 WO 9955865PCTINZ99/00051 Trp, Tyr Gly Leu Gin Trp, Thr 275 Asp Pro 290 245 250 255 Phe Tyr Ser Glu Gin Asn Gly Leu Phe Tyr Asp Pro 265 270 Ser Leu Phe Thr Gly Phe Leu Ile Tyr Ala Asp Gin 280 285 Glu Val <210> <211> <212> <213> Met Pro Gly Arg Lys Gly Glu Ser Leu Cys 145F Arg Ser Gly Val Ser 225 Val <400> Arg Pro Pro Leu Leu Pro Asp Gly Gly Giu Pro Arg Cys Ser Arg Val 115 Leu Asn 130 Gin Val Ala Ser Phe Phe Gly Ala 195 Gly Val 210 Thr Phe Phe Ala <210> <211> <212> <213> <400> Leu Vai Leu Trp Lys Thr Ser Ser Ala Asn Pro Gly Arg Ala Pro Pro Gly Val 150 Phe Phe Arg Tyr Leu Lys Gly Arg Pro Gly Arg Ala His 135 Tyr Asp Gly Leu Ile 215 Leu Ile His Asp Gly Pro Ser Asp 120 Tyr Tyr Leu Gly Glu 200 Gly Leu Pro His Gly Leu Val1 Al a 105 Thr Asp Phe Val Trp 185 Pro Ile Leu Ser Gly Ala Pro Gly Phe Pro Ala Al a Lys 170 Pro Giu Tyr Ser Gly Leu Pro Gly Pro Arg 110 Asp Lys Thr Ser Ser 190 Trp, Lys Gly Phe Leu Val Tyr Ser Asp Trp His Ser Ser Pro Met 1 Leu Lys Val1 296 444

PRT

Rat 296 Ala Lys Asp His Phe Leu Gly Ala Ser 5 Lys Ala His Ala Glu 25 Ala Gly Asp Lys Gly 40 Glu Gly Ser Ala Ala 55 Val Thr Ala Ser Thr Gly Pro Pro Ser Val Asn Ser Ser Lys Asp Thr Arg Glu Thr Ala Ala Glu Pro Tyr WO 99/55865 WO 9955865PCT/NZ99/00051 Pro GiU Giu Met Giu Tyr Phe Arg Tyr Giu Val Phe 115 Giu Lys Gin 130 Phe Asp Gly 145 Gly Ser Ile Asp Tyr Ile Giu Ile Ala 195 Met Giu Giu 210 Met Gly Met 225 Ser Gly Leu Lys Gly Lys Gin His Asp 275 Giy Arg Ile Giy Vai Gin 305 His Phe Lys Phe Thr Phe Tyr His Met 355 Ala Arg Thr 370 Vai Phe Aia 385 Giu Phe Vai Pro Lys Asp Aia Gin Giu 435 <210> <211> <212> <213> <400> Met Thr Met 1 Arg Ala Leu Trp, Ala Asp Lys Giu Phe 100 Met Pro Lys Phe Phe 180 Phe Phe Arg Cys Leu 260 Val Se r Ser Asp Leu 340 Ala Val1 Leu Ser Met 420 Thr L~ys Asn Ala Thr Giu Lys Tyr 165 Leu Lys Giu His Ser 245 Thr Leu Giu Lys Gly 325 Lys Gly Al a Phe Ile 405 Gly Lys 70 Arg Thr Pro His Ile 150 Thr Thr Met Gin Arg 230 Al a Ile Lys Arg Lys 310 Lys Asn Al a Lys Asp 390 Met Phe Lys Ile Leu Gin Leu 135 Ala Leu Thr Phe Val1 215 Asp Leu Lys Leu Gin Leu Gly Ile Ser Val1 375 Cys Lys Thr Arg Arg Lys Asp 120 Gly Gin Gly Val Asp 200 Gin Arg Thr Asn Giu 280 Phe Thr Leu Asn Leu 360 Giu Asp Gin Arg Ser Ala Val 105 Phe Leu Giu Giu Leu 185 Leu Ser Pro Thr Phe 265 Phe Gly Ala Thr Asp 345 Asp Leu Gly Arg Leu 425 Gly Tyr Ile Val Asp Arg Cys 170 Ser Asn Ile Thr Tyr 250 Leu Giu Gly Met Phe 330 Val Lys Ser Asn Leu 410 Met Phe Ser Asn Arg Gin Giu 155 Gly Thr Gly Ile Thr 235 Phe Giu Arg Met Gin 315 Gin Asp Val Asp Gly 395 Met Gin Arg Thr Giu Ser Tyr 140 Lys Leu Pro Asp Arg 220 Gly Phe Phe His Leu Arg Giu Thr Thr His 380 Giu Arg Al a Asp Pro Pro Ile 125 Ile Phe Ile Gin Gly 205 Ser As n Gly Gin Asp 285 Leu Gin Val Aila Met 365 Val1 Leu Gly Met Arg Asp Gly 110 Thr Ile Ala Ser Arg 190 Giu Gin Thr Ala Arg 270 Pro Ala Leu Giu Leu 350 Gin Cys Ser Leu Trp 430 Ala Trp Asp Phe Ala Leu Pro Lys 297

PRT

Human 297 Leu His Leu Ala Val Ile Phe 5 10 Val Gin Cys Ser Ser His Arg 25 Tyr Leu Arg Arg Val Ala Pro 40 Leu Phe Ser Ala Leu Ser Ala Arg Val Val Leu Ser Thr Ala Leu Ala Thr Ala Leu Leu Met 1 Leu Phe Met Met 1 Met Cys WO 99/55865 Asp Val Gly Leu Ser Asn Trp, Ser Phe Leu Tyr Val Thr Val. Ser 55 PCTINZ99/00051 <210> <211> <212> <213> <400> Lys Ile Ser Gin Cys His Gin Vai s0 <210> <211> <212> <213> <400> Pro Cys Ile Tyr Val Leu <210> <211> <212> <213> <400> Vai Trp Vai Pro Arg Phe Thr Ser Ser Pro <210> <211> <212> <213> <400> Giy Ser Trp Asn Thr Leu 298 52

PRT

Human 298 Asn Ile Ile Gin Giy Ser Ile Met Ile Leu Leu Ile Cys 5 10 Thr Cys Thr Ser Leu Pro Vai Gin Giu Aia Leu Ile Thr 25 Leu Tyr Phe Thr Tyr Cys Tyr Ser Giy Asn Ser Asn Lys 40 Leu 299 41

PRT

Human 299 Val Leu Phe Phe Phe Phe Phe Leu Ser Thr Ser Lys Ser 5 10 Ser Ser Leu Met Leu Gly Leu Tyr Ile Pro Ser Giu Aia 25 1 Gly Leu Lys Phe Lys Phe Met 1 Ile Phe Leu Ser Met 1 Ala Al a 300

PRT

Mouse 300 Gly Thr Leu Leu Giy Arg Val.

5 10 Thr Giu Ser Ser Tyr Arg Ser 25 Cys Cys Ser Pro Trp Ser Gin 40 Cys Leu Pro Pro Cys Val Asp 55 Pro Cys Leu Ser Vai Asn Gly 70 301 82

PRT

Mouse 301 Vai Leu Thr Ser Cys Phe Cys 5 10 Trp Leu Pro Ser Ala Ser Ser 25 Leu Pro Leu Leu Phe Leu Leu Leu Ala Ala Leu Leu Pro Ser Phe Leu Ala His Phe Gly Cys Gly Arg Val Val. Lys Thr His Asp Val Thr Ile 75 Va. Gly Giy Ser Ala Leu Phe Pro Cys Cys Pro His Leu His Ser Asn Gly Arg Tyr Cys Giu Ile Thr WO 99/55865 40 Leu Ser Arg Val Gin Arg Leu Asn Phe Asn Ile Gly His Leu Gly Val 55 Tyr Leu Tyr Val Asn Asn Asp Ile Arg Ser Arg Val Thr Pro Leu Leu 70 75 Ser Ser <210> 302 <211> 411 <212> PRT <213> Rat <400> 302 Met Pro Thr Met Trp Pro Leu Leu His Val Leu Trp Leu Ala Leu Val 1 5 10 Cys Gly Ser Val His Thr Thr Leu Ser Lys Ser Asp Ala Lys Lys Ala 25 Ala Ser Lys Thr Leu Leu Glu Lys Thr Gin Phe Ser Asp Lys Pro Val 40 Gin Asp Arg Gly Leu Val Val Thr Asp Ile Lys Ala Glu Asp Val Val 55 Leu Glu His Arg Ser Tyr Cys Ser Ala Arg Ala Arg Glu Arg Asn Phe 70 75 Ala Gly Glu Val Leu Gly Tyr Val Thr Pro Trp Asn Ser His Gly Tyr 90 Asp Val Ala Lys Val Phe Gly Ser Lys Phe Thr Gin Ile Ser Pro Val 100 105 110 Trp Leu Gin Leu Lys Arg Arg Gly Arg Glu Met Phe Glu Ile Thr Gly 115 120 125 Leu His Asp Val Asp Gin Gly Trp Met Arg Ala Val Lys Lys His Ala 130 135 140 Lys Gly Val Arg Ile Val Pro Arg Leu Leu Phe Glu Asp Trp Thr Tyr 145 150 155 160 Asp Asp Phe Arg Ser Val Leu Asp Ser Glu Asp Glu Ile Glu Glu Leu 165 170 175 Ser Lys Thr Val Val Gin Val Ala Lys Asn Gin His Phe Asp Gly Phe 180 185 190 Val Val Glu Val Trp Ser Gin Leu Leu Ser Gin Lys His Val Gly Leu 195 200 205 Ile His Met Leu Thr His Leu Ala Glu Ala Leu His Gin Ala Arg Leu 210 215 220 Leu Val Ile Leu Val Ile Pro Pro Ala Val Thr Pro Gly Thr Asp Gin 225 230 235 240 Leu Gly Met Phe Thr His Lys Glu Phe Glu Gin Leu Ala Pro Ile Leu 245 250 255 Asp Gly Phe Ser Leu Met Thr Tyr Asp Tyr Ser Thr Ser Gin Gin Pro 260 265 270 Gly Pro Asn Ala Pro Leu Ser Trp Ile Arg Ala Cys Val Gin Val Leu 275 280 285 Asp Pro Lys Ser Gin Trp Arg Ser Lys Ile Leu Leu Gly Leu Asn Phe 290 295 300 Tyr Gly Met Asp Tyr Ala Ala Ser Lys Asp Ala Arg Glu Pro Val Ile 305 310 315 320 Gly Ala Arg Ala Val Leu Lys Val Ala Leu Pro Leu Ala Val Ser Ser 325 330 335 Gin Gin Ile Trp Thr Leu Gly Arg Gly Gly Ser Thr Ser Ala Leu Leu 340 345 350 Leu Ala Gly Leu Gly Leu Ala Ser Glu Pro Cys Thr Lys Ser Glu Glu 355 360 365 Val Pro Lys Lys Ser Leu Leu Asp Thr Val Trp His Trp Gin Gly Glu PCT/NZ99/00051 WO 99/55865 370 PCT/NZ99/00051 Pro Gly Ala 385 Ala Val Pro Met 1 Leu Se r Ala Ser Phe Arg Lys Ala Pro 145 Ser Ser Leu Leu Pro 225 Tyr Leu Cys Ile Phe 305 Pro His Pro Gin Leu <210> <211> <212> <213> <400> Gly Ser Ile Gly Trp Thr Giy Leu Pro Pro Gin Arg Ile Ser Arg Ala 115 Gly Ser 130 Glu Val Val Arg Pro Phe Pro Tyr 195 Gin Glu 210 Glu Ala Ser Gin Lys Leu Giu Thr 275 Leu Glu 290 Glu Asn Ser Trp Phe Ser Gly Leu 355 Thr Gin 370 Arg Gin Leu Cys Gin Ala 405 303 617

PRT

Mouse 303 Pro Arg 5 Leu Ala Ser His Gin Trp Lys Phe Lys Leu Ile Pro 100 Gin Pro Gin Lys Gin Ala Leu Cys 165 Asp Thr 180 Giu Phe Asp Thr Tyr Gly His Asn 245 Glu Ala 260 Leu Pro Asn Val Ser Ser Thr Vai 325 Ser Arg 340 Gly Pro Giy Ser Glu Asn 375 380 Arg Gly Arg Leu His Thr Trp Ile Leu Val Ser 390 395 400 Cys Thr Cys Leu Phe Gin 410 Ala Ser Leu Trp 55 Asp Gly Ser Al a Gly 135 Arg Gin Lys Leu Arg 215 Asp Met Leu Al a Leu 295 Val Met Tyr Thr Pro 375 Ile Al a Al a Leu 40 Phe Tyr Ser Ala Ala 120 Gly Val1 Trp Ile Pro 200 Arg Phe Val1 Cys Thr 280 His Giu Asp Ala Pro 360 Val Leu Leu Arg Ala Pro Trp Pro Ile 105 Giu Pro Thr Al a Val1 185 Cys Lys Trp Met Trp 265 Ala Pro Cys Thr Thr 345 Met Thr Vali Leu 10 Val Tyr Leu Arg Ser 90 Ser Gly Glu Ile Leu 170 Ser Met Lys Gin Al a 250 Arg Gin Gin Pro Gin 330 Phe Pro Leu Trp Ser Cys Val Val Arg Ser Arg Glu Ser 140 Ala Cys Gly Ile Pro 220 Ile Thr Asp Ser Cys 300 Gin Gin Ala Val1 Leu 380 Ser Leu Pro Asp Arg Thr Giu Gly His 125 Phe Gly Glu His Glu 205 Phe Arg Leu Pro Glu 285 Phe Ser Gin Ala Tyr 365 Ile Asp Leu Leu Arg Ser Ala Ser Arg Pro Leu Lys Leu 175 Val Ser Ser Thr Cys 255 Thr Trp Phe Ser Thr 335 Ser Ile Pro His WO 99/55865 WO 9955865PCT/NZ99/00051 Al a Leu Leu Al a Asp 465 Leu Leu Gin Leu Pro 545 Leu Ser His As n Met 1 Leu Asp Ile Al a Trp Lys Leu Leu His Ala 435 Giu Leu 450 Leu Trp Trp Ala Leu Trp Ala Ala 515 Leu Ala 530 Leu Arg Leu Arg His Leu Leu Leu 595 Ser Pro 610 <210> <211> <212> <213> <400> Ser Ala Ile Cys Arg Asn Gly Giu Phe Ser <210> <211> <212> <213> <400> Ile Ser Phe Phe Val Cys Thr Ser Val1 405 Ser Asp Arg Gly Arg 485 Cys Leu Phe Leu Leu 565 Ala Leu Gly 390 Leu Leu Ser Thr Thr 470 Glu Al a Arg Ser Pro 550 Asp Lys Glu Phe Cys Gly Glu Ala 455 His Arg Gly Thr Arg 535 Arg Ala Arg Ala Ser 615 Asp Gly 425 Gin Gly Ala Ala Ser 505 Leu Cys Arg Pro Leu 585 Lys Leu Asp 410 Arg Arg Gly Arg Arg 490 Thr Cys Al a Leu Ala 570 Lys Asp Pro Arg Leu Arg 460 Gly Gin Cys Ala Gly 540 Arg Leu Arg Tyr Tyr Pro Val1 445 Asp Pro Gly Ser Pro 525 Asp Asp Ala Leu Gin 605 Pro Val1 430 Gly Val1 Leu Thr Gly 510 Arg Ile Leu Ser Giu 590 Gly Thr 415 Leu Ala Ile Pro Val1 495 Asp Pro Pro Pro Ser 575 Gin Ser 400 Gin Leu Leu Val1 Trp 480 Leu Pro Leu Arg Arg 560 Trp Cys Thr 304 72

PRT

Mouse Phe

S

Cys Thr Lys Leu Asn Phe Gin Ser Leu Leu Thr Val Ile Leu Leu 10 is Ala Tyr Ile Arg Ser Leu Ala Pro Ser Ile Leu Gly Leu Leu Gly Ile Phe Trp Lys Cys Ala Arg 40 Ser Pro Tyr Val Ala Ile Cys Cys Ile Val Met 55 Phe Ile Gin Met 1 Leu Ser Leu 305 649

PRT

Mouse 305 Pro Ala 5 Gin Val Arg Cys Ile Pro Trp Ser Leu Phe Leu 10 Ala Pro Leu Ser Val 25 Asp Ala Gly Phe Ile 40 Val Gly Ile Pro Giu 55 Ile Gly Thr Lys Ile Gly Val Ala Lys Ser Cys Pro Tyr Cys Asn Asp Arg Ser Asp Ala Thr Thr Leu Tyr WO 99/55865 WO 9955865PCT/NZ99/00051 Leu Asn Giu Giu Tyr Ile 145 Leu Ile Pro Asn Val 225 Pro Asn Leu Gly Asn 305 Gin Pro Phe Al a Val1 385 Arg Se r Met Phe Leu 465 Pro Ile Leu Leu Leu Gin Leu Phe Asn Leu 130 Giu Ser Giu Ser Leu 210 Asn Val1 His Tyr Ile 290 Pro Ser Giu Asp Ile 370 Thr Thr Val1 Thr Gly 450 Val Met Glu Asn Aila 530 Ala Asn Asn Leu Lys Pro Thr 100 Asn Ile 115 Giu Giu Giu Giy Arg Asn Giu Leu 180 Leu His 195 Leu Asn Leu Thr Asn Leu Ile Asn 260 Arg Leu 275 Phe Asp Trp Tyr Leu Pro Lys Vai 340 Cys Lys 355 Pro Asn Lys Gin Thr Gly Thr Pro 420 Ala Leu 435 Ser Ile Thr Ala Giu Thr Thr Gin 500 Arg Giu 515 Ala Ile Leu Val Gin Ile 70 Vai Gin Asn Leu Arg Thr Leu His Aia Phe 150 His Leu 165 Arg Leu Gly Leu Asn His Giu Leu 230.

Pro Gly 245 Arg Vai Asp Met Asp Leu Cys Gly 310 Vai Lys 325 Arg Giy Asp Ser Thr Ala Pro Asp 390 Ser Pro 405 Asp Thr Arg Leu Thr Giu Leu Glu 470 Ser Asn 485 Thr Ala Gin Giu Ile Gly Cys Trp Asn Arg Pro Ile Leu 135 Arg Ser Asp Thr Gly 215 Ser Thr Pro Ser Asp 295 Cys Val1 Met Giy Tyr 375 Ile Ser Ile Ser Thr 455 Pro Leu Pro Lys Gly 535 Tyr Asn le Lys Thr 120 Asp.

Asp Thr Asp Ser 200 Leu Leu Ser Pro Asn 280 Asn Lys Asn Al a Ile 360 Pro Lys Arg His Trp 440 Ile Giu Tyr Leu Giu 520 Al a Val1 Val1 Tyr Tyr 105 Tyr Asp Ser Ile Asn 185 Leu Gly Val1 Leu As n 265 Asn Ile Met Vai Ile 345 Val1 Ala Asn Lys Ile 425 Leu Val Ser Leu Arg 505 Pro Val His Gly Leu 90 Val Asp Asn Asn Pro 170 Arg Lys Asp Arg Arg 250 Ala Asn Thr Lys Arg 330 Lys Ser Gin Pro Thr 410 Ser Lys Thr Pro Phe 490 Met Tyr Al a Arg Ile 75 Tyr Lys Ser Ser Tyr i55 Gly Ile Arg Lys Asn 235 Lys Phe Leu Gin Trp 315 Gly Asp Thr Gly Lys 395 Ile Trp Leu Giy Tyr 475 Asp Tyr Lys Leu Asn Pro Ser His Asn Giu Leu Leu Ser 125 Val Ser 140 Leu Arg Gly Leu Ser Thr Leu Val 205 Val Phe 220 Ser Leu Leu Tyr Ser Tyr Ser Asn 285 Leu Ile 300 Val Arg Leu Met Leu Ser Ile Gin 365 Gin Trp 380 Leu Ile Leu Ile Arg Leu Giy His 445 Giu Arg 460 Arg Val Glu Thr Asn Pro Asn Pro 525 Val Ser 540 Gly Ser Asp Ser His 110 Lys Ala Leu Pro Ile 190 Leu Phe Thr Leu Leu 270 Leu Leu Asp Cys Ala 350 Ile Pro Lys Thr Ala 430 Ser Ser Cys Pro Thr 510 Asn I le Leu Leu Leu Leu Ile Val Leu Arg 175 Ser Asp Asn Al a Gln 255 Arg Pro Arg Trp Gin 335 Giu Thr Al a Asp Val 415 Leu Pro Giu Met Val1 495 Thr Leu Ala Phe Lys Asp Gin Pro Ser Phe 160 Thr Ser Gly Leu Al a 240 Asp Gin Gin Asn Leu 320 Al a Leu Thr Pro Gin 400 Lys Pro Ala Tyr Val 480 Cys Thr Pro Leu Ser WO 99/55865 PCT/NZ99/00051 545 550 555 560 Arg Asn Cys Ala Tyr Ser Lys Gly Arg Arg Arg Lys Asp Asp Tyr Ala 565 570 575 Glu Ala Gly Thr Lys Lys Asp Asn Ser Ile Leu Glu Ile Arg Glu Thr 580 585 590 Ser Phe Gin Met Leu Pro Ile Ser Asn Glu Pro Ile Ser Lys Glu Glu 595 600 605 Phe Val Ile His Thr Ile Phe Pro Pro Asn Gly Met Asn Leu Tyr Lys 610 615 620 Asn Asn Leu Ser Glu Ser Ser Ser Asn Arg Ser Tyr Arg Asp Ser Gly 625 630 635 640 Ile Pro Asp Ser Asp His Ser His Ser 645 <210> 306 <211> 150 <212> PRT <213> Rat <400> 306 Met Ala Ala Pro Met Asp Arg Thr His Gly Gly Arg Ala Ala Arg Ala 1 5 10 Leu Arg Arg Ala Leu Ala Leu Ala Ser Leu Ala Gly Leu Leu Leu Ser 25 Gly Leu Ala Gly Ala Leu Pro Thr Leu Gly Pro Gly Trp Arg Arg Gin 40 Asn Pro Glu Pro Pro Ala Ser Arg Thr Arg Ser Leu Leu Leu Asp Ala 55 Ala Ser Gly Gin Leu Arg Leu Glu Tyr Gly Phe His Pro Asp Ala Val 70 75 Ala Trp Ala Asn Leu Thr Asn Ala Ile Arg Glu Thr Gly Trp Ala Tyr 90 Leu Asp Leu Gly Thr Asn Gly Ser Tyr Lys Trp Ile Pro Arg Ala Ala 100 105 110 Gly Leu Cys Ser Trp Cys Gly Gly Gly Leu Cys Val Arg Gly Ala His 115 120 125 Leu His Ala Leu Asp Glu His Gly Gly Gin Leu Leu Arg Pro Leu Arg 130 135 140 Val Arg Ser Arg Leu Leu 145 150 <210> 307 <211> 580 <212> PRT <213> Rat <400> 307 Met Ala Ala Ala Met Pro Leu Gly Leu Ser Leu Leu Leu Leu Val Leu 1 5 10 Val Gly Gin Gly Cys Cys Gly Arg Val Glu Gly Pro Arg Asp Ser Leu 25 Arg Glu Glu Leu Val Ile Thr Pro Leu Pro Ser Gly Asp Val Ala Ala 40 Thr Phe Gin Phe Arg Thr Arg Trp Asp Ser Asp Leu Gin Arg Glu Gly 55 Val Ser His Tyr Arg Leu Phe Pro Lys Ala Leu Gly Gin Leu Ile Ser 70 75 Lys Tyr Ser Leu Arg Glu Leu His Leu Ser Phe Thr Gin Gly Phe Trp 90 Arg Thr Arg Tyr Trp Gly Pro Pro Phe Leu Gin Ala Pro Ser Gly Ala 100 105 110 WO 99/55865 WO 9955865PCT/NZ99/00051 Giu Trp Asn 145 Pro Val1 Lys Al a Arg 225 Arg Lys Ala Tyr Thr 305 Asp Gin Phe Glu Val1 385 Thr His Leu Glu Gly 465 Val1 Leu Glu Asn Phe 545 Gly Val Leu Trp 115 Lys Giu 130 Phe Ile Leu Gly Leu Pro Leu Leu 195 Asp Arg 210 Pro Ile Gin Thr Lys Asp Cys Pro 275 Ser Gin 290 Tyr Gin Leu Phe Leu Lys Leu His 355 Leu Ser 370 Leu Leu Leu Thr Tyr Gin Ile Gin 435 Arg Ala 450 Phe Tyr Ala Ala Phe Pro Pro Leu 515 Val Ile 530 Tyr Asn Gly Leu Pro Pro Val Leu Asp Leu Arg 180 Pro Leu Cys Leu Trp 260 Leu Asp Asp Asp Trp 340 Ala Thr Leu Ile Pro 420 Leu Leu Val Lys Val1 500 Leu Cys Leu Ala Leu 580 Trp Phe Gin Asp Thr Val Thr Asp Val Asp Lys Ser 120 125 Ser Ser Ala 165 Glu Cys Phe Arg Ser 245 Ser Al a Asn Val1 Thr 325 Lys Gin Leu Asp Thr 405 Al a Pro Leu Ser Pro 485 Ser Val1 Leu Leu Lys 565 As n Thr 150 Asn Val1 Ser His As n 230 Val Leu Ser Giu Ile 310 Al a Arg Arg Leu Ala 390 Ser Gin Ala Lys Pro 470 Val Asp Asn Thr Thr 550 Arg Val 135 Asn Asp Val Ser Thr 215 Ala Val Phe Gin Thr 295 Leu Met Pro Tyr Tyr 375 Val1 Lys Asp Asn Trp 455 Ser Asp Gly Leu Cys 535 Arg Leu Leu Thr Thr Cys Lys 200 Ser His Phe Arg Ser 280 Leu Gly Ile Pro Val 360 Asn Pro Gly Arg Ser 440 Thr Val1 Trp Ser Pro 520 Thr Thr Al a Ser Val1 Asp Thr 185 Al a Tyr Cys Asp Met 265 Leu Glu Thr Asn Asp 345 Ser Ser Trp Lys Gin 425 Val Giu Leu Giu Ser 505 Thr Val Phe Asn Gly Thr His 170 Glu Gly His Thr Ala 250 Phe Val1 Val Arg As n 330 Asn Gly His Tyr Asp 410 Gin Thr Tyr Ser Giu 490 Tyr Pro Val1 His Leu 570 Ile Pro 155 Tyr Asn Leu Ser Ser 235 Phe Ser Tyr Ser Lys 315 Ser Giu Tyr Pro Leu 395 Asn Pro Lys Thr Ala 475 Ser Phe Asp Ala Ile 555 Ile Phe 140 Thr Phe Leu Ser Gin 220 Ile Ile Arg Val Pro 300 Thr Arg Ala Gly Tyr 380 Arg Lys His Val Pro 460 Leu Pro Val1 Phe Val1 540 Giu Arg Cys Al a Leu Thr Val 205 Al a Ser Thr Thr Asp 285 Pro Tyr Asn Leu Leu 365 Arg Leu Pro Leu Ser 445 Asp Val1 Leu Arg Ser 525 Cys Glu Arg Aila Ser Arg Pro 190 Leu Val1 Trp Gly Leu 270 Ile Pro Al a Leu Pro 350 Gin Ala Tyr Ser Leu 430 Ile Pro Pro Phe Leu 510 Met Tyr Pro Al a Ser Phe Tyr 175 Trp Leu His Giu Gin 255 Thr Thr Thr Val1 Asn 335 Val1 Lys Phe Val1 Tyr 415 Giu Gin Asn Ser Asn 495 Tyr Pro Gly Lys Arg 575 Leu Lys 160 Ala Lys Lys Ile Leu 240 Gly Giu Gly Ser Tyr 320 Ile Pro Gly Pro His 400 Ile Met Phe His Met 480 Thr Thr Tyr Ser Ser 560 Gly Met 1 Asp Leu Phe Tyr Ser Asp Arg Ser Ile 145 Trp Leu Val Phe Glu 225 Leu Arg Leu Met 1 Phe Arg WO 99/55865 <210> 308 <211> 283 <212> PRT <213> Rat <400> 308 Thr Ser Gly Thr His Gin Gin Ser Vai Leu Asn Asn His Ser Phe Ile Asn Giy Gin Phe Gin 100 Leu Leu Asp 115 Pro His Phe 130 Trp Gin Leu Gin Asn Thr Asp Arg Cys v1 Leu Giu Pro 195 His Pro Tyr 210 Ile Leu Giu Pro Glu Vai Leu Pro Tyr 260 Asp Asp Aia 275 <210> 309 <211> 37 <212> PRT <213> Rat <400> 309 Leu Trp Val Phe Pro Val Aia Asp Val <210> 310 <211> <212> PRT PCT/NZ99/00051 Pro 5 Trp Phe Ser Val1 Leu Arg Leu Glu Gin Gly 165 Asp Thr Val1 Ile Phe 245 Leu Vai Leu 5 Lys Leu Giy Tyr Val Ile Ser 70 Leu Leu Giy Glu Lys 150 Phe Gin Gin Glu Lys 230 Arg Cys Phe Gly Val Gin Giu Ser Gly Leu Al a Ile 135 Lys Gin Pro Gly Asn 215 Gly Lys Glu Val Pro Cys Ser 40 Lys Val Arg Lys Gly 120 Tyr Lys Tyr Leu Arg 200 Val1 Gin Al a Gly Leu 280 Ala Asn 25 Tyr Ser Phe Gly Ile 105 Asp Al a Tyr Asp Thr Val1 Gly Asn Gly Asp 265 Arg Ala Giu Asp Trp Leu Met Pro Giu Glu Val1 155 Ile Leu Leu Lys Glu 235 Val1 Tyr Val1 Thr Lys Gin Leu Phe Phe Asp Val1 Leu 140 Leu Ser Lys Ala Trp 220 Giu Ile Asn Gly Leu Gly Phe Met Val Trp Thr 125 Ser Gly Cys Asp Leu 205 Giu Gin Giu Asp Gly Cys Thr Ile Ser Phe Lys 110 Lys Giu Ile Leu Ile Val Lys Val Ala Tyr 270 Gly GiU Gin Gin Arg Ser Thr Ile Thr As n Asn 175 Arg Leu Pro Asn Phe 255 Tyr Leu Ser Leu Thr Pro Leu Leu Ser Pro Leu Ile 10 Thr Val Ala Leu Giu Glu Ile Ser Thr Ile Cys 25 <213> Mouse Met Leu Giu Lys Pro WO 99/55865 <400> 310 Ala Ala Ser Trp Trp Gly Giy Thr Gin Val Arg Giu Ala Leu Phe Gly Leu Lys Ile Ser PCT/NZ99/00051 Gly Gin Val Leu Ala Leu Vai Leu Val Ala Ala 10 Gin Pro Leu Leu Lys Arg Ala Ser Ser Gly Leu 25 Arg Thr Trp Ala Trp Gin Leu Leu Gin Giu Ile 40 Asn Thr Giu Val Arg Leu Ala Leu Thr Asp Giu 55 Pro <210> <211> <212> <213> <400> Met Leu Leu 1 Trp Ile Leu Thr Tyr Ala Gin Giu Pro <210> <211> <212> <213> <400> Met Gly Thr

I

Leu Val Vai Met Ala Gin Giu Lys Thr <210> <211> <212> <213> <400> Met Asn Leu 1 Leu Lys Trp Ala Asn Ser Met Leu Ser Pro Met Thr 311 58

PRT

Human 311 Ser Ser 5 Phe Phe Ile Asn Gin Gly 312 52

PRT

Human 312 Pro Gin 5 Vai Met Ser Tyr Lys 313

PRT

Human 313 Leu Gly 5 Cys Ala Arg Ser Ile Ser Pro Pro Leu Val Ser Leu Ala Gly Ser Val Tyr Leu Ala 10 Val Leu Tyr Asp Phe Cys Ile Val Cys Ile Thr 25 Val Ser Leu Met Trp, Leu Ser Phe Arg Lys Val 40 Lys Ala Lys Arg His Gly Giu Asn Trp Leu Ser Trp, Met Phe Giu Lys 10 Vai Cys Tyr Phe Ile Leu Ser Ile Ile Asn Ser 25 Ala Lys Arg Ile Gin Gin Arg Leu Asn Ser Giu 40 Met Ile Phe Ser Met Cys Giy Leu Met Leu Lys 10 Trp Vai Ala Vai Tyr Cys Ser Phe Ile Ser Phe 25 Ser Giu Asp Thr Lys Gin Met Met Ser Ser Phe 40 Ala Val Val Met Ser Tyr Leu Gin Asn Pro Gin 55 Trp <210> 314 <211> 58 Met 1 Glu Val Leu WO 99/55865 <212> PRT <213> Mouse <400> 314 Phe Ile Thr Pro Phe Lys Ala Phe Leu Pro Leu Tyr Leu Leu Thr 5 10 Leu Ser Leu Ile Asp Ile Thr Ser Cys Asp Asp Leu Pro His Ser 25 Leu Pro Gin His Leu Ser Phe Giu Phe Vai Leu Trp Ser Met Tyr 40 Leu Ile Cys Cys Phe Vai Ile Ile Phe s0 PCT/NZ99/00051 I 'A Met Val Asn Lys Vai Trp Val Ser Ile Lys 145 As n Lys Met Arg Giu 225 <210> <211> <212> <213> <400> Ala Ser Leu Leu Giu Lys Ser Gin Ala Pro Asp Gin His Gin Phe Asp 115 Val Asn 130 Val Lys Thr Arg Giu Lys Asn Vai 195 Thr Ile 210 Asp Thr <210> <211> <212> <213> <400> Ala Glu Giu Leu Leu Leu 315 229

PRT

Rat 315 Ala Giu Ser Lys Leu Ser Val 100 Leu Asn Thr Trp Pro 180 Leu Asn Glu Leu Glu Lys Ser Lys Ile Lys Pro Thr Thr 70 Asp Lys Pro Ala Leu Val Leu Leu Asp Thr 150 Asp Tyr 165 Ser Tyr Lys Lys Lys Ala Phe Giu Thr Giu Giu 55 Giy Phe Giu Lys Lys 135 Val Leu Asp Ile Trp 215 Leu Arg Thr 40 Phe Tyr Val1 Asn Asn 120 Pro Ile Thr Thr Tyr 200 Val Gin Lys 25 Giu Asp Thr Lys Val 105 Leu Ile Ile Gin Giu 185 Giu Glu Lys Arg Leu Asn Val Ile 90 Gin Asn Ser Leu Vai 170 Aila Asp Ser Asp Leu Arg Giu Lys 75 Tyr Val Gly Val Cys 155 Giu Asp Gly Arg Leu Arg As n Lys Ile Ile His Lys Giu 140 Arg Lys Pro Asp Giu 220 Giu Asp Lys Pro Ser Thr Phe Asn 125 Ser Lys Giu Ser Asp 205 Lys Giu Thr Met Ala Asn Leu Thr 110 Tyr Ser Lys Cys Giu 190 Asp Gin Vai Leu Gin Ala Tyr Thr Giu Ser Ser Al a Lys 175 Gly Met Al a Lys Thr Gin Vai Gly Gly Arg Met Lys Glu 160 Glu Leu Lys Arg Arg 1 Ala Glu Thr Ser Gly Giu Met Giy Asn Ala Ala Leu Giy 10 Arg Val Leu Leu Phe Val Ala Phe Leu Ala Thr Phe Gin Arg Arg Ile Gin Pro Giu Glu Leu Trp WO 99/55865 Tyr Arg Asn Phe Val Ile Phe Leu Arg Ala Ser Leu 100 Leu Ile Val 115 <210> 317 <211> <212> PRT <213> Rat Pro Tyr Val 55 Ala Phe Leu Lys Ala Asp Ala Leu Ala Gly Arg Pro 40 Glu Ala Glu Tyr Phe Thr Pro Leu Ser Leu 75 Ala Thr Asp Ser Lys 90 Leu Asn Gly Val Phe 105 Arg Pro Asp Phe Phe 120 PCT/NZ99/00051 Pro Thr Gly Pro Ile Phe Phe Ala Gin Ala Cys Leu Thr Asn Ile Ile 110 Tyr Arg Cys Phe 125 Ser 1 Ala Pro Ser Asp Met 1 Phe Ser Met 1 Cys Leu Gly Leu Leu <400> Ala Gly Phe Gly Leu Arg Leu Leu Asn Arg <210> <211> <212> <213> <400> Lys Leu Leu Thr Arg Thr <210> <211> <212> <213> <400> Leu Gin Val Phe Gly Asn Ala Gin Ala Pro Leu Ser Val Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile 5 10 Pro Ala Leu Ser Leu Tyr Val Phe Thr Ile Ala Thr Asp 25 Val Ile Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val 40 Leu Ser Ser Val Phe Trp Phe Leu Val Arg Val Ile Thr 55 Asp Gly Pro Val Gin Asn Tyr Leu 70 318 43

PRT

Human 318 Ser Gly Met Phe Leu Leu Leu Ser Leu Ala Leu Phe Cys 5 10 Gly Val Phe Ser Gin Gly Gly Gin Val Asp Cys Gly Glu 25 Pro Arg Pro Thr Ala Leu Gly Asn 319 86

PRT

Mouse 319 Gly Pi Trp A.

Arg G: Gly ME Gly A: Phe Pi Ala Pro Ser Cys Phe 10 Phe Ile Phe Ile Ile 25 Ile Ser Ala Lys Asp 40 Trp Gly Ile Trp Gly 55 Lys Pro Cys Ser Leu 70 Pro Trp Val Phe Ser Gly Phe Phe Asn Val Leu Phe Ala Asp Gin Pro His Thr Ile Thr Cys Lys Arg Glu Gly Pro 75 Ile Ser Ala Gly Asp WO 99/55865 <210> 320 PCT/NZ99/00051 Lys 1 Asn Trp Asp Ile Al a Thr Giu Leu Pro Ser Ser Pro Val 145 Arg 1 Phe Pro Pro <211> <212> <213> <400> Gly Pro Val Ile Ala Trp Leu Gly <210> <211> <212> <213> <400> Arg His Asp Ser Gly Pro Leu Val Leu Leu Ala Ser Ser Ala Pro Thr 115 Pro Thr 130 Met Leu <210> <211> <212> <213> <400> Leu Gin Phe Phe Gly Thr Pro Giu s0 <210> <211> <212> <213>

PRT

Mous 320 Giu Phe Asn Gly 321 160

PRT

Mou s 321 Giu Arg Gly Leu Val1 Phe Ser 100 Pro Asn Ile 322 54

PRT

Mou s 322 Val Leu His Cys Val1 Trp Giu Phe Al a Thr Leu Trp Arcq Leu Ser Gly Leu Ala Asp 5 Cys Ser Trp Ser Cys Cys Ile Lys Tyr Phe Ile Phe Gly Phe 10 Phe Leu Gly Ile Thr Phe Leu Gly Ile Gly Leu 25 Lys Gly Val Leu Ser Asn Ile Ser Ser Ile Thr 40 Asp Pro Val Trp Leu Phe Leu 55 Giu Giu Pro Val1 Pro 70 Giu Pro Arg Leu Val 150 Gin Arg His Cys Al a Ser Pro Al a Asp Thr 155 Pro Gin Pro Phe Tvr Gly Arg Pro Phe 140 Phe Gin As n Leu Leu Val1 Al a Pro 110 Gly Arg Ile Thr Ser Gly Ser Lys Val Leu Phe Leu Phe Phe 10 Val Cys Val Leu Val Cys Cys Cys Phe Gly Phe 25 Val Asp Gin Ala Ser Pro Lys Leu Arg Asn Leu 40 Asp 323 280

PRT

Mouse WO 99/55865 PCT/NZ99/00051 Leu 1 Ala Val Ser His Leu Leu Lys Cys Gly 145 Thr Gin Pro Tyr Ser 225 Pro Thr Ala Ala 1 Ile Ser Trp Gly Phe Met Tyr <400> Asp Ser Arg Glu Phe Ala Trp Ser His His Thr His Trp Leu Phe Val 115 Ile Val 130 Lys Arg Lys Ser Asp Leu Leu Tyr 195 Arg Pro 210 Asp Asn Leu Gly Arg Glu Met Pro 275 <210> <211> <212> <213> <400> Leu Arg Leu Leu Gly Ser Ala Val Gly Leu Tyr Ser Ala Ile His Met 115 323 Arg Asn Ile Gly His Arg Leu 100 His Gin Ser Gin Arg 180 Leu Gly Glu Arg Gly 260 Ser 324 166

PRT

Rat 324 Arg Val Tyr Ala Val Ser Phe 100 His Ala 5 Ile Phe Pro His Phe Ser Pro Ala Leu Gly 165 Ser Glu Gly Ile Ser 245 Thr Asp Val 5 His Ala Gin Ala Val Ser Arg Cys Arg Met Arg Leu 70 Pro Pro Ser Lys Asn 150 Ala Ile Asp Leu Val 230 Gin Ser Met Gly Trp Trp Arg Thr 70 Ala Leu Glu Arg Glu Ala Ile 55 Ala Phe Tyr Leu Glu 135 Ile Leu Pro Gin Gin 215 Pro Ser Arg Asp Met Leu Gly Asp 55 Ile Val Leu Arg Ser Tyr Ala 40 Gly Ser Tyr Thr Ser 120 Arg Ala Ala Asp Val 200 Gly Gin Leu Ser Ser 280 Glu Leu Asn 40 Ser Phe Gly Leu Gly 120 Thr Val 25 Glu Arg Gly Tyr Lys 105 Arg Ser Ala Gly Thr 185 Pro Ser Pro Arg Leu 265 Leu Thr 25 Phe Val Leu Asp Lys 105 Gly Leu 10 Arg Thr Pro Ser Glu 90 Gly His Tyr Ser Arg 170 Pro Arg Asp Pro Val 250 Lys Pro 10 Thr Thr Asp Asp Thr 90 Pro Glu Val Trp Phe Trp His 75 Phe Ala Glu Glu Ala 155 Leu Val Arg Thr Val 235 Val Val Ala Trp Ile Ala Ile 75 Gly Phe Leu Asp Pro Met Met Thr Asp Gly Trp Lys Pro Lys Met Ser Leu Lys Glu 125 Thr Met 140 Ala Val Arg Ser Pro Thr Arg Pro 205 Glu Asp 220 Gly Pro Lys Arg Arg Thr Val Asn Gly Cys Leu Ala Ile Gly Ile Tyr Arg Phe Ser Cys Pro Leu 125 Lys Tyr Ile Glu Leu Ala Leu 110 Ile Leu Gin Phe Tyr 190 Pro Glu Arg Lys Pro 270 Leu Leu Leu Met Ile Ser Cys 110 Arg Asn Trp Phe Gly Pro Phe Tyr Asp Ser Ala Ser 175 Gin Ile Cys Glu Pro 255 Lys Lys Ala Gly Phe Ser Ala Leu Ser Ser Ile Ile Pro Leu Val Arg Ala Phe Ala 160 Met Asp Gly Trp Lys 240 Leu Lys Val Phe Val Leu Ile Gly Val Asp 126 WO 99/55865 WO 9955865PCTINZ99/00051 Phe Ser 145 Al a Ile 1 Ala Thr Glu Leu Pro Ser Ser Pro Val1 145 Ile Tyr Arg Asp Asp 225 Pro Giu Glu Glu Gin 305 Ala As n Phe Gly 130 Asp Ser Ala Pro 210> <211> <212> <213> <400> Arg His Asp Ser Gly Pro Leu Vai Leu Leu Ala Ser Ser Ala Pro Thr 115 Pro Thr 130 Met Leu Val Cys Tyr Pro Ala Gly 195 Ser Arg 210 Ile Leu Gly Ser Giu Giu Ala Pro 275 Thr Ala 290 Gly Giu Ala Gly Val Pro Pro Arg 325 338

PRT

Rat 325 Glu Arg Gly Leu Val Phe Ser 100 Pro Asn Ile Ala Ser 180 Gly Gin Ala Gly Lys 260 Val Ser Pro Pro Ser Ala Gly 165 Al a 5 Thr Leu Trp Arg Leu Ser Gly Leu Ala Al a 165 Ser Pro Glu Ala Giu 245 Giu Cys Ala Glu Ser 325 Gln Giu His Ser Ala Tyr Gin Thr Ile Asp Ser 135 140 Asp Pro Leu Ala Ser Leu Giu Asn Lys Gly Gin 150 155 160 Tyr Ala Thr Thr Asn 55 Ala Giu Ser Thr Asp 135 Val1 Ile Pro Al a Gly 215 Gin Thr Giu Val Ala 295 Ser Arg Gly Val Trp 40 Met Pro Val1 Leu Gin 120 Gly Gly Thr Giu Phe 200 Leu Asn Lys Val Thr 280 Giu Phe Ser Arg Gly Gin Val1 Val Ala Leu 105 Pro Ile Ser Arg Lys 185 Ser Asp Leu Gin Phe 265 Giu Gly Ser Cys His 10 Pro Leu Pro Val1 Gly 90 Pro Thr Val1 Leu Gln 170 Lys Glu Ser Arg Val1 250 Ser Glu Val Leu Ala 330 Pro Gin Pro Phe Tyr Gly Arg Pro Phe 140 Phe His Val1 Pro Gin 220 Pro Gly Gin Pro Al a 300 Gln Asn Giu Ser Val1 Leu Ser Glu Thr Val1 125 Phe Leu Lys Asp Asp 205 Gln Ala Gly Glu Glu 285 Ala Glu Arg Leu Gly Phe Ser Ser Giu Ala Pro Met Thr 175 Arg Ala Gin Ala Giu 255 Pro Pro Giu Gln Ser 335 Al a Leu Pro Leu Leu Gly Phe Val1 Tyr Phe 160 Ala Asp Pro Al a Leu 240 Giu Arg Asp Giy Gly 320 Pro <210> 326 <211> 347 <212> PRT WO 99/55865 <213> Human PCT/NZ99/00051 Ala Trp Val Ser Val Gly Ile Vai Val Leu 145 Pro Leu Phe Leu Asp 225 Ala Leu Phe Ala Thr 305 Pro Tyr Lys 1 Arg Pro Tyr <400> Trp Ser Gly Ile Ala Phe Asn Arg Leu Gly Ser Thr Cys Phe Arg Gly 115 Gly Phe 130 Thr Met Arg Arg Met Ala Thr Gly 195 Ser Ile 210 Phe Asp Asn Gly Leu Thr Cys Lys 275 Tyr Ser 290 Leu Tyr Gin Lys Lys Asp <210> <211> <212> <213> <400> Asn Ser Gin Giu Arg Leu Giu Asp 326 Arg P: Vai L4 Met L4 Arg L' Ile P] Gly P: Ser C' 100 Arg L' Ser L Asn A: Asn G~ Ii Leu TI 180 Trp L' Ala I Arg A: Trp V~ 2' Lys G: 260 Pro G Gin G~ Ala P: Giu P1 3: Tyr G: 340 327 141

PRT

Human 327 Lys C' Pro M~ Lys S~ Val H: e ro Yrg eu r 65 le rg al 1-n ln lu he 25 lu Arg Giu Thr Met Gly 70 Thr Leu Pro Val1 Thr 150 Asp Phe Arg Trp Trp 230 Phe Arg Leu Giu Tyr 310 Ser Val Tyr Thr Leu Leu Leu Arg Leu Leu Gin 135 Asn Phe Leu His Val 215 Asp Leu Asn Val1 Ile 295 Ser Ile Lys Tyr Val Pro 40 Pro Thr Phe Al a Ser 120 Asp Val Val1 Met Gly 200 Aia Asp Leu Pro Lys 280 Thr Thr Pro Lys Leu Thr Leu Gin Al a Leu Al a Leu Ile Val Leu 170 Ser His Ile Ile Tyr 250 Asp Ser Gly Phe Ala 330 Gly Lys Val Lys Phe Ile Ile Leu Leu 125 Glu Giu Tyr Phe Leu 205 Leu Ser Pro Val Val1 285 Giu Gin Trp Al a Val1 Val Leu Gly Leu Thr 110 Gly Tyr Leu Val Cys 190 Thr Me t Ala Giu Giu 270 Giu Thr Asn Pro Ala Ser Asp Gly Asp Ser Leu Al a Val Ala 160 Phe Ser Leu Pro Ala 240 Trp Ala Arg Asp Pro 320 Pro yis Leu Leu Phe et Trp Glu Phe er Lys Cys Thr 40 is Thr Asn Pro Cys Arg Lys Ile Val Gly Asn 10 Phe Lys Phe Lys Lys Gin Ser Gly Leu Gin Pro Pro Val Gin Gin Asp Cys Cys Leu Leu Gin Val Phe Val Arg Gly WO 99/55865 Thr Thr Leu Thr Leu Phe Arg Leu Val 100 Ser Glu Gin 115 Ser Leu Thr 130 Asn Phe 70 Thr Ile Phe Gin Gly Val Gly Gly 55 Ile Phe Ile Pro Ile 75 Asn Val Ser Thr Asp 90 Asp Ser Pro Val His 105 Gin Val Ile Leu Asp 120 Ile Leu Ser Thr His 135 PCT/NZ99/00051 Val Met Gly Met Ile Met Arg His His Arg Gly Gly Arg Lys Leu 110 Gin Cys Thr Ala Phe 125 Ser Pro 140 Arg 1 Cys Phe Pro Ser Asp 1 Thr Gin Val Cys Val Gly <210> <211> <212> <213> <400> Glu Arg Cys Cys Pro Pro Pro Leu Arg Gly <210> <211> <212> <213> <400> Gly Pro Ala Ala Arg Asp Phe Leu Gly Pro Ile His Ser Leu <210> <211> <212> <213> <400> Val Met Ala Ala Ser Phe 328 71

PRT

Human 328 Thr Ser Leu Glu Phe Phe Val Phe Leu Phe Leu Phe Ile 5 10 Leu His Ser Gly Gly Leu Gly Gly Val Pro Leu Pro Pro 25 Gin Ala Gin Arg Gly Glu Gly Pro Gly Lys Trp Met Ser 40 Pro Pro His Pro Val Val Ala Pro Pro Thr Pro Ser Pro 55 Cys Val Leu Leu 329 109

PRT

Human 329 Ser Pro 5 Pro Thr Asp Arg Val Val His Ala Ala Gly Thr Gly 100 330 155

PRT

Human Trp 10 Ala Ala Gly Ile Thr 90 Arg Pro Glu Pro Cys Tyr Pro Ala His Thr Thr Arg Pro Ser 1 Ala Ser 330 Ala Ala Gly Leu Phe 5 Ala Thr Arg Gly Leu Ser Arg Thr Val Val Gly Leu Ser Ala Arg Arg Leu Leu 10 Pro Ala Ala Arg Val Arg Trp Glu 25 Ala Pro Ser Ala Val Ala Gly Lys 129 WO 99/55865 WO 9955865PCTNZ99/00O51 Arg Asp Asp Val1 Asp Lys Asp 145 Met 1 Leu Ser Ser Asp Al a Lys Glu Leu Ile 145 Pro Pro Thr Glu Asn 225 Ala Ile Thr Gly Pro Glu Pro Ser Tyr Tyr 130 Pro Pro Tyr Asp Leu Lys Ala Ile <210> <211> <212> <213> <400> Gly Thr Ala Ile Ser Glu Cys Ala Gin Gly Ser Tyr Ser Val Glu Gly 115 Val Pro 130 Gly Asn Ser Giu Lys Ser Thr Gly 195 Tyr Ser 210 Ala Val Ala Val Trp Phe Ser Ser 275 Glu Phe 290 331 299

PRT

Human 331 Lys A: Leu D~ Pro G.

Tyr S Asp TI Glu A: Thr A: 100 Gly A! Pro SE Arg A: Tyr T] Thr A: 180 Glu LD Cys G.

Arg ME Leu Vi Ala T, 260 Lys L,.

Lys G] Thr Glu 70 Val Val1 Giu Asn Gin 150 Gin Cys Val Gly Thr 70 Arg Giu Ser Lys Val 150 Trp Ala Val1 Ala Giu 230 Thr Ser Val1 Thr Thr Lys Trp Leu Trp Gly 135 Leu Val1 Ser Arg Phe 55 Arg Val1 Asp Tyr Pro 135 Leu Phe Phe Phe Arg 215 Ala Leu Arg Ile Ser 295 Pro Asn Asn Gly Ser 120 Leu Pro Giu Leu Ile 40 Ser Leu Thr Thr Gly 120 Thr Thr Lys Ser Asp 200 Asn Val1 Ile Gly Tyr 280 Ser Trp Pro Met Ser 105 Arg Pro Glu Arg Al a 25 Pro Ser Val Phe Gly 105 Giu Val Cys Asp Asn 185 Pro Gly Glu Leu His 265 Ser Phe Gin Asp Arg 90 Thr Arg Ile Asp Lys 10 Leu Giu Pro Cys Leu Thr Val Asn Ser Gly 170 Ser Leu Tyr Arg Leu 250 Phe Gin Leu Glu Ser 75 Leu Phe Giu Met Giu 155 Leu Gly As n Arg Tyr 75 Pro Tyr Lys Ile Glu 155 Ile Ser Ser Gly Asn 235 Gly Asp Pro Val Asp His Val Val Ala Giu 140 Leu Ser Asn Val Asn Thr Thr Val Pro 140 Gin Val Tyr Aia Thr 220 Val Ile Arg Ser Pro Gly Phe Al a Glu 125 Ser Cys Val1 Pro Giu As n Gly Cys Lys 125 Ser Asp Met Val1 Ser 205 Pro Gly Leu Thr Ala 285 Glu Tyr Phe Tyr 110 Arg Asn Leu Thr Val1 Trp Lys Ile Met 110 Leu Ser Gly Pro Leu 190 Asp Met Val1 Val Lys 270 Arg Pro Asp Phe Leu Leu Cys Phe Val1 Lys Lys Ile Thr Val1 Ile Al a Ser Thr 175 Asn Thr Thr Ile Phe 255 Lys Ser Giu Lys Gly Pro Val1 Phe Ile His Leu Phe Thr Phe Ser Val Thr Pro 160 Asn Pro Gly Ser Vai 240 Gly Giy Glu Al a Cys Val Cys Pro Asn Gly Gly Glu Ala 145 Arg Arg Cys Pro Pro 225 Phe Cys Pro Pro Gly Glu Leu Asn Leu WO 99/55865 <210> 332 <211> 299 <212> PRT <213> Mouse <400> 332 Arg Al a Gly Ala Ser Leu Ala Cys Cys Thr Cys Gly Ile Cys Pro Pro Gln Asp Arg Phe Gly Gly Leu Cys Trp Met Gly Pro 100 Ala Ala Cys Leu 115 Pro Thr Ser Gly 130 Cys Glu Asp Thr Val Cys Glu Cys 165 Cys Leu Cys Pro 180 Lys Pro Gly Phe 195 Thr Gly Val Pro 210 Gly Arg Ala Gly Gly Pro Gly Cys 245 Asp Pro Ile Ser 260 Thr Cys Arg Giu 275 Gin His Ser Ser 290 <210> 333 <211> 109 <212> PRT <213> Mouse <400> 333 Thr Arg Val Gly Asn Gly Tyr Asn Tyr Giu Met Ala Leu Tyr Ser Leu Pro Ser Asp His PCT/NZ99/00051 Cys Pro Gin Gly Gly 70 His His Leu Al a Cys 150 Gln Ala Phe Cys Thr 230 Ala Gly Val Ser Tyr Gin Gly Lys 55 Lys Ala Cys Glu Cys 135 Pro Gin Gly Gly Asp 215 Thr Leu Gln Pro Lys 295 Cys Gly Ala 40 Thr Gly Thr Glu Cys 120 Leu Al a Gly Phe Asp 200 Pro Cys Arg Cys Thr 280 Ala Pro Arg 25 Ala Gly Cys Asn His 105 Ser Cys Gly Ala Arg 1 R r Gly Ile Asp Cys His 265 Gin Met Al a Phe Cys Gly Giu Gly Al a Cys Gly Phe Pro 170 Gly Cys Ser Leu Asp 250 Cys Leu Lys Met 10 Ile Pro Giu Leu Gly Gly Asp His His Ser Cys Gin Pro His 155 Cys Gin Leu Gly Asp 235 Cys Val Ser His Phe Pro Pro Cys Lys Cys Pro Asn Gly 140 Gly Asp Phe Gin Leu 220 Cys Gly Asp Ser Leu Ser Val1 Glu Cys Ser Ala Asn 125 Phe Ser Pro Cys Gln 205 Cys Arg Gly Ser Ile 285 Gly Cys Ser Arg Al a Cys Gly 110 Gly Tyr Gly Val Glu Cys Leu Arg Gly Tyr 270 Arg Thr Pro Tyr Tyr Phe Lys Ser Asp 25 Ala Leu Gin Ser 40 Cys Lys Lys Ile 55 Tyr Ser Glu Glu 70 Ser Pro Glu Arg Ile Trp Ser Leu Gly Cys Phe Tyr Gly Asp Lys Gin Cys Asp Tyr Pro Arg Gln Leu Val Asn WO 99/55865 PCT/NZ99/00051 Cys Ile Asn Pro Asp Pro Glu Lys Arg Pro Asp Ile Ala Tyr Val Tyr Asp Val Ala Lys Arg Met His Ala Cys Thr Ala Ser Thr 100 105 334 787

PRT

Mouse Lys 1 Thr Gly Leu Met Tyr Met Pro Gly Leu 145 Ser Leu Arg Ser Ala 225 His Ala Val Glu Lys 305 Leu Glu Pro Ser Ser 385 <210> <211> <212> <213> <400> Val Glu Phe Asp Phe Gly Ala Ile Glu Leu Ile Leu Glu Tyr Leu Pro 115 Met Asn 130 Lys Pro Asp Phe Ser Met Ile Arg 195 Phe Ala 210 Asp Glu Arg Pro Ser Leu Arg Pro 275 Lys Pro 290 Ser Ser Gly Arg Gly Arg Trp Ala Leu Gly Leu Leu Arg Phe Lys Pro 55 Ala Gly Gly Arg Cys 135 TLeu Lys Phe Arg Trp 215 Leu Pro Met Glu Val 295 Lys Pro Asp Ser Ser 375 Ser Ala Val 40 Ser Lys Ile Ser Phe 120 Met T,,-1 Cys Gly Leu 200 Gly His Ile Gin Ile 280 Lys Ser Pro Ser Ser 360 Gly Leu Gly Arg Leu Lys Cys Leu 105 Arg Ser Asn Thr 185 Phe Val Ile Cys Arg 265 Thr Asp Glu Phe Gly 345 Ser Val Ser Trp His His Met Gin Glu Ile Pro Ala Gly 170 Ile Asp Leu Met Arg 250 Cys Ser Leu Ala Asp 330 Ile Glu Ser Phe Glu Val Val Glu 75 Glu Lys Val Pro His 155 Met Ala Thr Thr Met 235 Pro Trp Glu Ala Arg 315 Asn Ser Cys Ser Glu 395 Lys His Asp Met Pro Leu His Leu 140 Ser Tyr Lys Gin 220 Lys Arg His Thr His 300 Pro Asp Gin Lys Val 380 Arg Val Trp Asp Ala Val Leu Glu 125 Leu His Leu His 205 Lys Val Pro Ala Glu 285 Glu Glu Cys Thr Leu 365 Asp Glu Gly Lys Arg Lys Gly Ala 110 Thr His Val Ser Pro 190 Asp Lys Val Arg Asp 270 Asp Pro Ser Ser Leu 350 Pro Ser Ala Gly Trp Arg Arg Val Glu Val Asp Ile 160 Asp Glu Tyr Phe Gly 240 Cys Gin Cys Glu Arg 320 Ser Gly Ser Phe Thr 400 Lys Leu Glu Ser 370 Ser WO 99/55865 WO 9955865PCT/NZ99/00051 Gly Ile Asp Val Al a 465 Ala Lys Phe Lys His 545 Arg Leu Ala Thr Ile 625; Gin Arg Gly Val Leu 705 Val1 Gin Thr Leu Ser 785 Leu Ser Asp 435 Ala Pro Glu Ser Ala 515 Ala Al a Gly Tyr Gin 595 Leu Ile Pro Leu Thr 675 Leu Gin Giu Leu Giu 755 Phe Thr Gly Gly 420 Leu Gly Asn Arg Val 500 Gin Ser Cys Val1 Al a 580 Pro His Asp Leu Leu 660 Ala Leu Thr Glu Ser 740 Thr Gin Pro 405 Asp Val1 Gin Leu Lys 485 Asn Asn Val Gin Asp 565 Ala Gly Leu Leu His 645 His Leu Ile Ala Leu 725 Ala Leu Gly Ile Arg Ser 440 Cys Arg Gly Asp Glu 520 Val1 Gin Leu Gly Val1 600 Gin Asp Ala Ala Ala 680 Lys Leu Al a Leu His 760 Ser Gin Leu 425 Ser Vai Lys Ile Giu 505 Ala Asp Glu Gin His 585 Asn Arg Val1 Glu Gly 665 Ala Ala Al a Asp Al a 745 Gly Ser Lys Lys Ser Trp Ser 475 Glu Gin Thr Glu Ile 555 Lys Pro Gin His Ile Gly Glu As n Val1 Ala 715 Ile Gin His Al a Lys Ile Leu Leu 460 Thr Leu Trp Arg Gly 540 Val Asp Ile Thr Tyr 620 Cys His Ala Gly Met 700 Arg Asp Gly Ile Thr 780 Le u Leu Leu 445 Leu Pro Leu Thr Leu 525 Arg Arg Al a Val1 Leu 605 Arg Ser Thr Leu His 685 Ala Gly Leu Arg Asn 765 Leu Val Gin 430 His Leu Leu Leu Ala 510 Leu Thr Thr Trp Lys 590 Asp Val Leu Ser Thr 670 Leu Arg His Ser His 750 Leu Leu <210> <211> <212> <213> <400> Pro Gly Cys 1 Val Giu Lys 335 194

PRT

Mouse 335 Lys Ser 5 Asp Ser Cys Thr Val Cys Arg His Giy Leu Cys Arg Ser 10 Val Val Cys Glu Cys His Pro Gly Trp Thr Gly 25 WO 99/55865 PCT/NZ99/00051 Pro Arg Ala Ser Asp His Ile Pro 145 Ile Ser Cys Tyr 1 1 Cys Val Phe Leu Ser Ser Gin Gin Arg 145 Pro Arg Gin Ile Asn 225 Glu Cys Gly Gly Cys Gly Glu 115 Arg Met Ser Val Asp Gin Glu Ala Arg Asp Pro Cys Leu Gly His Ser Cys 40 <210> <211> <212> <213> <400> Arg Tyr Gin Cys Asp Val Asn Ser His Arg Ser Tyr Cys His Asp Ile 115 Thr Cys 130 Cys Val Ala Ser Tyr Met Ile Gin 195 Arg Ala 210 Val Ser Tyr Val Thr Cys Tyr Gly Ser Ala Glu Pro 100 Gin Glu Gin Lys Glu Cys Lys Arg 165 Glu Glu 180 336 274

PRT

Human 336 Cys Gin 5 Glu Pro Asn Glu Tyr Gly Asp Gly Leu Cys Cys Pro 100 Asp Glu Val Asn Glu Pro Asn Pro 165 Thr Ile 180 Ala Thr Gly Asn Ala Met Leu Asp 245 Met Gly 70 Phe Tyr Asn Asp Arg 150 Arg Val Hisr Gly Cys Thr Phe 70 Gin Gin Cys Phe Tyr 150 Leu Thr Ser Ser Leu 230 Leu Ala Ala Lys Cys Pro Tyr 135 Gly Lys Glu Arg Phe Asp Phe 55 Ser Tyr Gly Glu His 135 Ile Cys Ser Val Gin 215 Val Glu Thr Leu Cys Leu Cys 120 Ala Gly Tyr Arg Cys Gin Met 40 Leu Cys Arg Tyr Ser 120 Gly Gin Arg Glu Tyr 200 Gly Leu Met Gly Cys His Cys 105 Met Ser Cys Val His 185 Val Leu 25 Gly Cys Ser Cys Gin 105 Gly Gly Val Glu Arg 185 Pro Asp Ala Val Asp Asp His 90 Gin Gly Cys Gly Phe 170 Leu Asn 10 Gly Ala Arg Asp Val 90 Leu Ala Tyr Ser Gin 170 Ser Gly Phe Arg Thr 250 Tyr Lys Gin Gly Ile Thr 140 Thr Cys Cys Val Asn Cys Phe Val 125 Ala Cys Thr Gly Cys Asp His Ser 110 Arg Ser Cys Asp Cys 190 Leu Pro Gly Ser Pro Pro Cys Ile 75 Asn Leu His Arg Glu 155 Pro Val Ala Tyr Pro 235 Met Asn Cys His Asp Glu Ala Gin Cys 140 Asn Ser Pro Tyr Ile 220 Val Asn Asn Glu Gin Glu Pro Thr Cys 125 Val Arg Ser Ala Asn 205 Arg Thr Ser Arg 30 Gin Gly Cys Gly Arg 110 Ser Asp Cys Ile Asp 190 Ala Gin Gly Leu Lys Ser Ile Gly Glu Lys Gin Gly 175 Arg 15 Ser Arg Tyr Ser Arg Leu Glu Thr Leu Val 175 Val Phe Ile Pro Met 255 Cys Ala Ser His Ala Val Pro 160 Ser Ala Cys Cys Cys Glu Tyr Phe Cys Ala Asn Cys 160 His Phe Gin Asn Arg 240 Ser WO 99/55865 PCT/NZ99/00051 Tyr Arg Ala Ser Ser Val Leu Arg Leu Thr Val Phe Val Gly Ala Tyr Thr Phe His 1 Ile Val Al a Lys Ser Thr Asn Val Met 2.45 Thr Leu Arg Ser Ser 225 Arg Ser Leu Giu Leu 305 <210> <211> <212> <213> <400> Giu Glu Asp Leu Met Lys Ile Asn so Thr Arg Gly Pro His Ala Lys Arg 1.15 Gin Arg 130 Ser Glui Thr Lys Glu Gly Gly Asp 2.95 Glu Tyr 210 Gly Leu Arg Cys Ala Ala Gly Gly 275 Gin Phe 290 Phe Ala 337 32.6

PRT

Mouse 337 Giu Pi Gly A., Asn L( Giu I.' Pro L( Gin S( 8! Ala G' 100 Phe I' Leu TI Ala G' Ser V4 Asn S( 2.80 Pro V4 Lys G' Gin S( Val A! Phe ME 260 Met G' Ala A: Phe I.' Cys Ser Leu Gly Pro 70 Leu Asp Ser Glu 11u 150 Pro Cys Ser Val1 Asn 230 Thr Leu Giu Leu Leu 310 Asn Cys Pro Val 55 Pro Lys Met Ile Phe 135 (,11 V Pro Glu Tyr Tyr 215 Thr Ser Gin Ala Ile 295 Gin As n Ile Giu 40 Gly Ser Leu Val1 Tyr 120 Thr Pro Thr Ile Val1 200 Lys Asp Gin Gin Lys 280 Val Tyr 265 Giy Thr 25 Thr Pro Pro Lys Tyr 105 Arg Cys Tyir Leu Phe 185 Leu Gly Tyr Giu Arg 265 Met Leu Phe Ser Val1 Thr Phe Pro Trp Thr Gly Tyr Lys 170 Trp Gin Giu Arg Leu 250 Giu Lys Gl1y Leu Glu Gly Tyr Ser Arg 75 Gly Leu Pro Ser Glu 155 Al a Giu Val2 Giu Phe 235 Ser Val Gly Phe Met 315 I le As n Arg Gin Leu Asp Gin Ser Phe 140 Thr Pro Thr Leu Ala 220 Arg Gly Met Met Ala 300 Lys Leu Thr Ile Phe Giu Ser Leu His 125 Arg Arg Val2 Val1 205 Thr Val Ala Leu Met 285 Thr 270 Ala Thr Arg Ile Cys Asn Giu 110 Thr Ile Thr Val Pro 190 Gly Phe Cys Phe Thr 270 Pro Leu As n His Gin Al a Al a Lys Arg Lys Ala Ser 160 Gin Met Asp Ile Cys 240 Pro Asp Asp Ile <210> <211> <212> <213> <400> Met Leu Ser 1 Leu Ala Leu 338 237

PRT

Mouse 338 Leu Arg Ser Leu Leu Pro His Leu Gly Leu Phe Leu Cys 5 10 His Leu Ser Pro Ser Leu Ser Ala Ser Asp Asn Gly Ser Cys Thr Pro Asp Asp Gin Leu Lys 145 Ser Lys Asn Lys His 225 WO 99/55865 Val Vai Leu Met Ala Asn Vai Asn Asp Asp Ser Pro Ser Ser Val 100 Thr Asn Trp 115 Gin Val Leu 130 Met Giu Gin Giu Thr Ser Thr Thr Ala 180 Thr Thr Ala 195 Ser Leu Ala 210 Ile Leu Leu Asp Asn Ile Val Ser Gly 55 Ser Val Ser 70 Val Gly Thr Tyr Tyr Asn Thr Val Pro Ile Val Val 135 Val Gin Pro 150 Gin Thr Ile 165 Lys Asp Thr Asn Thr Thr Ile Arg Thr 215 Tyr Gly Ala Trp Leu Thr 120 Asn Ser Asn Al a Al a 200 Leu PCT/NZ99/00051 25 Thr Asp Val1 Ser Thr 105 Ser Arg Ala Thr Asn 185 Vai Gly Ser Val1 Ile Gly 90 Ser Glu Thr Ser Thr 170 Thr Thr Ser Asp Thr Leu 75 Thr Gin Asp Al a Thr 155 Pro Thr Thr Pro Ile Tyr Lys Tyr Ser Val Ser 140 Pro Thr Ala Ala Leu 220 Glu Val Val1 Lys Ser 110 Lys Ser Pro Asn Thr 190 Thr Giy Ile Thr Lys Cys Val1 Val Ser Giu Thr 175 Thr Thr Al a Ser Val1 Glu Asn Phe As n Val Ser 160 Ala Ala Al a Leu Vai Phe Leu Ile Ser Lys Leu Leu Phe <210> <211> <212> <213> <400> Met Leu Cys 1 Glu Phe Gin Ile Phe Lys Arg Gin Trp Gly Gin Leu Lys Lys Leu Arg Ile Asp Lys Ile Ser 115 Asn Gly Thr 130 Leu His Pro 145 Ser Thr Ile Thr Val Glu Giy Gly Gly 195 339 46.9

PRT

Mouse 339 Leu Cys 5 Tyr Phe Leu Ser Lys Gin Asp Phe Arg Leu Ala Gin 100 Glu Gin Met Thr Vai Giu Phe Asp 165 Giu Arg 180 Ala Gly Leu Tyr Val Pro Ile Ala Gly Ala Ala Gin Thr 10 Giu Val Lys Glu 70 Val1 Giu Gin Ile Asn 150 Val Gin Al a Ser Phe Ile 55 Giu Phe Ile Aia Asp 135 Ile Gly Thr Val1 Lys Gly Leu 25 Ile Pro Ser 40 Val Gln Ala Phe Val His Lys Ser Leu 90 Met Gin Ser 105 Glu Lys Ile 120 Trp, Asn Giu Pro Glu Ile Giu Asn Leu 170 Gly Met Trp 185 Ser Arg Thr 200 Pro Gin Gly Tyr 75 Asp Leu Leu Trp, Ile 155 Thr Trp Cys Ser Aia Giu Asp Leu Lys Arg Lys Arg 140 Leu Val Arg Thr Arg Glu Phe Lys Gin Lys Asp Ser 125 Asp Tyr Pro His Al a 205 Ser Leu Ser Asp Asp Asn Leu 110 Met Tyr Trp Asp Leu 190 Pro Asn Lys Thr Leu Hi-s Asp Gly Asp His Lys Glu 175 Val1 Leu Asn Ser Tyr Asp Giu Gly Val Lys Leu His 160 Phe Al a Asp Met Arg Leu Lys Val Leu Met Gln Vai His Ala WO 99/55865 WO 9955865PCT/NZ99/00051 Cys 225 Ser Ser Ser Leu Lys 305 Asp Lys Asp Al a Thr 385 Val1 Val1 Phe Gly 465 Met

I

Al a Lys Pro Arg Lys Tyr 210 Leu Ala Asp Ala 290 Thr Cys Gly Leu Val 370 Ile Arg Thr Gly Val 450 Val1 Gly Arg Lys 260 Giu Al a Met Arg Ile 340 Val1 Ser Ser Arg Ser 420 Tyr I le Ser Gly Gly 245 Phe Thr Ile Al a Arg 325 Pro Tyr Ala Thr met 405 Ser Arg Ser Arg Met Asn Glu 265 His Ser Thr Lys Gly 345 Lys Val Leu Ala Gin 425 Pro Leu Cys 25 Lys Ile Leu Ala Ile Val1 250 Gin Giu Ile Gly Giu 330 Ile Asn Phe Ala Ser 410 Ile As n Leu Lys Leu Val1 His Trp 220 Giu Lys Lys Leu Pro 300 Tyr Val Pro Trp Leu 380 Tyr Glu Arg Met Gly Ile Arg Val 285 Met Ser Al a Tyr Leu 365 Leu Pro Gly Thr Lys 445 Gly Ala Leu 270 Ala Glu Gly Al a Ala 350 Gin Ala Leu Ala Giu 430 Val1 Asn T.e. Ly TIl q'j, Leu 455 <210> <211> <212> <213> <400> Arg Leu Ser Arg Ile Arg His Cys Tyr Arg Arg Phe Glu Glu <210> <211> <212> <213> <400> 340 99

PRT

Mouse 340 Leu Ala 5 Val Asp Tyr Ser Glu Giu Giy Gin Ile Lys 460 Leu Ser Met Thr Lys Glu Ala Lys Pro Ser Gin Arg 341 431

PRT

Mouse 341 WO 99/55865 WO 9955865PCT/NZ99/00051 Met Leu Gin Phe Tyr Val1 Arg Val1 Leu Pro 145 Val1 Pro Asn Phe Met 225 Leu Ser Val Gin Gly 305 Gin Phe Leu Ile Leu 385 Val Arg Asp Gly Leu Met Leu Phe Thr Phe Gin 130 Giy Leu Arg Val1 Pro 210 Met Thr Gly Leu Asp 290 Val1 Gly Al a Phe Ile 370 Tyr Phe Gly Al a Ala Trp Val Giu Gly Giu Cys 115 Glu Giu Al a His Leu 195 Thr Gly Ala Pro Leu 275 Al a Asn Ala Leu Ile 355 Met Gly Thr Lys Arg Trp Gly Gly Leu Phe Pro Gly Thr Gly Asn Giu Thr Ala 100 Ala Ser Arg Val His Phe Leu Val 165 Gly Ala 180 Ser Ser Gin Val Lys Leu Gly Leu 245 Giu Pro 260 Ala Gly Leu Phe Leu Phe Leu Leu 325 His Ala 340 Phe Tyr Thr Leu His Thr Ala Leu 405 Lys Ala 420 342 51

PRT

Mouse 342 Trp Glu Arg Tyr Arg 70 Pro Giu Gly Met Thr 150 Val Pro Trp Leu Val 230 Ile Arg Tyr Al a Ser 310 Giu Leu Thr Arg Val 390 Leu Val Ala Val Ser Pro Phe Leu 40 Leu Leu 55 Gly Leu Lys Ala Ser Thr Leu Gin 120 Thr Gly 135 Asp Ser Ala Gly Met Tyr Cys Gin 200 Ala Lys 215 Ser Arg Ser Ile Ser Ser Ile Ala 280 Tyr Lys 295 Cys Leu Gly Ala Val Giu 25 Leu Vai Cys Pro Pro 105 Val1 Ser Gin Leu Arg 185 Tyr Ala Arg Gly Pro 265 Phe Met Phe Arg Ser 345 Gin Ile Val Val1 Glu 425 Vali 10 Al a Asn Gin Phe Asp 90 Ser Ser Tyr Phe Tyr 170 Tyr Giu Ser Ser Vai 250 Ala Asp Ser Thr Phe 330 Ile Phe Ala Gly Tyr 410 Pro Leu Pro Val1 Tyr Pro 75 Giu Trp Tyr Gly Leu 155 Cys Ser Al a Lys Tyr Ser Thr Ser Ser Val1 315 Met Cys Gly Ile Gly 395 Al a Pro Al a Pro Ala Leu Leu Val1 Gin Leu Ala 140 Val1 Val Phe Leu Val 220 Glu Met Thr Phe Val 300 Gly Gly Ser Al a Leu 380 Leu Arg Val1 Thr Gin Gly Arg Val Leu Val Thr 125 Thr Leu Leu Ala Lys 205 Ile His Phe Leu Thr 285 Gin Ser Arg Ala Ala 365 Leu Gly Gly Gin Leu Ser Tyr Arg Lys Leu Leu 110 Trp Al a Met Arg Ser 190 Phe Pro Trp Leu Ser 270 Ser Met Leu His Phe 350 Val1 Ser Val Arg Lys 430 Pro Ser Trp. Thr Ala Ser Lys Asn Ala Cys Ala Pro Lys Leu Gly Ile Thr Ser Asn Arg 160 Lys Gin 175 Leu Ser Val Ser Val Met Glu Tyr 2An Leu Ser 255 Gly Leu Asn Trp Met Phe Leu Giu 320 Ser Glu 335 Gly Gin Phe Thr Cys Leu Ala Val 400 Lys Gin 415 Val1 <210> <211> <212> <213> <400> Leu 1 Asn Cys Ser Leu 1 Asn Cys Ser 1l Asp Ser Giu Gin Lys Ser Val Met His Tyr WO 99/55865 Lys Phe*Ser His Pro Cys Leu Giu Asp His Asn Ser Tyr Cys Ile 5 10 Gly Ala Cys Ala Phe His His Giu Leu Lys Gin Ala Ile Cys Arg 25 Phe Thr Gly Tyr Thr Gly Gin Arg Cys Glu His Leu Thr Leu Thr 40 Tyr Ala PCT/NZ99/00051 <210> <211> <212> <213> <400> Lys Phe Gly Ala Phe Thr Tyr Ala <210> <211> <212> <213> <400> Ala 1Ala Gly Ser Asp Val Lys Met Giu His Trp Tyr <210> <211> <212> <213> <400> Lys Cys Lys Lys Val Ile Cys Leu Asn Ala 343 51

PRT

Human 343 Ser His Leu Cys Leu Giu Asp His Asn Ser Tyr Cys Ile 5 10 Cys Ala Phe His His Giu Leu Giu Lys Ala Ile Cys Arg 25 Gly Tyr Thr Gly Glu Arg Cys Giu His Leu Thr Leu Thr 40 344

PRT

Human Leu 5 Cys Lys Ile Leu Al a Leu Lys Leu Ile His Trp Al a Lys Pro Ser Gin Arg Thr Lys Pro Arg Lys Tyr 345 77

PRT

Mouse 345 Lys Cys Leu Glu Val Thr His Pro Trp Asn Ser Arg Lys Gly Pro Lys Ile Arg Tyr Ser Asp 10 Met Lys Pro Lys Tyr Pro His Cys Giu Giu Lys 25 Thr Lys Ser Met Ser Arg Tyr Arg Gly Gin Giu 40 Lys Leu Gin Ser Thr Lys Arg Phe Ile Lys Trp 55 Giu Lys Arg Arg Val Tyr Glu Giu 70 <210> 346 <211> 77 WO 99/55865 <212> PRT PCT/NZ99/00051 Ser 1 Val Met His Tyr Met 1 Leu Cys Thr Pro Asp Asp Gin Leu Lys 145 Ser Lys Asn Lys <213> <400> Lys Cys Lys Lys Val Ile Cys Leu Asn Ala <210> <211> <212> <213> <400> Leu Ser Ala Leu Val Val Met Ala Val Asn Asp Ser Ser Ser Thr Asn 115 Gin Val 130 Met Glu Glu Thr Thr Thr Thr Thr 195 Ser Leu 210 Hum 346 Lys Leu Ile His Trp an

C

G:

TI

P]

A

347 215

PRT

Mouse 347 Leu A His L< Leu Ai Asn Vc Asp S Pro Vc 8 Val T 100 Trp TI Leu I: Gin V Ser GI 1 Ala L3 180.

Ala As Ala I! ys 5 Lu hr ro sn rg 5 eu sp al yr 65 sn le Le Ser Arg Lys Gly Pro Lys Ile Arg Tyr Ser Asp 10 Met Lys Pro Lys Tyr Pro His Cys Glu Glu Lys 25 Thr Lys Ser Val Ser Arg Tyr Arg Gly Gin Glu 40 Lys Leu Gin Ser Thr Lys Arg Phe Ile Lys Trp 55 Glu Lys Arg Arg Val Tyr Glu Glu 70 Leu Pro Ile Gly Ser Thr Asn Pro Val 135 Pro Ile Thr Thr Thr 215 Leu Ser Tyr 40 Gly Ala Trp Leu Thr 120 Asn Ser Asn Ala Ala 200 His 10 Ser Ser Val lie Gly 90 Ser Glu Thr Ser Thr 170 Thr Thr Leu Ala Asp Thr Leu 75 Thr Gin Asp Ala Thr 155 Pro Thr Thr Leu Asp Leu Thr %Ala Glu Gin Thr 125 Lys Ile Val Val Lys 205 Phe Asn Glu Val Val Lys Ser 110 Lys Ser Pro Asn Thr 190 Thr Leu Gly Ile Thr Lys Cys Val Val Ser Glu Thr 175 Thr Thr Cys Ser Ser Val Glu Asn Phe Asn Val Ser 160 Ala Ala Ala <210> <211> <212> <213> <400> Gly Tyr Ser 1 Pro Gin Phe <210> 348 21

PRT

Mouse 348 Asp Gly Tyr Gin Val Cys Ser Arg Phe Gly Ser Lys Val 5 10 Leu Asn 349 140 WO 99/55865 <211> 417 <212> DNA <213> Mouse PCT/NZ99/00051 <400> 349 gctagccgtg cacccagctc ttctcgggca ggcgctgcgg atgcgcccgg gctagagcgt tgcctcgccg cctccccggc ttgagcgaag gctgccgcgc ctgcaccccg aggtgcctgg ggagggctct tctactccgc tccggagcgc gc tccc cggc agccgccggc gcccgcgcgc cgagctagcc cctctacaac cgaggtggag gtgcaggcga tccccgccgt atgccgctcc gcctgccagc gagaccatcg tacctgccgt atgcttgtgt gccgagcgcc cccgggcacc cgctgctgct tgccgtcgga tgtatgccaa ggcagtacca gaccaaggcg ccgtccgcgg cgggcgggcc cgccgcgctc gtggagaccc ggtgctggcg agctggagag tggggca 120 180 240 300 360 417 <210> <211> <212> <213> 350 1837

DNA

Mouse <400> 350 cccccacctg taagcggccg aacaacatgc tccccgacca gtggccagca tctcacagca gatgccctg cctcatctgg aaggggatag agagggttcc gtgtttgccg ccgaaggacc agcaccctca catccctgtg tggagagga t aagagagtgt gactcccagc tgtCtctgcc tgcagaat cg cggagggcca gcccgcgttg gtaccagcat cgaccctaac ggactggt ca atgaggtgtc gcagtgagat tccacacaga cagccacggc ctctgtggga gtttgatgtg <210> <211> <212> <213> cccagccaag gcctggaaga ctccacttct tctctcttca aattaatgtg tcgggaaggg acatcagccc aattcccctt ttttcaaagg ccggaggcag taggagt ccg ggcatgtgct gcagctccgc agcggaggac caaggcaagc tccagacaca cctgccaaaa cactggcatt atgtcctctt aggcctttgt ggatagccag tgtgccggac cgggagtgcc ggacaggcca tgggccagca cctgcaggcg ccctcaggac caggctgcca cgtgagaact aatcctgatg ccgagtgccg acgccatccc gcttctacca ggaagtgcat gtgctcagcc gagcttcgag tggcagggtc ggactccttc tgggcgcacc aaatggctct ggctctcccg ttttcccagg gttggctgag actctgcacc gctggagacc agacactgtg ccctgccaac tggaggcacg cggaggggaa cctgctggac caagcgcttt ttatggcagg ctgatcagga ttgctccagg cgcagagtag gctcacgcaa gagctggtga ctgtcagcca ggcacagtca ttgcccaaat tgacacaagt ccggctttgt ggagagcgca gccatctaca gtgaaccggg gcggtcgaca aggtccaagc agagt cggag tcaactcgac gagacgggcc gtgccccaga gctaagcagc tgggacgagc caagtggagg actgctgatc gtcagggagc ctggctctgc tgctacagaa tgcattccag gtcaactgtg agttctgcag gtgcaggccg aatctaatgg gccttgacag tggcagagca tagttctgct gggctcggga agatcaccgg aatccagagc ctggacctgg gcagagcttc tggcctg tcgctttgtc cgcggcgtcg tgCtcctgtt agaccatggg tcctgtttct gcttcgccat ccttgcagtt aggaagtgaa tagccctgaa ttcttatcat tgagagaaag tgctcacgct atgccaccaa cagactgcag tcgctggcaa cctgtCcctt ccatctgtcc aaggtgtgga ccccgaagct gcaccacatt tgctgaggga tggcggtgcc cattcccttc cggc tttggg cactgaatca gctactcctc tagcccgaag tgcagaggag tcttcctgtg atcaggaaat ctcgcgcacc caccaggtct cttcagagtg gaagatcgct gttagatggc cgctgcctgt tggttccact ggaaagcat c acgcctgagc cgtcacggat gggcatcgtc ggccagtgag tggcctcctc ggtggaacct tgccttgtgc ctacagctgg aggcccctgt taggtaccac gagcctggaa ggggggcttc ggactcccga ctgtcgggga agcggtggc c agtgccagca cgctcccagg ctgggcgtgg catgtgatgg gctatgcagc gatgcctctg gcaccctccg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1837 351 941

DNA

Mouse <400> 351 taagccctca ggccctccta atgctatccc CCtttgttcc tgcagcgtgg acccagtCag cagccaggcc atggagctct ctgatgtcac Cctcattgag ggtgtgggta acgaggtg at ggtggtagca ggcgtggtgg cgctgactct agccctggtc Ctagcctggc tctccaccta tgtagcagac agtggtaaca accagctgct gggcaccatt gtgtcagcag gtgacacgtc 120 180 240 WO 99/55865 WO 9955865PCT/NZ99/00051 tgttctccac acacccccat agacgccact ggacatccaa gctggggtta caagttcctc cctaaaaagg ggtttcctga gacttccata ttctttatcc aatgaagttg gaacattacc ctgggccatg ccatcagggg ggagaacctg ggcctgccta gatgatggct aatgacacgg tgagtaggcc agaagctgtg gacagacctt agtctttcct atctaccagg aacaactgcg tggaccagct gcaatgatga gagctagggg aaaggcaagc cctgcctctc aggagctagc ggagagaggc catatatgtg cagtgtcttt ttcatccttg gtcggctgct tgatccactg ggtaaaccaa caaggctgaa agagatggag aggcctgggg tcccagcccc tgtggccagg cagttgctcg agcacaggag catgtccagg tagcaaatac gcaggaccca ccaccgctca ggcactccag gagaccagtg cccagcctgg agcagtcgcc agcctcatca ccagaggaca tgacttgttc ggattttaag ccttgatctc ttccctggac gcacgcacac

C

agccaaccga acagtggggg agcatctcct cagaagcccc atgttcgcct ctgtgggtac ctcagatgat gggaaatgga tctagcctta aagagaacca tgagttccct <210> 352 <211> 571 <212> DNA <213> Mouse <400> 352 gctgactgta cctataattc ttgtgatttg agtatgtgtg atttggatgt cttttggttc gtggtgtcac tgggcCctgt ccagtgtacc caaatgtggc tctctcagac cctttgtggc cagctgagaa ccctccctcc CCCCtcctca tgctgaccct tatgggaatg tcagggctct gaactggccc ttgctttgtt accatgaatt catgtggttg cgtgaacaag gggtggctca attgttgcat tttgtctgtt tgggatgttg tcaatatctg ctcaccttga ttctctgcct acgtctgtga gggctcagct tagaaattgc cttacctctg gccttgggtg gaaagagaca ggtgtaaact gcagtgcatt cagctgataa g gttacctccg gctgtgcgcc atgtgtctac attccgtctg tgtgtgggag gagacccctt taactgcttt gttcccaagc ttccattcct tgagctctca tgacatccac cggtgacagt tgggaaagtc attgtctctg gtggttttct gcaaagcctg cccccttgtc cgactcttga <210> 353 <211> 467 <212> DNA <213> Rat <400> 353 cggagaatga gcgggtggcc tctatgcctt tccggctgct catggtgcgc caggccccga aaggccatgt tctaccacgc ctgagacctc tcacctgtga gatgccctgg acaccttgct gttctccagg acaaacgtgg catccgagtg gtaggaggac gtggctgcag tatcccgctc aggcaccgcg ctacgacagt cgggcacgac gattttgggg actttgatat tcctttctgc ctgctgcggc ggcCtcgtgt cccgaccccg tacctggaaa acctggggca aatacctctg cgacgtcaat tcatctcttg ggcActgaca gcgtgctgct cccactacag atgcctttcc gtttttCtct aattccaaag gcctctgtgt tcaaaga ggacacgagc gcccctgcac ggagcgagtc ctacgatgag gacactgatt agtggtggag tcgaaaccaa 120 180 240 300 360 420 467 <210> <211> <212> <213> 354 528

DNA

Rat <400> 354 gtgactcctg ctgtaggacc agcaccggcc ttaatgctaa tctcgagttg ccactcccaa aggagggcct gtgcaggctt ccaggagcag caggaaggaa acttctggag agtctgccca tatcctgttg ttaagctgtt gccctatagc cagaggagtg gcccaggagc tgaccccaaa ctccaggaag agccaaatgt gccagccccc tggacagcca gaccccagaa ccttgtgctc tccacagaag ccctggctaa ggccaggaag cactggcctc ggtttctgcc actggccata cttgccacag ttccccaggg acacaagcat CCgttcagg ctgCagtgtg gctcgagctt tcctacagag ctgcagcgtg tggcatcata cagaggagag CtCt t tgagt ggacaggaca tagttacttc agcttgtaag gccacttt tcctccacct cccctggtaa tctgggggtc agtgaggttt ggtaatgttg ctgggacttt acccacattg caacagaagt WO 99/55865 WO 9955865PCT/NZ99/00051 <210> <211> <212> <213> 355 473

DNA

Mouse <400> 355 ggcagcagga ccgcggtcac ggatctcgat gtggttaaca ggcatttgtt gcgtctttcc ctggcggagg acactgggca ttactccttc Cggggcaggc cgcacacaag gacatgtggc ctgtgtggac atgcctgggc agtggggcaa gttaaaagga tgagcctctg tgtttgtgat t cctgtggc c tgcaagttcg caggacacaa tcagcgtggt atgaaggcac tacatcagtt caggtgtcaa tgcgggtggg ttcagcactg ctacgcacac gccatccatc caagttcctt cacccgctcc tgtagaatgc caaggctcaa accctggcca ataagaatct catgaggac t cttatgctcc ccgaagaacc tccctggatg cttaagctga ggagcaggat ttccaatcct attattggta atcagttctg atggattctc tgcacttggt acctgtccat aca 120 180 240 300 360 420 473 <210> <211> <212> <213> 356 431

DNA

Rat <400> 356 cttaactagc gcccccatcc caacctaaaa ccaaatggaa ggcttcggct gggctaacgc gagaggcgat ggcgtcaagt cgtacgggag cctggtattc ttgcaatgaa atctagaagg taaaagagga aattgatatt tccttgcaga t accatgtttc atggccggag gcgagtgtgg agtaactggc gtattgctgt ggacctcatg cggctatcca ctgacggatt agctccaggg tgggactatc tgtccggagt ttatttttgt tccctgtggg gagttcagga ctagccttgt cacctaggtt ctaggaggtg gaatgtcgtt gaagagacaa acacaatgcc catcaagtat ttgttttttt Ccctggcttc ttcctggaga cttgtgatgg atcatgcgct ccgaaggact gaaccgcagc 120 180 240 300 360 420 43'a1 <210> 357 <211> 1206 <212> DNA <213> Mouse <400> 357 ccaacactcg acagtgggat tggct ccagc gaggagtgc t aataaaatca tgcgacggag ctgcgaagtt gatggcgcca gacttgcgcg cgtccccagt gcgccctgcc tacatctcgt cggcacccag gtgtgagctg agaaaatatt ggatccccct tggtatgtgc agggatggca gagctgtcgc gcgggcaaca aacctg ccatgcgttc tggggcactg ccgtgggcgc agggcagaga gtgcttccgg gcctgctagg tggagtgcgg gcgtgcccaa cctaccggga tcatgtaccg cgtgccttgt cagtaccttc cgtgtcacct gcatctgcac cagccactgg ctaatttatg gggatcctga catcacccar gctgcatgga agggcacagc tcaggtcaga cgtgatgggc ggccacctgc caacatcaac gttcctgggc CCccggcaag c tgcgagggg cgaatgcgaa cggccgctgt ggatcagacc caaccccggc gcgccaggcc aggtggcccc gcctggcatt tcacatggac gcacgtatca gtactgggat gatccccctg cgatgagttg gaaacactgg tggccgctgc tccgaggatt agtctggtgc accgcctggt ctcgtccact gcgtgccgca yttcccgcgg ctgcgcaccg caaaagtctt ggcagcgcac caagaactct acttgcttcc aaagtaccag tgacgccatc atttcccaaa caaggactga caaagttaga ctatgatctc gtgtttgcat gctcattcct tttggggagc ctgtgcccgg tgaagactcg ccaacttcac gcctcccctg tgctgggggg gcttccaggt cgcgctgtcg gcgctcaggt actgcgtggt gtggcaacaa tgggccgctc cagaggagga ccgattttat c ctggc ctgg agggagattt acccaagacc cccacctgct atggctggcc gtttggtcca cctggtctgg tggcgtgtgc tgtcagccgg ccacccaggc caaagattcc gcgtc caac a ctgcggctct cggacaccca agtgtgcccg gtgtcgcgct caacgttacc cattggggtt agagaacttc ttattgttat aaccacttgg ttataatagt cctgctgccc ttctaggctg tcagaccaga ctcagggtga 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1206 <210> 358 <211> 1052 <212> DNA WO 99/55865 <213> Rat PCT/NZ99/00051 <400> 358 Ccagaaagaa cgatttagat Ctcttggcct gtgcccttcc gacttccaga agggtggtcc gccctccagg agcaccagga atggccaaga cggccaggac ggacaggcaa ccgaggaaaa gtcctcgagg acccaagggg agggacctaa gggcaagaaa gccgagccaa gtcggccttt ccatcaagtt tgacaagatt agttcgtctg cagcgtgcca aacacctggc catcggccta acaccggcaa ccacgacgtg aagtctggtt acagattttc ccgacagcct gttcaccggc agacaagctg gggttgagcg gaggatctct gaactgaggc gcctcctctg gtgctgcttt gacagttttt gtgtgctgct tcaactggtg tcctcaggaa ggagaccgag caaggaccaa gtcagtggta ggggaacctg tcggtggcgg ctgatgaatg gggatctatt gtgcacaatg gcctcgggct tactcggagc ttcctcatct tccaggcagg tggggactgg aaaaaaaaaa agaaaggtga gacccaatgc tgcagtctgc tggtgggaag gggacagtgg agggcaaagc cccccgggaa ggctcccagg taaccaagag agggaggcca actttaccta gccagtaccg ccaccatcct agaatggact acgctgatca gactaagatt cagttcttgg aa ccaccatgat ttggtgcctt ctggtcccca aatgggtttt agaagaaggt tggggccatt acatggtata cccctgtagc ttacccacgt ctacaatgca tgacattacg cattcggact agctctcaag cttctacgac aggagacccc ccgcaagggt gagcttttat ctcctggatg tgctcgcagg aggccacctg cctggtaagg ccacctggca gggagagcgg ccgggcaaga tgcggcagta gagcgactgc tccagtggca ctggccaaca tttgacgcca gagggtgatg ccttattgga aatgaggtat gctgatagaa tcccaggcaa 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1052 <210> 359 <211> 1134 <212> DNA <213> Rat <400> 359 aattcggcac gcggtggaag agcaagcccg acccccggct ttacagaaac cctgcatgtg ctgtgagtgt cctgtctgtg catccgaaag CCgctccatg gcgggtggaa cttcgatcga ctcggctacc ttgtccttct gtctttggtc aagagaacag gccgttcctc gccgtcaata gatgccgtgg <210- <211, <212,- <213-, gaggcggtca cagagatggc ataagcatga caagccaaca atcagcgggc gtggagccca aggtatgagg gtaggggccc ccggatgcct gctgccgccg ggcgctcagc cacaagatgc agcttctggg ccctctctct tctagtgtct agatggttga acagctccac gctcggtggg cccccattcc gaacccgggc ggagggcggt agctgctgtg agagctctga acatttacaa tgccggtgcc agcgcagcac tcttactcta atactgagca cc gcat ccat agcgatggaa tcagttagat gcagtcttcc agaaatgtac ctgtaggtct gacggccaca atcttaagga tgcgacgaaa cacttttnca ttCtcgtttg gggaggagag tttggtggct agatatccgg ccagaatgtg tggccatgat cacaaccatc catggccttc gctgcacaat tggaggaccc gctacaggtg gattgccatg c tgggtc tt c tcgactgtta ctggggtaga cgattggtga tgtttatagc gtgtgaccca gtgccaatac tcctgaacgg gcgtctagtc gtggtggggt tgcaaatgca tctcagaagg gtggaagcct aaggtcatta ctgatgctgg gaagaagaga cgagcaaaca caggagcagc gcagtgtcag ccttcaaatg taactaggga agggagggaa aattcctccc tctttgggag gccctcagcc tttagcttgg cactaccagg ttgctggctc gcttgctggt tctgtccccc actgcaactg actgcctgct tcgtcatcta tggaccctct atgaggatgc ccgtcctgga ggaagacggt ggacccagac cccgtggcat gtgggattgg aggaaggcag tcctgtcctc acggagctgt tgtgctctac Cctg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1134 360 876

DNA

Mouse <400> 360 tgccagctgc cccttcgagt gacatcagca ccttgggaag ctgcccgtgg agctgtgtag ctcagtaccc tgcctgatga aaccgcatct cccgaatccc ctggatagca accccctaca atcttcaagt acctaacaat gcttatcatc cctgcggcag cctccgttcc gctgggagac cgtCtccttc gagtccacct ggaagctggc agcaacaaca cttgatgtga ctgcgggatc cttcctctgg tgccgcctca gcccagata t cggaggggag agttaggagc gcagcaatga tcaatgttcg tccgcctgga ggcacctgca gcctgaaggg Ccgccctcgg cctgcctcca gctgcagtcc aaggaaccag tttctcctgt ggtcgttctg gaaacttcac ggacctggtc WO 99/55865 WO 9955865PCT/NZ99/00051 CCttcccgcc tatgatggtg ggaaatgagt gatccccggg attgacttta cagctgcctt cgagaggagc cgggagcgga ccccaagttt gcctggactc ccacagatga ggcctagaca ttgacagcca ctgaattaag ctgcagggga agcaacagca tagtccttgc aggcttccac tt t ttcagag acctagggaa cgttcctggg ccttgtagca ggagaggcgg acagagtggg cctgccgaag agcgttgaca ctgtctttcc gatggcgc tg gaagatgaag ggggatgtgg cgcccagaca ggatgg atttatttcc gtggcagcaa ggatctcgga gcgatggaga atcgaagtgc agaagccat c ctttgcagtt gggacgtcgt gaggtggtca gctggctcgt cctggagcag agctgaggag tagcagcagg gtggcaggaa <210> 361 <211> 495 <212> DNA <213> Mouse <400> 361 gtcgcgccag ctgagagccc ggacagaggc ccctctgttc caacttggcg ggaaggaacc cattcctgaa gaggctaatc gacagatctg accaaactca ccgactcttg cctgccctta ttcagctata agagagctag aatactgcct gaagaaatta tgagctgact tgcat ctaggtttga cccagggcct tcggggaagt agaatctttc tcatctccag ctgttcttga acaatcttca caagcttaaa ccctcgtgcg gctgaaggca ccctcagtgt attcagttct caataaactt tatacatgat gaaacttaat aaacctgagg ggattccacg gcgagaagca gtttggagaa actgaacgat cagtc tct Ct aatcagctga gtcagccata acgctgcacc cggagggcaa gcggccaact taaatgtgga ggtgggatca ctgatgacct catctcttcc acaaactgaa tccagcacaa 120 180 240 300 360 420 480 495 <210> 362 <211> 349 <212> DNA <213> Mouse <400> 362 tctctgtcta tcttgcctgc agtagtatgg cggccttcct atggaaccca gggctttgtt acctccctct gtgtacaaag accaaggcca gatgcgagcc gaaatgttaa gcatactctg tgtgagggta tgtaacaggc taggcctgac ctcctttctt acccagaagt ttctagagag tcacccaggc tttttctttt aaggctctgc gggtgaccaa taattaaacc ggagtgaaga ccacttatcc ctctcttcgt ccctgagctg catcttcctg aggttcatcg aaggggcca atctacagcg ggtgcttggg tgccaagccc tctttgagca ggagtttgct 120 180 240 300 349 <210> 363 <211> 380 <212> DNA <213> Mouse <400> 363 gagtatgaag ccagagtctt gacaaggtga agctgacctg atcatcttca tgatcgcagt tccacagctg cagccttggc acagtcacgg ccaccgctgt tacggctgca ttgccaggtg ggcagcatgg gcctagggca agagaagtca gagggaccga gacatttgca catgaactcc tatcatcaac gctcaccaag ctgagaaaag ttcccagcct atcgtcctcg tccccgtctg ctcgtggtca attggtgagt aatccagaaa atttcaccaa gagttatcat tgcggtccaa tcattctgct gccatgtgca caaagagacc tcttgtctcc ctatagaatc catccgggtt ggatgaagtt ggacagcata 120 180 240 300 360 380 <210> 364 <211> 351 <212> DNA <213> Mouse <400> 364 gcggcagaga acgagatgcc ggtggctgtg ggtccctacg ggcagtccca gcccagctgc ttcgaccgcg tgaagatggg ctttgtcatg ggttgcgccg tgggtatggc ggccggggcc ctgttcggca ccttctcctg tctcaggatc ggaatgcggg gtcgggagct gatgggcggc 120 180 WO 99/55865 WO 9955865PCT/NZ99/00051 attgggaaaa ccatgatgca gagtggcggt acctttggca ctttcatggc catcggaatg ggcatacgat gctaattagg gcacggatgc cctgctacac ccaaacttcc tcatccattt cgaaccttgt acaataaagt ttttttcttc ttgttaaaaa aaaaaaaaaa a 240 300 351 <210> 365 <211> 854 <212> DNA <213> Rat <400> 365 gcggtggctc cagccagtat gtggagtagg tctgtcacta tatgtgaagc gtagatgctt tcaaaccccg gcctcagcgg gaataaactg cctctggcct ctagcaaagc gcaaatgtca taaatgagtg aaggatcctt tgattcctga <210- <211- <212,ctctgtgtcc gcagccgccc gaccagccca cggaactaag tgtgtgtgag tccaggatac gccatgccag ccacatgctt ccagtacagt ccgcctgggt agtctgtcct cattggtttt cactctgaat caagtgcaaa acat cacgtcctga tggggcctgg cgggattatt acggcctgct cccagatgca accgggaaga cacagatgtg ctaccagacg tgtgaagaca ccaaatggaa tccaatagaa gaactgaaat acccgtacgt tgcaagcagg ggggctcagg cgctccctct ggttgccagc gctatggctg agtttggtga cctgcagtca tgaatacaca ccacatgttc cagcagaagg gagtgtgcct gatgtgtgaa atatcagtcg gcagccccca gatacagggg acaagaaagg gctgctcccc actggcacac gaaaaggaac gtgtgtggga agacgtgaat cggtagctac aaactccagg gccacgatgt agatatcgat cacatttgga ccgatatgat tgccaattgc gaatggactg agcccacccc tgggtggcag cagcctgggg agcaaaggag ccgaataaat gagtgtgcat aaatgctttt acatgtgcca gtgtgtccat gaatgtgctt agctactact tgtgtagata ctcaataccc cagtgttctg 120 180 240 300 360 420 480 540 600 660 720 780 840 854 <400> 366 ggcgcaccca tgtacttcag cgagggccga gagagaggca aggtgtatgt ctacaacctg agacagaacc ggtttgtttt taatggcact ctgaaggatt cccacagcta ccagaacgcc cggttcgggt catgcattgc ctccgttcaa gacctcaacc aagattccta caatgacgtg gtggtggggg cccctcagga ggacagccac agaggggcca tctacatctt ccatggcttc caaaccaaca tcctgaa <210> 367 <211> 475 <212> DNA <213> Rat <400> 367 cttccaaacc cggcttgcag tgtggac cta tcagatcaac caagcgcaat cctggcaccc gagacggtat tgtcctactc <210-, <211, <212-, <213-, aacatcctga cattttggct gcagtgggcg gccagcctcc ggcagggatg cacttccaca atgccacggg tcttctggtc agaagcccgt gcagcatcca ccctgggcaa actttgagcc ccacctgcct cagcaaccgt cacatctgga aggaacactg gcagagaata c gga caac tg cgctgtggtt ttccaagatc ggctgccttc cggcatcagg tgagggtgca tcaaaggatc tcagcctcag gacctcaatg ttgtgggcgc aacatcttcc ctctgcttcg tacaatgcaa gaccagttca aacttccacg agctggctcc aggacgggct gtcccgtagt acaaggactg gacctatctt ccatggatga ccaacagggc tcctg 120 180 240 300 360 420 475 368 392

DNA

Mouse <400> 368 gccgcggagc aggaagcgag cagccggcgg aggcgcggcg gcgccgggcc ggccttgttt tcctcaggct cgctccgctc tgagccgcag cctcgcttgc ctcaggctcg ctctcggccg WO 99/55865 WO 9955865PCT/NZ99/00051 cggccttctt tccttcaggc tcggtcgcgg ccttgcttgt cccaggcttg ctccccggcc gcctccgtcc tctcttcaag ctcgctctgc ggccgttccc acctccttcc aggctcgctc cccgccaccg cattcctcct cctcctccca ggctcgctcc cgggccgccg cccctcagcc gcccaggctg cgccggtgct cgcgtggggc cttgttgcgt ttcagctcgg ggtcgccgca ggggcggggc gctgagcggt ctgccgcggc ct <210> 369 <211> 824 <212> DNA <213> Rat <400> 369 cgggcactgt ctactttgag tgCccgctgc gcatcacctc cgaccagttc cctgggctgt ggtgggctcc cgagcagtgt ggaggacggc gacagaggac ggccacactt agctatgact gggtagataa ttatttctct gactgccaag gcagagcgca acaggacccg aagtgtgtag tgtgtgaaca atgggagcag aagtgcctag gaaaacacgg atctgtgtga gaaatggtgg gctgctaagg gggtactggt tccctgccac Ctcccgctgg ccggctatgg acagcagcca aggaatccca acatcgatga cggaagggtc ggccagggcc atgtggatga aaggtagcta aggagcagat tcctgcagca gggacttggt tgtcagagcg cacttacagg acacctggga gggcgaggcc tctggtatgt ctgtctgcag gtgtggcaca ctatgagtgc ctgcaaaaaa gtgtgagaca ccgctgtgtc cccagagtcg gatgttcttt gttcaccgcc cagtgaccgt atttcctccc cagcattgtt tgtggccagt tcggcgtgct tgcaggaaag gagcaagcta cgagattgtg tgcagccgtg gtggtgtgtc tgtgctgaag gcgggcttct ggtgtgatca atcttcattg gtgctggagg acccaggctg tctc gtggccttgg ttggtCcctg gctgggccct cctgtggagc caaaggcctg gctaccagca caggagagaa gcttcagaca tcgcggagat tctgtgcact gagctgtggc gcttcatcaa cccctagagg <210> 370 <211> 1663 <212> DNA <213> Mouse <400> 370 gcagcaccca ggcgtactgg cgggcggcat ccaccgcgcc ggcgctgtgc gatccgctac gaagatggtt gcaccctaag gcgcagggtc agagacttca aagacaaatt gctgtgtgtg caagtggctt aaa ataaggg gggaggaaca caaagcttcc tatgactggt gcaggtcctt ccccacccca cttaaaggag gtagaagatg ttcgggagga cctcttggca aaagtgcact gacgatcctg ccatgccaca aatgctgaga aagtaataaa gcgccaagcg agcgagccga cccccggccg cctccggcca gcCtcgcgcg agcgacgtga atcgtcacca ctgcagagca tacgaagaat gcagaggact atatattgct aaaggcttcc tttgctgggc gttttgtatt gtgagcatgg gctcagagag cagagtttca ctacatctgt cccccacccg ctgggtcttt cttctgaggc caagggaaga atgggagctc ccccctcagt cgccctgccc cactgcccct cccctgagtg atatatttga caccaggcac gcagagcaga ccgcacgcac gcatgaggct tggacgggtc agaagctgga ccaagagcat ccaaacgctt agggtggacg ttgcagatta atgaagctct agatgtgaga ggttggcggg tgtccatatg ttgagaccgt cctggcggct gtgtgactcc gcctagagga c accc cagc t ttcttgcaaa atccaaagtc tgcaggatta ccccccccca gaatacgcaa tctcctgtgt cattagaggc ctgcatgcag agttccccaa cgcgacagac gagaggcgtg aggccggcgc cctggcggcc caagtgtaag aatgaagcca gtccaggtac catcaagtgg atcatggaaa aaataaaagc tcttaccagg tccagctcgc 99gc9999g9 tcaccacaca tcacagcact ctgtgcagct actgtggccc actcagtcta cattcccctg ctgagggttt cccagcagtg gatgcaggac aagctttgtt acagcactgt acatattgcc cgcactgtat gtttcatgtt aaaaaaaaaa ggcaggagca cttgaaaccg cctccttgcc gcgctgctcc tgttcccgga aagtacccac cggggccagg tacaatgcct gaaaaactcc Cctttctttc gtcagttttt ctgcgcacca acctcaagcc tctgagcttt actgctccgc gccacaggct ctgttgcagg cttaccagaa t cacgaccag ctgaaaggtc tgagaaaatg acacagccag tctttccctc tctctgagtt ttcagtaccc ggctgtgtat ctttctaaga aaa cccatcgacg agaaccaagc tccctgctcc tgc tgc tcc t aggggcccaa actgcgagga agcactgcct ggaacgagaa aggccagttg tcacaagcat acattttata gacttcatta tttccttttt ataagcgcct tccaggctta ctcctgggct gcaattggga ggagcttcat gcaagtgatc ggctgctttg attctcgatg agctacacat accccaacag aggatgttag ctcccccacc ctgctatgta tgaaaagaga 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1663 WO 99/55865 <210> 371 <211> 568 <212> DNA <213> Human PCTNZ99OOO5 1 <400> 371 ccgtcagtct agaaggataa gttccaatat cagtctatct gtgactgtaa cacctccaat gctgacaaca tagaaggacc aacagttact gcatcaacgg aggtgtctaa aattgaaatc ggcctttgtg aagaattttc ttttcagatg aaacaacaaa gatcacaatg aaatgagaag ggagtgatgg aagccaagtg gagaaagaaa tttattcaac cacagcccag catagccttg tgcttgtgca gccttacaat atcaaggcat acttgtcaag ataaaattca aacaagcc gttaagcaac gcaatgacag caaggtaact aagttctcac ttccaccatg gtctgt.tctg ctgtagagat ctgactagac gcgttggcct tacaggaaat cactgaccga ggacagttaa acctttgcct agctagagaa gagaaagacg cagtgagccc tcgaaaataa ttagactttg ggctttggga agaggcagcc c aaaac agaa ggaagatcat agccatctgc accactgtga aaaattaaag tgaaagttgg ccatccttaa 120 180 240 300 360 420 480 540 568 <210> 372 <211> 5583 <212> DNA <213> Rat <400> 372 ctggtgcaga gcgtcgccaa gtgaagtgca tgtgtgtgtg ggggctgctg ctgtgccgca tcaccgctcg gcgcccccaa ccagtctctc cgagggctct cttcccactg gaatcggatt tcaagcaacc agcctctgca gttgaagtcg cgctctgtcc ctattgatat tcaggacctg agagcggagg aaagacgtgt tactgtgtga gcatctctcc tcggacaccg tccacttttc ttgggaagat gagtggcatt cgatcttgaa caaggtggcg cagtggactg tcatgggctg agagactgga tttgaatgga tcagacacct cagagttctt cattccagga tcttaaggag ttcctgagct gctgtttctt agattcaagc aattccaagg tggattacaa ccagatcagc aagtgctcac tctgaacaat tgcctaaact taggacattt cctggctctc ggactggctt gcccatccca cctgaggggc gtggtcacca gtcattcatg cctgtagcaa caacattgta tgcctgagac catcacagaa gagcattctc accatacaaa aacttgctcc agatgccttc ataaaatcac agaactccca tattgaatgc caacaagata tgaaccttct ctccttatac ctctcagagc catccaaact tcaagtggct agcggattat ccagtccccg ccgcctggct ggacgccggg caaaccatcc ggagtggaga ggctgcctga gctttggacc gccaccatta tgctagaggg tcttcgcgga tcacagctgc aagttgccca gcttctgtct gggtgctgtg acgcaaccga ggctggcaga cctcatgcgt gcactgcgca aataacatca cagctcatgg ctagaaagac gggactgcga aaggctttcc tgcattgaag aacaatatta cgactccact cgccaaaggc cataatgtag gctccctcct gactgccgag atacgtttgg aagcttcgac caaggactgc aaaagtttat aactgccttc gacaataagc atgcatttgg ctccacacca aacaaaagaa agggaggcgg ttggctgtcg gaccccgtga atacccggtg tgccaggccc ctgttaaagc tgccgtggaa cactgcaagt ttcggggtct cggatcttgt gctctcctgc ggctgcaaga aagctaaagt cactgtccct gcccggccca gtgtgcccag caaggatcac agaacaagat tgcgtttaaa agctctaccg gtggtgcagt atggggcatt ctagactttc ccaacaacct o acgggtggg cagaggttca gcagtgtgct ggaaaggtct aacagaactc gactagacct gttctctgaa ttgaaggact gggtagatgc ttcagactgt cccagaatcc acccaattga ttggacagat gattgccaag cgaagcagag gctgagccct cgccccggcg t tgcgccttc cccctcctca tcggaagtcc aggagctctt accccaagcc gctctgctag cccatatcac ccagcgccag ccctcaaagc atctctggcg gtgctcctgt gaatatcccc gaagacagat cagcaccatc cagaaataac gcttgatctc tgacattaaa ccgagctctg agtggcaagt atactgcgac cttgtacact aaaacgagag gcactgcccg cactgagatc cataagggtc gagtaataac ttcccttgtc gttttcctta ttttcaggac tgccaagggc tttcatttgt gaccagcggt caaaagcaag atatcctcca aagacggctt gcgccccgca cgcgacatga tagcttcggg gccttgtact tcccttgtcc ttaccaccaa tgagtcgggc aaaggcttgg tgttccatat gaactgggcc aaggggtctg ttagtgttgt tcaggcagca cgcaacacgg tttgcgggtc gagaggggag cttcagttgt agtgaaaatc aatctgcagt cgagatctgg ttcaaccata tgccacctgg cagtgtatgg tttgtctgca attgcttgta cccacaaatc atccctccag cagatctcgg ctgtatggaa cagctactat ctgcacaact accttctcag gactgccatc gcccgttgca aaattccgtt 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 WO 99/55865 WO 9955865PCT/NZ99/00051 gttcagctaa gagactgctt actgctccaa tgcgtctcaa ctcaattgcg tcgaaggtgc agcataagat taagctgtgt atgacaatca cactaaacct ggctcagaag aggaaatacc ataatagctg tacgatgtag aactgtatct atttaacact gcaacatgac cacggacctt ctgtcgtgcc ccaaccctct ataaggaacc tcacaactcc agtgtaaccc tggatt t tta ttcatgcctg agaatgatgg atattgatga acaactacac acttctgtgc aggg-,attc aa atgactgcca acacatgtgt tcctccttcg tcagggtgaa aattggtcag ttcgacctca tgtacaaggg gctatgacac gaaacttcca gagga agc cc cactttacgt ggcagaacgg aggacttccg agaaagtgtg gtgaggaagg acaaatgtgt tggagggcca tgatcaagtg gcagcagtgg taagggatta ctcgcttgga agaggcggaa aggtggtgaa ctttggcgaa atatttgaaa tgtctgcatt aaa agagcagtat tgcagacttg tcaaaaactc taataatgaa taaaatcaac gtctggtgtg gttcaaagga gggaaacgac aattaccaca cttggccaat gaaaagaatt aatccaggat ctctccactc c aa caaggg c ggatgggaac tatagactta ccaacttctc tgatggattg tgaaggtgcc ttactgtgat tggaattgcc ctccaaaaaa ctgcttgtca tcgatgcacc tatcagtaat attctggtgt t tgcgaagat gtgtctttgc acaagacctg g t I..a u.

agataacaag ctgtcctgaa caccagcccc tgaaccaata tgtgaatttt gacaaacatc tgacaaggac cggctctcac cattgtagag taaaatcatc aggaggtatg caccagcttc gaaagtgcct tgcccatggc gtggatgggg acatgggacc cggcggggt c caagcacggg attcaccggg ttaccaaaag gtgcagaggc atactctttc gtgcggctgc ggttgtacac tatattgtaa tggaaaaaaa ttcattccag gcttgtCCtg aacaaaatcc ttcacagtgt cttagcaaca aatgagattc ttggagagcc agtttcacag gttgcaccag cctttcaact gtaacaggaa gtagccattc tcccgttgtc ttgaaggtct cagtttacac agtaacaaca accttaattc aaatctcttc tttggtgacc tgtaacatgc cgctgtgccg tttacatgtc aatccatgta tgcccatatg ccatgtaaac acttgtgctg aatgattgtg ccaccggaat aatccctgcc actccgggat tgcaaaaacg ggctacagtg tgtgataatt tgccagtgtt gtaaacaaag acacttcaga cacattgctg ccggcttctg ctactgaccc accaatttgt cctgggaaaa catggctgta atgcaaaccg acatgccagc cccctctgtg tgcttgccca ctctgtgatg aagtgcaggc gacagctgtg cagcagggtt gggtgtgCtg gaatgcacag acgagatgtg ttcttgacca aatacagaac ataaaataaa gtzacagaaga aaaaatgtcg cagaccatat tagaagccac ataagatcac tgcttaccag tcaaaacatt gactcggttc gagc at ttgg gtaactgtca atcctcgatg aggacttcac cttcggaatg tacctaaagg tggtcccgaa gaataagcac tcagttacaa gtttactgtc tt t cagcct t agtggttatc gtcccggaga aaggtcctgt aaaatgatgg gtttcaaggg atggaggaac atgggtttga aaaataattc acacaggcga agcatgactc acaLtggtga gtgctcattg gcttgttctg ttgattgtca tgc ctggc ta agtcctatct ttgccacaga tggaactcta ccatttacag tggattcgag caaaacaatc ataacgtggc tccggaacct gaattctgcc ccagcagcca accagagaac tcaacgcctt aagaagaaga tctctgggct acagagaaat acgctgcctg gggggcagtg atggatcttc cctcctaagt tgttggacta agacttattt agacacgctt ttatcgatca ctgtgaaggg tccccagtac gggaatattt tgatatcgag taaccgtttg gatgctgaga tgtgcgtctg tactctccat cctggcatgg ccaaaaaccc ctgtgatgac tacttgcttg cat tcc aaga ggaactctcc cctttccaac ccgtctgaga tctacatgga gtcacactta cgactgggtg aatggcagat ggatgttact cacctgtaac ccaggactgt ttgccattta aggagaaagc tacatgcgtt actgtgtgag caagtgcatc geactgtgac cacagatgca tgagttttct gaatggagcc cttgggagag tcagattcct tgaagacagc tcgagggcga tgtggagaca tctttccctc tactctgaat ttcgctgcgc ttacattaac tggctgtgaa atcaggcttc caatgatccc ctcctacagc tctgtttaac cgggcagccc ttcttgtcga tcaaacgact ctgtggacct atttgtggac gcagctcgag attcatgctt ttattatgat gtactaaaaa aaattaagtg accacagtag acagcagagc aagaaacttc gagggggcat gaaaatgttc agtaatcgaa ctctctttat tcattatcta cttggagaat tacttcttga ggaaacgatg gatacagtag gatgtcacag aactacaaac caaagcttca tgtatccctc aatgacattt gcaattggag aagtcggaat aaattgttac attcaagcca aatgacccgg gatgtcccca aaagaaggag tgtgacatca gatggaatta gaaaaactgg ctgacgccaa atcgactttg gtgaacggaz ccacccatgg cagtgtatca aagtgtgaga tcagccaagg ggcatcctct gt tcgagc ca atcaatgatg tctgtggatg ttcgactctc caggcccctg agtgaactgc ccatgccaca acctgtgaat tgtctcggaa tgcaagtgcc ccctgccagg tatlzgtgaat ggggaacgga aagaaagtat ctgagaagca gaggtcgaga aagcttctgt cataatggaa aataaagact aaaaaaaaaa 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5583 <210> 373 WO 99/55865 <211> 83 PCT/NZ99/00051 Met Al a Giu Leu Gin Met Met Arg Thr Ala Gly Leu Ser Giu Glu Arg 145 Ser Ile Leu Gin Ala 225 Cys Leu Cys Cys <212> <213> <400> Pro Leu Pro Ala Gly Cys Ala Leu Tyr Gin Leu Val <210> <211> <212> <213> <400> Pro Pro Val Ser Met Gly Val Asp Ser Phe Asp Ile Thr Pro Val Lys 115 Thr Gly 130 Asn Gly Gin Gly Val Val Thr Leu 195 Val Glu 210 Leu Cys Glu Arg Cys Trp, Pro Phe 275 Tyr Arg

PRT

Mouse 373 Pro Leu Arg Ala Arg Al a His Pro Ala Gly Leu Leu Ala Ala Leu 10 Cys Gin Leu Pro Ser 25 Giu Leu Ala Giu Thr 40 Giu Val Pro Gly Leu 55 Giu Gly Gly Leu Phe 70 Cys Leu Ala Ala Ser Pro Giu Trp Arg Pro Leu Ser Ile Val Tyr Ala Lys Val Tyr Asn Tyr Leu Pro Trp Tyr Ser Ala Giu Vai Glu 75 374 405

PRT

Mouse 374 Leu L( Pro TI Lys I' Ile L( Glu A] Ser Pi 8! His L( 100 Glu S( Leu A:' Ser V Pro V4

DE

Phe A: 180 Ala SE Asp A: Thr T1 Arg TI 24 Arg G.

260 Tyr S( Thr I.' Leu Ile Ala Phe Ser 70 Gly Glu Ile Leu Pro 150 Al a Val1 Glu Thr Al a 230 Leu Ser Trp Cys Leu Ser Val1 Leu Lys Arg Phe Lys Lys 135 Gin Leu Giy Pro Asn 215 Asp Giu Arg Lys Pro Pro Leu Ala 40 Leu Arg Val1 Pro Gly 120 Arg Ile Pro Vai Lys 200 Gly Pro Thr Gin Arg 280 Gly Ile Glu Lys Gly Ala Val1 Asp Val Ser Ile Lys 170 Phe Arg Leu Cys Arg 250 Asp Phe Cys Tyr Val1 Leu Ser Ile Gly Ser Phe Arg Ile 155 Gin Pro His Ser Arg 235 Giu Thr Gin Asp Leu Val Trp Ser Ala Leu Ser Gly 125 Phe Thr Arg Trp Leu 205 Leu Giu Ala Leu His 285 Gin Leu Asn Cys Ile Cys Gin Thr 110 Gly Pro Asp Giu Asp 190 Leu Ser Pro Gly Ala 270 Pro Pro Asn 305 Cys Leu Thr Val1 Ser 385 Ala Met 1 Met Trp Thr Asp Pro Gly Leu Leu Cys 145 Asn Thr WO 99/55865 290 Gly Gly Thr Pro Leu Ala Glu Cys Arg 340 Thr Leu Gly 355 Gin Ala Val 370 Tyr Gly Arg Leu Cys Arg Gi Va Le Ii Gi Se As Gi Gl 13 Le As Le PCT/NZ99/00051 <210> 375 <211> 180 <212> PRT <213> Mouse <400> 375 u Leu Ser A 1 Val Ala G u Ser Thr T e Val Ser A n Leu Val A r Gly Gly A 8 p Ala Thr G 100 u His Leu L 115 y Ser Ser A 0 u Ser Pro S p Thr Glu G u Lys Arg 180 <210> 376 <211> 68 <212> PRT Ile 310 Gly Asp Phe Arg Leu 390 Val1 Val Val1 Gly Gin 70 Asp Glu Asp Pro Pro 150 Leu 295 Pro Gly Val Arg Glu 375 Met Thr Val1 Ala Asp 55 Gly Asp Pro Ile Glu 135 Ser Ala Glu Glu Leu Arg 360 Asp Val1 Leu Al a Asp 40 Thr Thr Lys Gly Gin 120 Ala Leu Val sp 5 ly yr la sn sn 5 ly eu rg er lu Gly Val Val Asn 330 Phe Leu 345 Ala Lys Ser Arg Ala Val Ile Glu 10 Leu Thr 25 Ser Gly Ser Val Pro Glu Ala Glu 90 Ala Arg 105 Gly Leu Pro Leu Ile Asn Ala Arg 170 300 Asp Arg 315 Cys Ala Leu Asp Ala Phe Ala Arg 380 Pro Cys 395 Gly Val Leu Ala Asn Asn Leu His Pro Thr 75 Giu Thr Gly Glu Pro Lys Gly Leu 140 Val Arg 155 Pro Glu Tyr Pro Ser Val1 365 Val1 Arg Gly Leu Gin Leu Glu Ser Met Arg 125 Asp Leu Asp His Cys Lys Leu 335 Ser Ala 350 Lys Arg Gly Ile Gly Val Asn Glu Val Leu Leu Leu Gly His His Pro Asp Ser Glu Pro 110 Gin Ala Asp Gly Lys Phe Thr Val 175 Leu 320 Ser Gly Phe Al a Pro 400 Val Al a Gly Val His Gly Ser Gly Ser Leu 160 Gly Met 1 His Trp Ser <213> <400> Cys Leu Leu Pro His Cys Asp Pro Mouse 376 Pro Val Thr Val Trp Cys His 5 10 Leu Ile Pro Ser Val Gly Lys 25 Cys Met Pro Trp Val Cys Val 40 Leu Trp Leu Cys Leu Leu Lys 55 Trp Ala Leu Trp Val Ala Ser Gin Cys Thr Gin Met Gly Asp Cys Leu Cys Leu Glu Thr Glu Thr Pro Cys WO 99/55865 GlY Phe Leu Ser PCT/NZ99/00051 Met Pro Al a Ser Cys Ala Val1 Met Ser Glu Ser Gly Ala Met 1l Ala Gln Arg Ser <210> ':211> ':212> ':213> <400> Pro Phe Leu His His Tyr Tyr Leu Asp Gly Leu Asp Val Glu ':210> <211> <212> <213> <400> Trp Phe Gln Ala Gly Leu Glu Val Ser Leu His Thr <210> <211> <212> <213> <400> Asp Leu Ile Pro Leu Ile Val Arg Giy Arg Ala His 377 107

PRT

Rat 377 Arg His Arg Giu His Thr Val1 100 378

PRT

Rat 378 Leu Ser Cys Ser Ser Ser Leu Gly Giu Asn Asp Leu Leu Pro Pro Arg Arg Gly Met Ile Pro Val Phe 55 Trp Ile Asp Ser Trp Trp Ser 55 Val Arg Asn Phe Tyr His 55 Lys Trp Pro Gly Lys 40 Pro Gly Leu Lys Val1 Pro Thr 40 Arg Asp Thr Met Val1 Trp 40 Glu Pro Leu Leu Pro 25 Al a Tyr Ser Gly Arg 105 Pro Tyr 25 Al a Lys Phe Leu Phe Al a 25 Tyr Asp Ser Ser Gly Leu 10 Glu Gly Met Phe Asp Glu Phe Ser 75 Asn Thr 90 Gly Leu 379 138

PRT

Mouse 379 Asp Val Ile Leu 20 Arg Ile Tyr Ala Pro Gly Lys Asp Val1 Ile Cys Asp Arg 75 Leu Ile Phe Arg Gin Leu 75 Val Val Thr Tyr Leu Leu Ser Ile Ile His Pro Val Leu Ala Leu Arg Phe Met Lys Cys Ala His Arg Thr Glu Ser Ser Ser Arg Cys Ser Gly Leu Thr Cys Leu Phe Val Pro Al a Pro Leu Phe Ser Gly Arg Ile Pro Cys Gly Trp Leu Tyr His Leu Leu Asp Tyr Leu Ile Gin Cys Gly Gly Pro Pro Cys Thr Pro Gly Ser Gly Pro Leu Pro Asp Thr Asp Arg His Gin Glu Gin Cys Leu Ser Met Phe Phe Lys WO 99/55865 WO 9955865PCT/NZ99/00051 Asn Leu His Arg Ser Ser 115 His Gin Phe 130 <210> <211> <212> <213> <400> Met Ala Ser 1 Met Ala Tyr Arg Gin Ile Pro Val Gly Arg Leu Ser Asp <210> <211> <212> <2i3> <400> Met Arg Ser 1 Thr Val Gly Gly Gly Val Val Leu Lys Ile Asn Thr Leu Leu Gly Cys Asp Giy Gly Arg Pro 115 Ala Gly Phe 130 Cys Giu Leu 145 Met Tyr Arg Arg Pro Gin Val Cys Arg 195 Leu Cys Gly 210 Leu Val 100 Leu Asp Vai Glu 380 81

PRT

Rat 380 Ser Ser 5 Gly Ser Met Arg His Asn Arg Val 381 257

PRT

Mouse 381 Gly Ala 5 Ser Val Cys Trp Thr Arg Ala Trp Phe Leu Val Giu 100 Thr Leu Gin Val Arg Thr Gly Arg 165 Ser Cys 180 Ala Ala Asn Asn Cys Val Asp Met Pro Gly His Glu Gly Thr Thr 105 110 Asp Leu Ser Ile Val Gly Gin Val Lys Arg Ile 120 125 Cys Leu Lys Leu Asn 135 Asn Trp Leu Ser Gly 10 Leu Val Phe Val Leu 25 Phe Ala Met Lys Ser 40 Ala Pro Lys Asp Leu 55 Gin Asp Ile Lys Tyr 70 Val Asn Val Val Leu 1s Leu Phe Ile Phe Val Arg Arg Gly Pro His Lys Glu Glu Ile Asp Glu Pro Gin Leu Leu 75 Leu Trp Gly Ala Leu Gin Val Ser 55 Ser Asn 70 Gly Leu Cys Gly Arg Ser Cys Gly 135 Ala Arg 150 Cys Gin Leu Val Pro Cys Asn Val 215 Pro Val1 Gin 40 Arg Phe Val Pro Cys 120 Ser Cys Lys Asp Pro 200 Thr Leu Met 25 Gly Giu Thr His Gly 105 Val Asp Arg Ser Gin 185 Val Tyr Leu Gly Arg Giu His Cys 90 Lys Pro Gly Gly Cys 170 Thr Pro Ile Trp Ser Giu Cys Pro 75 Leu Ala Asn Ala His 155 Al a Gly Ser Ser Gly Gly Glu Ala Cys Gly Pro Cys Cys Thr 140 Pro Gln Ser Asn Ser 220 Val1 Al a Asp Thr Ala Asn Cys Arg Glu 125 Tyr Asp Val1 Al a Pro 205 Cys Arg Leu Ser Cys Ser Lys Lys Met 110 Gly Arg Leu Val His 190 Gly His His Val1 Val1 Ser Gly Ile Asp Leu Leu Asp Arg Cys 175 Cys Gin Leu Pro Val Lys Val Ile Ala Trp Pro Leu Asn Ser Ser Gly Pro Glu Val1 160 Pro Val1 Giu Arg Giy Gin Ala Thr Cys Phe Leu Gly Arg Ser Ile 225 Ile Val1 WO 99/55865 Cys Thr Gly PCT/NZ99/00051 230 235 240 Gly Pro Lys Val Pro Ala Giu Glu Giu Glu Asn Phe 245 250 255 Met Pro Gin Gly Lys Glu Gly Val Lys Ser 145 Pro Gly Gly Ala Ala 225 Leu Asn Phe Met 1 Pro Cys <210> <211> <212> <213> <400> Ile Ser Met Leu Leu Val Ala Pro Asp Gly Gly Pro Lys Ala Ser Gly 115 Gly Lys 130 Ser Arg Arg Giu Gly His Ile Tyr 195 Ile Gly 210 Asn Thr Lys Giu Gly Leu Leu Ile 275 <210> <211> <212> <213> <400> Lys Leu Ala Gin Pro Pro Met Ala Ser Ser Asp Gly Ala Pro Gly Lys Leu 165 Asn Phe Val1 Asn Asp 245 Tyr Ala Cys 5 Asn Arg Leu Leu Aia Phe Ala Arg Leu Pro Gly 40 Ser Gly Met 55 Gly Gin Asp 70 Arg Thr Gly Ile Gly Arg Gly Lys His 120 Giu Pro Gly Ser Ala Phe 150 Pro Ile Lys Ala Ser Ser Thr Tyr Asp 200 His Asn Gly 215 His Asp Vai 230 Glu Val Trp Asp Pro Tyr Asp Gin Giy 280 Cys Arg Pro Val Giy Asn Al a 105 Gly Leu Ser Phe Gly 185 Ile Gin Ala Leu Trp 265 Ala 10 Asp Gin Gly Asp Arg 90 Gly Ile Pro Val Asp 170 Lys Thr Tyr Ser Gin 250 Thr Pro Gin Pro Met Gly Lys Arg Gly Pro 14 0 Val Ile Val1 Ala Ile 220 Ser Phe Ser Cys Lys Pro Gly Asp Gin Gly Lys 125 Cys Thr Leu Cys As n 205 Arg Thr Tyr Leu Val 285 Leu Cys As n Ala Gly Pro Pro Gly Pro Lys Gly Cys Ser Asn 175 Val1 His Phe Leu Glu 255 Thr Asp Pro Pro Gly Giu Lys Gly Pro Gly Tyr 160 Glu Pro Leu Asp Al a 240 Gln Gly Asp Pro Asn Giu Leu Val Ala Val Val Gly Cys 10 Lys Ser Ser Giu Asp Ile Arg Asn Ile Ser Gly His Ile Tyr 40 Leu Val Pro Lys Cys Ile Gin Asn Val WO 99/55865 PCT/NZ99/00051 Ser Pro Glu Ser Asp Glu Ile 145 Gin Asp Cys 1 Ala Val Arg Pro Asn Gin Ile Ala Pro 145 Tyr Lys Phe Arg Asp 225 Gin Ser Asp Gin Gly Glu Val Pro Glu 130 Gly Gin Arg Lys His Arg Val Leu 115 Glu Gly Arg His <210> <211> <212> <213> <400> Gin Leu Leu Pro Ser Ser Ser Leu Asp Glu Arg Ile Val Val Cys Leu 115 Gly Arg 130 Ser Phe Asp Gly Arg Trp Arg Ile 195 Glu Asp 210 Ser His Leu Pro Ser Ser Thr Leu 275 Asp Cys Asp Val Ser Thr Gly Ala 100 Ile Arg Asn Glu Pro Arg Trp Lys 165 Lys Met 180 384 292

PRT

Mouse 384 Pro Leu 5 Pro Asp Asn Glu Arg Asp Leu Gly Ser Arg Leu Leu 100 Lys Gly Arg Gly Ser Pro Gly Leu 165 Ser Gly 180 Ser Glu Gly Ala Val Pro Ser Glu 245 Arg Arg 260 Gin Leu Asn Glu 70 Thr Leu Lys Asp Ala 150 Leu Leu Arg Ile Leu Leu Asp 70 Ile Asp Lys Ala Cys 150 Asp Asn Leu Gly Gly 230 Leu Glu Trp Cys 55 Ala Thr Leu Pro Ala 135 Asn Gin Ser Val Ser Gin Asn 55 Leu Pro Ser Leu Ala 135 Pro Ser Glu Ala Asp 215 Glu Ser Glu Gin Leu Tyr Ile Leu Asp 120 Arg Thr Val Leu Thr Ser 40 Val Pro Val Asn His 120 Leu Ala Gly Ser Arg 200 Gly Asp Leu Pro Glu 280 His Cys Lys Tyr 105 Ala Ser Val Gin Ile Leu 25 Leu Arg Leu Ser Pro 105 Ile Gly Glu Phe Thr 185 Asp Asp Glu Val Ala 265 Arg Val Leu Val 90 Met Tyr Met Leu Glu 170 Ile 10 Gly Pro Arg Val Phe 90 Leu Phe Asp Asp His 170 Asp Pro Leu Asp Ala 250 Gly Glu Val Leu 75 Ile Ala Thr Ala Glu 155 Gin Ser Ser Val Asn Arg 75 Cys Gin Lys Leu Leu 155 Ser Asp Arg Glu Arg 235 Gly Glu Arg Glu Cys Ile Phe Glu Ala 140 Arg Arg Asn Leu Glu Gin Leu Arg Ser Tyr Val 140 Phe Val Phe Gly Gin 220 Ser Asp Glu Lys Pro Glu Val Leu Gin 125 Ala Val Lys Asn Arg Leu Leu Asp Leu Pro Leu 125 Pro Pro Asp Ser Pro 205 Ile Ala Val Arg Gin 285 Met Cys Ile Met 110 Leu Ala Glu Thr Lys Gin Cys Ser Phe Arg Pro 110 Thr Ser Gly Ser Glu 190 Arg Asp Ala Glu Arg 270 Gin Pro Arg Tyr Leu His Ala Gly Val 175 Leu Leu ser Thr Ser His Ala Met Arg Arg Gly 175 Leu Gin Phe Glu Lys 255 Arg Gin Val Tyr Leu Val Asn Ser Ala 160 Phe Gly Asp Leu Leu Cys Leu Gin Glu Pro Arg 160 Ser Ser Pro Ile Glu 240 Pro Pro Gin WO 99/55865 Ser Gly Gly Trp, 290 PCT/NZ99/00051 <210> <211> <212> <213> 385 164

PRT

Mouse Ser 1 Ala Ala Glu Ala Thr Ser Asp Leu Giu 145 Glu Ser 1 Pro Phe Pro Val Giu 1 Asn Ala <400> Arg Gin Giu Gly Ala Arg Val Pro Asn Gin Asp Leu Asp Asp Asn Gin 115 Gin Lys 130 Ile Thr Leii Thr <210> <211> <212> <213> <400> Leu Ser Ser Thr Ser Leu Asp Lys Gin Ser <210> <211> <212> <213> 385 Leu Lys Ser Gin Asn Thr Leu 100 Leu Leu Ser C'v q Ala Arg Gly Val Ser 70 Leu Leu Ser Val Lys 150 Pro Gly Gin Trp Phe Ile Leu Leu Ser 135 Asn Arg Pro Leu Arg Ser Ile Pro Pro 120 His Leu Phe Ser 25 Asn Ile Ser Ser Ala 105 Ser Asn Arg Asp 10 Val1 Leu As n Thr Ser Leu Al a Lys Thr Pro Pro Al a Vai Giu 75 As n Thr Ile Leu Leu 155 Gly Leu Asn Pro Trp Gin Asp 110 Leu Leu Gin Phe Leu Leu Giu Asp Ser Ile Asp Pro His His Lys Gly Giu Gin Leu His Asn Giu Asn 160 386 71

PRT

Mouse 386 Ile Leu Pro Ala Vai Arg Val Ser Pro Arg Pro Thr Tyr 5 10 Ala Ser Ser Met Ala Ala Phe Leu Val Thr Giy Phe Phe 25 Phe Vai Val Leu Gly Met Glu Pro Arg Ala Leu Phe Arg 40 Ala Leu Pro Leu Ser Cys Ala Lys Pro Thr Ser Leu Cys 55 Ser Phe Leu Gly 387 126

PRT

Mouse <400> 387 Tyr Glu Ala Arg Val Leu Glu Lys Ser Leu Arg Lys Giu Ser Arg 5 10 Lys Giu Thr Asp Lys Val Lys Leu Thr Trp Arg Asp Arg Phe Pro 25 Tyr Phe Thr Asn Leu Val Ser Ile Ile Phe Met Ile Ala Val Thr 40 WO 99/55865 WO 9955865PCT/NZ99/00051 Phe Al a Thr Leu Giu Al a Gin Ala Arg Met Gly Gly Ser Leu Tyr Thr Cys Pro Gin Cys Met 145 Ile Val1 Leu Ala Ile Leu Ala Val Thr Asp Giu Cys His 115 <210> <211> <212> <213> <400> Ala Glu Pro Ser Val Gly Ile Gly Met Gin Ile Arg <210> <211> <212> <213> <400> Gly Ser Pro Pro Leu Leu Trp Leu Lys Thr Giu Ala Asn Lys Asp Val 115 Val Asn 130 Leu Leu Asn Cys Cys Pro Asp Ile Val1 Met Ala Val 100 Val 388 84

PRT

Rat 388 Asn Cys Met Met Ser Cys 389 284

PRT

Rat 389 Ser Pro Pro Pro Al a Vali Cys 100 Asn Thr Pro Gin Ser 180 Asp Leu Gly Vai 55 Asn Ser Ser 70 Thr Ala Val Tyr Giy Cys Gin Asp Ser Ile Ile Tyr Arg Ile Pro Ser Val Arg Ser 75 Ile Ile Asn Leu Vai 90 Ile Ala Arg Trp Leu 105 Ile Giy Ser Met Gly 120 Ser As n Val1 Thr Leu 125 Thr Ala Ala Ile Arg Val Ile Ile Leu Lys Ile Gly 110 Gly Glu Met Pro Val Aia Val Gly Pro Tyr Gly Gin 10 1s Phe Asp Arg Val Lys Met Gly Phe Val Met Gly 25 Aia Aia Gly Ala Leu Phe Gly Thr Phe Ser Cys 40 Arg Gly Arg Giu Leu Met Gly Gly Ile Gly Lys 55 Gly Gly Thr Phe Gly Thr Phe Met Ala Ile Gly 70 7S Vai Ala Trp Al a Cys Cys Arg Giu His Asp Tyr 165 Ser Glu Ser Ser Val1 Leu Cys 70 Giu Cys Cys Gly Aia 150 Ser Gly Cys Arg 10 Pro Val1 Pro Lys Lys 90 Tyr Pro Cys Asn Thr 170 Gly Lys Gly Trp Gly Gly Arg 75 Phe Thr Arg Phe Ser 155 Al a Pro Ala S er Gly Thr Val1 As n Gly Gly Pro Cys 140 Arg Glu Asn Val1 Gly Leu Ser Cys Ser Glu Lys Cys 125 Leu Thr Gly Gly Cys Gin Al a Pro His Lys Cys Thr 110 Gin Ser Cys Pro Arg 190 Pro Giu Leu Arg Tyr Giy Val1 Cys His Gly Ala Arg 175 Val1 Ser Ser Cys Leu Thr Met Arg Pro Asp Gly Val Gly Ser Arg His Arg 160 Cys Cys Asn WO 99/55865 WO 9955865PCT/NZ99/00051 Arg Gly 225 Asn Leu Gly Giy Val Asp Val Pro Gin Phe Glu Leu.

Gly Ser Lys Giy Arg Leu Ser 2.45 195 Arg Cys 210 Phe Giu Gilu Cys Asn Thr Asn Gly 275 <22.0> <2112> <22.2> <213> <400> Ala Pro Tyr Asn Ser His Gin Asp Gin Giu Thr Asn <210> <212.> <212> <213> <400> Gin Thr Leu Ala Asp Leu Asn Ala Leu His Arg Asn Pro Ile Tyr Asn 115 Asp Giu 130 Gly Gin Asn Thr Phe 215 Lys Tyr Ile 230 Leu Asn Thr 245 Gly Ser Phe Gin Cys Ser 200 Giy Ser Tyr Tyr Cys 220 Ser Arg Arg Tyr Asp 235 Arg Thr Cys Ser Pro 250 Lys Cys Lys Cys Lys 265 Val Ile Pro Giu His 280 205 Lys Cys His Ile Cys Vai Asp Ile 240 His Ala Asn Cys 255 Gin Giy Tyr Arg 270 Phe Ser Glu Gly Arg Gin Asn Arg Phe Vai Gin Asn Ala Arg Phe 40 Gin Asp Ser Tyr Asn 55 His Arg Gly Ala Ile 70 Giu Arg Gly Lys Val Phe Asn Gly Thr Leu Gly Ser Cys Ile Ala Asp Vai Val Vai Giy Tyr Ile Phe His Gly 391 Asn Pro Asn Val Phe Gly Phe 100 Ala Gly Glu Lys His Leu Ala Lys Thr His Glu 120 Phe Arg Pro Phe Val Arg Ile Cys Phe 105 Arg Thr Ile Gin Cys Leu Val Ile Ala Thr Tyr Arg Phe 155 Arg Ser Al a Val1 Phe Ala Ala Met Ala 2.40 His <210> 392 <2112> 124 <212> PRT WO 99/55865 <213> Mouse PCT/NZ99/00051 Ala Pro Leu Ser Ser Pro Arg Ala Gly 1y Cys Ser Cys Asp Al a Lys Asp Asn 145 Glu Phe Phe Leu Tyr 225 Gly <400> Ala Glu Ala Leu Pro Gin Arg Pro Ser Ser Ala Thr Pro Ser Phe Gin 115 <210> <211> <212> <213> <400> His Cys Gly Leu Ser Ala His Cys Val Asp Gln Phe Lys Ala Cys Ser 115 Glu Cys 130 Thr Glu Asp Gly Ala Glu Gly Val 195 Val Phe 210 392 Gin Phe Ala Cys Ser Ala Ala 100 Leu 393 242

PRT

Rat 393 Asp Gly Cys Leu Ile Cys Cys 100 Arg Glu Gly Ile Met 180 Ile Thr Glu Ser Arg Leu Leu Phe Ala Gly Cys 5 Tyr Phe Gin Asp Val1 Leu Gly Thr Ser Cys 165 Thr Ile Al a Val Ala Ala 120 Arg Leu Arg Cys Ser Leu Pro 105 Gly Tyr Glu Ala Gly Thr Gly Gly 105 Val Pro Val Gin Met 185 Ala Gly Arg Arg Pro Ser His Pro Val1 Ala Gly Arg Arg Trp Glu Se r Ala Gly Gly Cys Ile 170 Val Thr Ala Gly Pro Leu Al a Pro Leu Trp Al a Ser Gly His Thr Cys Gly Cys 125 Giu Gly Ser Gin Al a 205 Al a Gly Arg Arg Leu Leu Arg Vai Gin Val Giu Lys Ala Cys Lys Val Glu Gin 160 Phe Phe Asp Gly Trp Leu Ser Giu Arg Ser Asp Arg Val Leu Glu Gly Phe Ile Lys 230 21S 3 Arg <210> 394 <211> 99 Met 1 Ala Lys Pro Arg Lys Tyr Met 1 Thr Glu Asn Lys Ser Met 1 Leu Ser Val Asn Leu Gly Asn WO 99/55865 <212> PRT <213> Mouse <400> 394 Arg Leu Leu A Ser Arg Val As Ile Arg Tyr St His Cys Glu G Tyr Arg Gly G Arg Phe Ile L~ 81 Glu Glu PCT/NZ99/00051 <210> <211> <212> <213> <400> Ala Leu Ala Leu Gly Pro Ser Tyr Ala Ile Gly Glu <210> <211> <212> <213> <400> Ser Gly Ser Ile Cys Ser Pro Arg Asn Ile Arg Val Ala Phe Asn Leu 395 103

PRT

Human 395 Gly Vi Thr G siy AAc Ile A Cys I1 Cys Ai 8! Arg A 100 396 1529

PRT

Rat 396 Ile G: Leu A.

Gly S( Asn I' Thr A Leu G' 8! Gin At 100 Gin L( La rr Lu Ln Is Lu nn La Le :-g .g Ala Ser Val Met 55 His Tyr Ile Ala 1.hl Lys 55 Gly Leu Leu Gin Va1 Va1 Arg 55 Thr Met Lys Pro Leu Lys Lys 40 Val Cys Asn Ser Ala Val 40 Phe Ala Lys Thr Ala Asp 40 Asn Lys Glu Glu Glu Leu Cys 25 Lys Ile Leu Ala Vai Va1 25 Asn Ser Cys Leu Leu Pro 25 Cys Thr Thr Asn Leu 105 Leu Leu 10 Lys Leu Va1 His Trp 90 Tyr 10 Thr Lys His Ala Lys 90 Ser 10 His His Glu Asp Lys 90 Glu Leu Leu Cys Glu Thr Pro 75 Asn Leu Va1 Thr Leu Phe 75 Ser Leu Ala Gly Arg Phe 75 Ile Arg Phe Leu Ser Met Thr Lys Glu Leu Thr Glu Cys His Pro Ser Cys Leu Leu Ala Ser Leu Leu Leu Arg Lys Lys Leu Lys Phe Pro Ala Leu His Tyr Leu Pro Ala Asp Gly Thr Arg Gly- Ala Lys Pro Ser Gin Arg Asn Pro Asp Glu Glu Asn Ala Ala Leu Leu Leu Ile Leu 110 Thr Leu Gly Lys Met Ser Arg Ala Ile Asn Asp Leu Val Leu Gin Arg Asn Arg Glu Asn Ala Cys Pro Tyr Ser Thr Val Met Thr Ile His Glu Cys Val Cys Ser Gly His Arg Arg Lys WO 99/55865 WO 9955865PCTINZ99/00051 Leu Lys 145 Asn Leu Al a As n Arg 225 His Cys Cys Lys Ile 305 Ser Ser Leu Glu Asn 385 Leu Ser Ile Pro Asn 465 Lys Ser Giu Asp Phe 545 Arg Al a Arg Tyr 130 Ala Gin Giu Ser Asn 210 Gin Leu Ser Pro Gly 290 Arg Pro Giu Val Gly 370 Cys Ser Al a Cys Ile 450 Lys Giu Gly Gly His 530 Thr Lys Phe Leu 115 Arg Phe Ile Val Phe 195 Leu Arg Arg Gly Ile 275 Leu Leu Tyr Leu Leu 355 Leu Leu Leu Leu Asp 435 Giu Arg Gin Asp Thr 515 Ile Val Ile Giu Glu 595 120 125 Asp Leu Ser Giu Asn Gin Ile Gin Ala Leu Arg Ser Leu 180 Asn Tyr Pro Gly His 260 Ala Thr Glu Lys Ala 340 Tyr Phe Arg Tyr Arg 420 Cys Thr Ile Tyr Cys 500 Thr Pro Leu As n Gly 580 Asn Gly Cys 165 Thr His Cys Arg His 245 Gin Cys Giu Gin Lys 325 Pro Gly Ser Val1 Asp 405 Ala His Ser Gly Phe 485 Phe Val1 Gin Giu Leu 565 Ala Val Ala 150 Ile Leu Met Asp Val 230 Asn Ser Thr Ile Asn 310 Leu Asp Asn Leu Asp 390 Asn Ile Leu Gly Gin 470 Ile Ala Asp Tyr Ala 550 Ser Ser Gin 135 Val Glu Asn Pro Cys 215 Gly Val1 Phe Cys Pro 295 Ser Arg Ala Lys Gin 375 Ala Lys Gin Lys Ala 455 Ile Pro Asp Cys Thr 535 Thr Asn Gly His Asp Asp Asn Lys 200 His Leu Ala Met Ser 280 Thr Ile Arg Phe le 360 Leu Phe Leu Thr Trp 440 Arg Lys Gly Leu Ser 520 Ala Gly Asn Val1 Lys 600 Ile Gly Asn 185 Leu Leu Tyr Giu Ala 265 Asn Asn Arg Leu Gin 345 Thr Leu Gin Gin Met 425 Leu Cys Ser Thr Ala 505 Asn Glu Ile Lys Asn 585 Met Lys Ala 170 Asn Arg Aila Thr Val1 250 Pro As n Leu Val1 Asp 330 Giy Giu Leu Asp Thr 410 His Al a Thr Lys Giu 490 Cys Gin Leu Phe Ile 570 Giu Phe As n 155 Phe Ile Thr Trp Gin 235 Gin Ser Ile Pro Ile 315 Leu Leu Leu Leu Leu 395 Val1 Leu Asp Ser Lys 475 Asp Pro Lys Arg Lys 555 Thr Ile Lys 140 Leu Arg Thr Phe Leu 220 Cys Lys Cys Vai Giu 300 Pro Ser Arg Pro Asn 380 His Ala Ala Tyr Pro 460 Phe Tyr Giu Leu Leu 540 Lys Asp Leu Gly Gin Aia Arg Arg 205 Ser Met Arg Ser Asp 285 Thr Pro Asn Ser Lys 365 Al a As n Lys Gin Leu 445 Arg Arg Arg Lys Asn 525 Asn Leu Ile Leu Leu 605 Ile Leu Leu Leu 190 Leu Asp Gly Giu Val 270 Cys Ile Gly As n Leu 350 Ser As n Leu Gly Asn 430 His A-rg Cys Ser Cys 510 Lys Asn Pro Giu Thr 590 Glu Pro Asp Arg 175 Ser His Trp Pro Phe 255 Leu Arg Thr Ala Gin 335 Asn Leu Lys Asn Thr 415 Pro Thr Leu Ser Lys 495 Arg Ile Asn Gin Glu 575 Ser Ser Arg Tyr 160 Asp Val Ser Leu Ser 240 Val His Gly Giu Phe 320 Ile Ser Phe Ile Leu 400 Phe Phe Asn Al a Al a 480 Leu Cys Pro Glu Leu 560 Gly Asn Leu WO 99/55865 PCT/NZ99/00051 Lys Thr Leu 610 Ser Phe Thr 625 Gin Ile Thr Ser Thr Leu Ala Trp Leu 675 Pro Arg Cys 690 Val Ala Ile 705 Cys Ser Pro Val Val Arg Pro Arg Asp 755 Val Pro Lys 770 Ser Asn Asn 785 Thr Gin Leu Pro Pro Arg His Gly Asn 835 Ser Ala Leu 850 Cys Asn Met 865 Pro Gly Ile Leu Leu Thr Val Thr Ile 915 Asn Asp Gly 930 Cys Pro Tyr 945 Cys Ile Ser Gly Glu Asn Glu Ser Cys 995 Asn Asn Ser 1010 Pro Pro Glu 1025 Ala Gin Asp Pro Lys Gly Cys Asp Ile Met Leu Arg Ser Asn Arg 615 Gly Leu Gly Ser Val Arg 630 Thr Val Ala Pro Gly Ala 645 Asn Leu Leu Ala Asn Pro 660 665 Gly Glu Trp Leu Arg Arg 680 Gin Lys Pro Tyr Phe Leu 695 Gin Asp Phe Thr Cys Asp 710 Leu Ser Arg Cys Pro Ser 725 Cys Ser Asn Lys Gly Leu 740 745 Val Thr Glu Leu Tyr Leu 760 Glu Leu Ser Asn Tyr Lys 775 Arg Ile Ser Thr Leu Ser 790 Leu Thr Leu Ile Leu Ser 805 Thr Phe Asp Gly Leu Lys 820 825 Asp Ile Ser Val Val Pro 840 Ser His Leu Ala Ile Gly 855 Gin Trp Leu Ser Asp Trp 870 Ala Arg Cys Ala Gly Pro 885 Thr Pro Ser Lys Lys Phe 900 905 Gin Ala Lys Cys Asn Pro 920 Thr Cys Asn Asn Asp Pro 935 Gly Phe Lys Gly Gin Asp 950 Asn Pro Cys Lys His Gly 965 Asp Gly Phe Trp Cys Thr 980 985 Asp Ile Asn Ile Asp Asp 1000 Thr Cys Val Asp Gly Ile 1015 Tyr Thr Gly Glu Leu Cys 1030 Leu Asn Pro Cys Gin His 1045 Phe Lys Cys Asp Cys Thr 1060 1065 Asp Phe Asp Asp Cys Gin Ile Ser Cys Val Gly Asn Asp 620 Leu Leu Ser Leu Tyr Asp Asn 635 640 Phe Gly Thr Leu His Ser Leu 650 655 Phe Asn Cys Asn Cys His Leu 670 Lys Arg Ile Val Thr Gly Asn 685 Lys Glu Ile Pro Ile Gin Asp 700 Asp Gly Asn Asp Asp Asn Ser 715 720 Glu Cys Thr Cys Leu Asp Thr 730 735 Lys Val Leu Pro Lys Gly Ile 750 Asp Gly Asn Gin Phe Thr Leu 765 His Leu Thr Leu Ile Asp Leu 780 Asn Gin Ser Phe Ser Asn Met 795 800 Tyr Asn Arg Leu Arg Cys Ile 810 815 Ser Leu Arg Leu Leu Ser Leu 830 Glu Gly Ala Phe Gly Asp Leu 845 Ala Asn Pro Leu Tyr Cys Asp 860 Val Lys Ser Glu Tyr Lys Glu 875 880 Gly Glu Met Ala Asp Lys Leu 890 895 Thr Cys Gin Gly Pro Val Asp 910 Cys Leu Ser Asn Pro Cys Lys 925 Val Asp Phe Tyr Arg Cys Thr 940 Cys Asp Val Pro Ile His Ala 955 960 Gly Thr Cys His Leu Lys Glu 970 975 Cys Ala Asp Gly Phe Glu Gly 990 Cys Glu Asp Asn Asp Cys Glu 1005 Asn Asn Tyr Thr Cys Leu Cys 1020 Glu Glu Lys Leu Asp Phe Cys 1035 104 Asp Ser Lys Cys Ile Leu Thr 1050 1055 Pro Gly Tyr Ile Gly Glu His 1070 Asp Asn Lys Cys Lys Asn Gly 1085 Tyr Thr Cys Val Cys Pro Glu 1075 Ala His Cys Thr Asp Ala Val 1080 Asn Gly WO 99/55865 PCT/NZ99/00051 1090 1095 1100 Gly Tyr Ser Gly Leu Phe Cys Giu Phe Ser Pro Pro Met Val Leu Leu 1105 1110 1115 112 Arg Thr Ser Pro Cys Asp Asn Phe Asp Cys Gin Asn Gly Ala Gin Cys 1125 1130 1135 Ile Ile Arg Val Asn Glu Pro Ile Cys Gin Cys Leu Pro Gly Tyr Leu 1140 1145 1150 Gly Giu Lys Cys Giu Lys Leu Val Ser Val Asn Phe Val Asn Lys Giu 1155 1160 1165 Ser Tyr Leu Gin Ile Pro Ser Ala Lys Val Arg Pro Gin Thr Asn Ile 1170 1175 1180 Thr Leu Gin Ile Ala Thr Asp Giu Asp Ser Gly Ile Leu Leu Tyr Lys 1185 1190 1195 120 Gly Asp Lys Asp His Ile Ala Val Giu Leu Tyr Arg Gly Arg Val Arg 1205 1210 1215 Ala Ser Tyr Asp Thr Gly Ser His Pro Ala Ser Ala Ile Tyr Ser Val 1220 1225 1230 Giu Thr Ile Asn Asp Gly Asn Phe His Ile Val Giu Leu Leu Thr Leu 1235 1240 1245 Asp Ser Ser Leu Ser Leu Ser Val Asp Gly Gly Ser Pro Lys Ile Ile 1250 1255 1260 Thr Asn Leu Ser Lys Gin Ser Thr Leu Asn Phe Asp Ser Pro Leu Tyr 1265 1270 1275 128 Val Gly Gly Met Pro Gly Lys Asn Asn Val Ala Ser Leu Arg Gin Ala 1285 1290 1295 Pro Gly Gin Asn Gly Thr Ser Phe His Gly Cys Ile Arg Asn Leu Tyr 1300 1305 1310 Ile Asn Ser Giu Leu Gin Asp Phe Arg Lys Val Pro Met Gin Thr Gly 1315 1320 1325 1330 1335 1340 Thr Cys Gin Pro Ser Ser Gin Ser Gly Phe Thr Cys Giu Cys Giu Giu 1345 1350 1355 136 Gly Trp Met Gly Pro Leu Cys Asp Gin Arg Thr Asn Asp Pro Cys Leu 1365 1370 1375 Gly Asn Lys Cys Val His Gly Thr Cys Leu Pro Ile Asn Ala Phe Ser 1380 1385 1390 Tyr Ser Cys Lys Cys Leu Giu Gly His Gly Gly Val Leu Cys Asp Giu 1395 1400 1405 Giu Giu Asp Leu Phe Asn Pro Cys Gin Vai Ile Lys Cys Lys His Gly 1410 1415 1420 Lys Cys Arg Leu Ser Gly Leu Gly Gin Pro Tyr Cys Giu Cys Ser Ser 1425 1430 1435 144 Gly Phe Thr Gly Asp Ser Cys Asp Arg Giu Ile Ser Cys Arg Gly Giu 1445 1450 1455 Arg Ile Arg Asp Tyr Tyr Gin Lys Gin Gin Gly Tyr Ala Ala Cys Gin 1460 1465 1470 Thr Thr Lys Lys Val Ser Arg Leu Giu Cys Arg Gly Giy Cys Ala Gly 1475 1480 1485 Gly Gin Cys Cys Gly Pro Leu Arg Ser Lys Arg Arg Lys Tyr Ser Phe 1490 1495 1500 Giu Cys Thr Asp Gly Ser Ser Phe Val Asp Giu Val Giu Lys Val Val 1505 1510 1515 152 Lys Cys Gly Cys Thr Arg Cys Ala Ser 1525 <210> 397 <211> 8 <212> PRT <213> Mouse WO 99/55865 WO 9955865PCT/NZ99/00051 <400> 397 Trp Tyr Asn Ala Trp 1 S Asn Glu Lys <210> 398 <211> 7 <212> PRT <213> Mouse <400> 398 Val Ile Ile Thr Thr Lys Met 1 <210> <211> <212> <213> 399 2206

DNA

Rat <400> 399 gtttcgtctt aacgccctct tggaacatct cagcccacac atccgcggtg actgcaagta gagcgtcaac agcaagaaga agtgtccagc catgaaggaa gaagaagaag cgttctggat agcctactcc acaccagaca acctggtgaa actgaagtgt tgagaagcag ccagaacact gaaaattgcc caggaacgag agag-,-t, ctaccc tcagagaaat ttcgaaattg catggaggag tttgagcagg tcacagagat cgtccaacta gacctacttt tttggagctg tcagcgtaaa ctgcagcatg cgggagaatc tctgagaggc caagaagctg accgccatgc gactttccag gaggtggaga tgcgttaagc ttttaccaca ggccaggaca gtggcgaaag ctttgactgc gacggcaatg gcggctgatg agaggcctgg catgtggaaa tgtgcccaag ctcctgcacc ttagcacccc agtagtgccc acatccccat ccatcctccc ctgacccagt gtctaagaca ggaacaagtc gggtaaatgc ggggagccct actgtggatt taagtaacac aagtttggaa atactctggc cctggtaccc tgatctggca ggcaccagga aggctctttg ggctctccag aacctcctgc gggactctgc ttcactagag tatagacctg cagagcgcag atcactttaa ttatagcact ctgcgttggc agactaagcg ccggtctcct ctgacgctgg gcgctgcaga tcagagacag aaatcttccg tcatgacccc tgggcctgga aaaagtttgc ccttcaagat ttcaaagcat ct gggaaca c atctcaaagg acgttctaaa agttcggtgg agaggcagct acttcttcac tggctggagc tcgagctgtc gggagc tgag agaagcccaa aaaccgcctg gcaatcctgg ctttctggaa cagtgttccg ttcaaagcag cccacactgg aaacgtccct aggcaaaggg gggcacctgg ccaccagcac tctttttttt ccagggctga ctcagagcct ttgcaggaaa agaactggcc gagactgatg gtggaagaag agataagggg c actgc ggc c aaaagtaatg gtattttgcc acaggacttt tcagtacata tgacgaaggc gtttgacttg cattcgctcc cctcaagtct gaaactgacc gctggagtt t catgctgctg gaagaagcac tttcctgaag atccctcgat ggaccacgtg c aa taaggag ggacatgggc ggactttgct agtggccttc gtgacctctg ctaggctctg agaccatagc c agc cccagg gccatcttcc aagtctgtga tcaggggaag agctcccgat ttcctcccgg gcccctgttc atctgccctc taccccaaaa gtgggctccc ttggtggcgt gctcacgcag aagagcaagg gagccttacc gagtatgaga accttgaaag gtgcgctcca ataaagcgct agcatcttct acaacgg-tgc aatggagatg cagaccagca ggcttatgtt attaaaaact gaacgccatg gcctacagtg ttcaaggatg aacattaatg aaagtgacca tgtgacgtgg tttgtctcca tttacccgtc ctacccaaat atgctgctga gcctcagctg aatctgcagt tcccttaacc aggcatctct tcccactgtt tgaacggtaa ggtctgcgtc tcaaagtcgc ctccctgcga cttgtgtctt tgtctaatac aaaaaa gctggtacca tcctcggagc aatctccacc acacccggga cagaggagaa ataggatccg taatcaacga taacacccaa tcgatggaaa atacccttgg tctccact-cc gagaagtaga tgggcatgcg cggccctcac tcctggaatt acccggtaga gagtgcagtc ggaagggcct acgtggacac tgcagcaagt tgtttgcact tcatgaagca tcatgcaggc agtaccccac tgcttctggg gctgacctct cagatcaaag agtgccccgt gcagtctctc ttaaagctgc tgcagjatgac agacaccagc tgctttgagc tgcctcctct gtcccctctc actcgtaaat 120 180 24 0 300 360 420 480 540 600 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2206 <210> 400 <211> 160 <212> DNA <213> Mouse WO 99/55865 WO 9955865PCT/NZ99/00051 <400> 400 tcgcaggacg ctcactggac agcttgggct tttttcagtt gattttatgg tttgcatctt tctctttctc tttttctgtt tcttgttccc ctttcccctt ttcctggtga. gaaagcacat attactgagc cattgcaagc aatgggaggg gtccacaatg <210> 402.

<211> 430 <212> DNA <213> Rat <400> 401 ggcaccagcc cggcttctgt tccatggcgt cgctcctgtg gcctggggag tgatcatgtt ttaattgagg atgtcccctt aacctgtacg agcaagtcag gggggcttct ccttctgcca agcgcagtcc gactctcccc cactcatctg gctccgctca ctgtgggcct gataatgctc cacagagaaa ctacaactgt agttcgtctc attcccctcc gtctccagcg aagctggccg gggatatttt gattttgaga ttcatcgccg aataagcgca ttatttaaag atccctccct cctgtggcat tcaatgtcca acggccctca cgggcctcta aggaatacat actcctcagt acctccgccc cgtcctcagc ttctgctgtg gaacatatac cctcctcctc ggtgcgctag ccatctgttc 120 18 b 240 300 360 420 430 <210> 402 <211> 190 <212> DNA <213> Rat <400> 402 ccgaatacgc ggccgcgtcg ttgcacactg aattgaagaa ttttgtLLLLL ggttLtgctt cggccgcgaa acatactgcc tgtagagtta gtatttctgt tttttatatg atgttggttt ttcttgtttt gttttagttt gtttctttgg tttacttccc aggtttgaet atttgccaat gccgtcgacg 120 180 190 <210> 403 <211> 17-74 <212> DNA <213> Mouse <400> 403 ccaaagtgga gggcgagggc ccggcgaatt cgcaggctgg tgcgccatgt gcactggaag acgacaggga acgaatggag gatacattct acctgtgtac tggagacagg ctccctggag ttcgcatcgt gcacgagaca tgctgcacct agacctgaag tttctgactt tgggctggcc atggcctgtt tggtacaatc tgtttgacac caaacatgat agaagaagcc atttgcagat gccaccgccc agagctgcca tagggataat gcaacggtgc ttacctctga aacagaagac atgagccagg cgagaaaagc gcctcaagcg cgcctctgct cacagttgga ctctgggatc cctctgaatg caagctccca tggactcagc cttttcctcc caggcgacct gggccccaca gggacaccag caggctgatg gcagtgccag cctgctgcac cggggCCggt gagaaggtgg acgtggctcg ctcctggagg ggcatatgcc aagctgctgg gccgtgggca ccagcgaaca aagtgcaatg gcttacctcc gtatacagct gaaaagaaca cccatctgca tggcatgcag ctttgtgaga tctctagagt cCccccttcg tcccagactc tcgtccagca agaggatcgc gacatccaga aagatcctac ctggctgtgg gggctctggg gctcgggcgg cgatcaagtg aagctaagaa aggaacctgt cctcagagcc tgaacttcct tcctgctgga gcatgtccca ctccagagcg tcgccattgt tcctacacat gaccccggcc acccacaggt agcctgatga ccaagagtga ataacgactg ttgaaggccc gtggcaagag tgtcactgtc agaagaagct agccccaaga aggccggaca gctgctgcgc cttcgggcag ctcgcccagt gatggagatg cggcttggtc attgccttgg gcattgcatg tgcccactac ctctcatgac aattcgtgag gatctggggt catgatgaaa.

gcgtgcctgt gcggc ccac c ggaggtgaaa ggccaggccc cagtctctcc cgaagagctc gctctcgggg ttttgagcgg agtggatgcc tgtggacttg ggaggagtgt accttcgacg gtgtacaagg ctgcacgtcg gccaagttcc atggagtaca gacctgcgct tctccgccac catgtcaaga ctcagcatgg aagagccgct gtgcttacac gtggtaaagg gccagcctga ttccaagaaa gacctggctc gagtcctcac gagttgctgt agccgaagtt gtgtcctcag gaagcttcaa atcatatcag gttctagaca gtcaagtggc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 WO 99/55865 WO 9955865PCT/NZ99/00051 tgctgcttaa tggctgtgga tcaatgccaa aggccagcac gccgaacacc tccgccgtgg ctgcctggca caatgccaac gcggaaggga ggatgaagac aaggctgctg catgcatgta tgtggatgtg aggccacctt cccaacctga cgtggaattg cagtggactg ctagagaaga gcctgccagc ggcctgcagg cccattggta ccaacaggaa tggagctact ccctgcactt atgcttctgt atggacagga gaaaggatgc agct gggctctaca gctagcccgg tgcagcccag caatgaggtg gaacattgtg ctggttgcct ccactgcata aagaccagtg aatggggatg gactttgagg cgcaccctgc ctgcactatg 1440 1500 1560 1620 1680 1740 1774 <210> 404 <211> 372 <212> DNA <213> Mouse <400> 404 ccacagcaca tcgtcctgac gactgcccgc ctctggggct caccctgact gctgacttac ccaacgattc gggaaatgtc gcgtccccca gcctggatga gtgctggaca aggtcacagc cgagagaaga gg tgtcctcttc tcctttagag agctatgagg agaagagctg ctacgtcagg ccagagccgt ccagggacca gagacagtct tcccggcttc tcacatgggg tgtatctgtc cccaacagac agagctagag ttacccatct tgctgcccgt cagctgggca agctggcaca cctcccggcc acccggctgt agactcctgc gccccatttg ggaaccccca gcccacctca agcctggact 120 180 240 300 360 372 <210> 405 <211> 396 <212> DNA <213> Mouse <400> 405 gagcttcgaa gctttctccg ccttccatgc ggaaaccaaa gcgggcactt tcatcgcccc cgctctcccg tgcgccttgc acaccacccc ccattctcag atatcaacca gcaacatccc tcttccaaga gcagcggccg tcctgtctac tgaccacccc ccccgtccgg ggcccctcct cgacaggttt gaagac tga cggccggagc tccaacatca tctgagcgga gaaggctctg gtatca ctggggccac ccctcatcat ccccttacca gctttgagcc gcctctactt aagaggccga ggaaggggag ccccaccaag gagccacctg ccccccttac caatgccat c 120 180 240 300 360 396 <210> <211> <212> <213> <400> 406 Leu Val Ala Leu Trp Lys Lys Thr Asp Phe Leu Gly Ala Ser Ala Val Thr Ala Ser Thr Gly Ala His Ala Glu 25 Gly Pro Pro Ser Lys Ala Gly Asp Lys 40 Al a Lys Ser Lys Asp Al a Val Asn Ser Thr Arg Giu Glu Pro Tyr Val Ser Pro Glu Ser His Glu Gly Ser Lys Ala Asp Thr Glu Lys Lys Lys Arg Arg Ser Gly Phe Ser Asp Arg Lys Giu Tyr Giu Asn Al a Ile Arg Ala Thr Pro Asp Lys Ile Phe Arg Tyr Giu Val Phe 115 Giu Lys Gin Thr Leu Lys Asn Glu Pro Thr Pro Gin Asp 120 Gly Val Arg Ser Gly Glu Thr 110 Thr Pro Asn Ile Lys Arg Pro Glu His 130 Phe Asp Gly Lys Lys Ile Leu 135 Ala Leu Asp Gin Gly LysLys lie Gn Giu Arg Giu PeAlAsGu Phe Ala Asp Glu WO 99/55865 WO 9955865PCT/NZ99/00051 145 Gly Asp Giu Met Met 225 Ser Lys Gin Giy Gly 305 His Phe Tyr Ala Val- 385 Glu Pro Ala Arg 1 Val Leu Glu Ser Ile Tyr Ile Ile Ala 195 Giu Giu 210 Gly Met Gly Leu Gly Lys His Asp 275 Arg Ile 290 Val Gin Phe Lys Thr Phe His Met 355 Arg Thr 370 Phec AlIa Phe Vai Lys Asp Gin Giu 435 <210> <211> <212> <213> <400> Arg Thr Cys Ile Phe Leu Giy Ser <210> <211> <212> <213> Phe Tyr 165 Phe Leu 180 Phe Lys Phe Giu Arg His Cys Ser 245 Leu Thr 260 Val Leu Ser Glu Ser Lys Asp Giy 325 Leu Lys 340 Ala Gly Val Ala T eu P 1-4 Ser Ile 405 Met Giy 420 Thr Ala 407 53

PRT

Mouse 407 Leu Thr 5 Phe Leu Vai Arg Thr Met Gly Vai Asp 200 Gin Arg Thr Asn Giu 280 Phe Thr Leu Asn Leu 360 Giu Asp Gin Arg 155 Gly Thr Gly Ile Thr 235 Phe Giu Arg Met Gin 315 Gin Asp Val Asp u-i-y 395 Met Gin Ile Gin Gly 205 Ser Asn Gly Gin Asp 285 Leu Gin Val1 Al a Met 365 Val Lu Gly Met Ser Arg 190 Glu Gin Thr Al a Arg 270 Pro Al a Leu Giu Leu 350 Gin Cys Ser Leu Trp 430 Trp Asp Phe Ala Leu Pro Lys 440 Gly Gin Leu Gly Leu Phe Ser Val Asp Phe Met 10 Phe Leu Phe Phe Cys Phe Leu Phe Pro Phe Pro 25 Lys His Ile Leu Leu Ser His Cys Lys Gin Trp 40 Ser Val Leu Arg Ser Val Ser Ser Asp Pro Ser 10 408 119

PRT

Rat <400> 408 Gly Thr Ser Pro Ala 1 5 Leu Ala Met Val Asn Tyr Arg Lys 1 Thr Gly Leu Met- Tyr Met Pro Gly Leu 145 Ser Leu Arg Ser Al a 225 His Ala Val Glu Lys 305 WO 99/55865 Pro Pro Pro Ala Cys Gly Leu Gly Ile Pro Phe Thr Leu Tyr Glu Leu Leu Leu 100 Lys Giu Tyr 115 <210> 409 <211> 590 <212> PRT <213> Mou <400> 409 Val Giu Gly Phe Asp Ala Phe Giy Gin Ala Ile Lys Ile Leu Pro Glu Tyr Met 100 Leu Pro Trp 115 Met Asn Phe 130 Lys Pro Ala Asp Phe Gly Ser Met Asp 180 Ile Arg Giu 195 Phe Ala Ile 210 Asp GJlu Lys Arg Pro Glu Ser Leu Ile 260 Arg Pro Thr 275 Lys Pro Asp 290 Ser Ser Leu PCT/NZ99/00051 Ser Ile Phe Glu Gin Gly Met Giu 5 Gly Val1 Cys Val Glu Asp Leu Asn Leu 165 Gly Lys Val Asn Leu 245 Gly Phe Giu Glu Ala Leu Asn Asp Ser Phe Arg Arg Phe Lys Pro Ala Gly Gly Arg Cys 135 Leu Lys Phe Arg Trp 215 Leu Pro Met Glu Val 295 Lys Ser Ser 40 Val1 Phe Tyr Ser Gly Ala Val1 40 Ser Ile Ser Phe 120 Met Leu Cys Gly Leu 200 Gly His Ile Gin Ile 280 Lys Ser Leu 25 Al a His Glu Asn Phe 105 Arg Gly 25 Arg Leu T y, Cys Leu 105 Arg Ser Asp Asn Thr 185 Phe Val Ile Cys Arg 265 Thr Asp Giu Leu Trp Ser Asn Cys Cys Trp Trp His His Met4 Gin Glu Ile Pro Ala Gly 170 Ile Asp Leu Met Arg 250 Cys Ser Leu Al a Al a Giu Val1 Val1 G!1 Giu Lys Val Pro His 155 Met Al a Thr Thr Met 235 Pro Trp Glu Al a Arg 315 Gly Ile Leu Gin Ala Arg Gly Val Trp Asp Val Leu Giu 125 Leu His His Leu His 205 Lys Val Pro Ala Giu 285 Giu Glu Pro Met Ile Asn Al a Leu 110 Leu Gly Lys Arg Giy Al a 110 Thr His Val1 Ser Pro 190 Asp Lys Val Arg Asp 270 Asp Pro Ser WO 99/55865 WO 9955865PCT/NZ99/00051 Leu Glu Pro Ser Ser 385 Gly Ile Asp Val Ala 465 Al a Lys Phe Lys His 545 Arg Leu Lys Leu Giu Ser 370 Ser Asp Ile Val Giu 450 Asn Val Thr Ala Asn 530 Vai Arg His Arg Leu Giu 355 Gly Arg Leu Ser Asp 435 Ala Pro Glu Ser Al a 515 Al a Ala Gly Tyr Ser 325 Gin Ser Arg Ser Pro 405 Asp Val Gin Leu Lys 485 Asn Asn Val Gin Asp 565 Ala Pro Asp Ser Ser 375 Ser Asp Ser Asp Giu 455 Asn Arg Lys Asp Glu 535 Gly Gly Gin Pro Ser Ser 360 Gly Leu Ile Arg Ser 440 Cys Arg Gly Asp Glu 520 Val1 Gin Leu Gly Asp 330 Ile Glu Ser Phe Lys 410 Met Ala Lys Gly Val1 490 Asp Ser Phe Asn Gly 570 Leu Asn Ser Cys Ser Glu 395 Lys Lys Ser Trp Ser 475 Giu Gin Thr Glu Ile 555 Lys Pro Cys Thr Leu 365 Asp Giu Leu Leu Leu 445 Leu Pro Leu Thr Leu 525 Arg Arg Al a Gly Ser Leu 350 Pro Ser Ala Val Gin 430 His Leu Leu Leu Ala 510 Leu Thr Thr Trp Lys 590 Ser Gly Ser Phe Thr 400 Al a Gin Ala Asn Met 480 Arg His Glu Met Leu 560 Pro

Claims (14)

1. An isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of: sequences recited in SEQ ID NO: 68, 118, 268, 269 and 371; complements of the sequences recited in SEQ ID NO: 68, 118, 268, 269 and 371; reverse complements of the sequences recited in SEQ ID NO: 68, 118, 268, 269 and 371; reverse sequences of the sequences recited in SEQ ID NO: 68,118, 268, 269 and 371; nucleotide sequences having at least 75% identity to a sequence recited in SEQ ID NO: :i 68, 118, 268, 269, and 371; and nucleotide sequences having at least identity to a sequence recited in SEQ ID NO: 68, 118, 268, 269 and 371.

2. An expression vector comprising an isolated polynucleotide of claim 1.

3. A host cell transformed with an expression vector of claim 2.

4. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of: sequences provided in SEQ ID NO: 187, 196, o* o. 342, 343 and 395; sequences having at least 75% identity to a sequence provided in SEQ ID NO: 187, 196, 342, 343 and 395; and sequences having at least 90% identity to a sequence provided in SEQ ID NO: 187, 196, 342, 343 and 395. An isolated polynucleotide encoding a polypeptide of claim 4.

6. An expression vector comprising an isolated polynucleotide of claim

7. A host cell transformed with an expression vector of claim 6.

8. An isolated polypeptide comprising at least a functional portion of a polypeptide having an amino acid sequence selected from the group consisting of: sequences provided in SEQ ID NO: 187, 196, 342, 343 and 395; (2) 19/12/2002 sequences having at least 75% identity to a sequence provided in SEQ ID NO: 187, 196, 342, 343 and 395; and sequences having at least 90% identity to a sequence provided in SEQ ID NO: 187, 196, 342, 343 and 395.

9. A method for stimulating an immune response in a patient, comprising administering to the patient a composition comprising an isolated polypeptide of any one of claims 4 and 8. A method for stimulating keratinocyte growth and motility in a patient, comprising administering to the patient a composition comprising an isolated *i polypeptide of any one of claims 4 and 8.

11. A method for inhibiting the growth of cancer cells in a patient, comprising administering to the patient a composition comprising an isolated polypeptide of any one of claims 4 and 8. any one of claims 4 and 8.

12. A method for modulating angiogenesis in a patient, comprising administering to the patient a composition comprising an isolated polypeptide of any one of claims 4 and 8. 19/12/2002

13. A method for inhibiting angiogenesis and vascularization of tumors in a patient, comprising administering to a patient a composition comprising an isolated polypeptide of any one of claims 4 and 8.

14. A method for treating neurological disease in a patient, comprising administering to the patient a composition comprising an isolated polypeptide of any one of claims 4 and 8. A composition comprising a polypeptide of any one of claims 4 and 8 in combination with a component selected from the group consisting of: physiologically acceptable carriers and non-specific immune response enhancers.

16. A composition comprising a polynucleotide of claim 1 in combination with a component selected from the group consisting of: physiologically acceptable carriers and non-specific immune response enhancers.

17. The composition of any one of claims 15 and 16, wherein the non- specific immune response enhancer is an adjuvant. Dated this 3rd day of October 2002 Genesis Research and Development Corporation Limited Patent Attorneys for the Applicant PETER MAXWELL ASSOCIATES 03/10/2002