CA2304312A1 - Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications - Google Patents

Abstract

Antisense oligonucleotides which bind to two or more RNA targets are disclosed.

Description

MULTIPLE TARGET HYBRIDIZING NUCLEIC ACIDS, THEIR PREPARATION, COMPOSITIONS, FORMULATION, KITS & APPLICATIONS
This invention relates to multiple target anti-sense oligonucleotides (MTA
oligos). of low or no adenosine content. The present agents are effective in the prophylaxis and treatment of diseases and conditions associated with inflammation, impaired airways, including lung disease and diseases whose secondary effects afflict the lungs of a subject.
The agents are targeted to specific genes, genomic flanking regions, initiation codon, intron-exon borders, and the like, or the coding and non-coding regions of RNAs, including those encoding certain proteins, particularly those associated with diseases having multiple mediators, by affecting (either attenuating or enhancing) various contributing pathways. Examples are pulmonary diseases such as allergies, asthma, impeded respiration, pain, cystic fibrosis and cancers such as leukemias, e.g. colon cancer, and the like. The present agent may easily be administered prophylactically and therapeutically in conjunction with other therapies, or may be utilized as a substitute for therapies that have significant, negative side effects.
Respiratory ailments, associated with a variety of diseases and conditions, are extremely common in the general population, and more so in certain ethnic groups, such as African Americans. In some cases they are accompanied by inflammation, which aggravates the condition of the lungs. Asthma, for example, is one of the most common diseases in industrialized countries. In the United States it accounts for about 1 % of all health care costs.
An alarming increase in both the prevalence and mortality of asthma over the past decade has been reported, and asthma is predicted to be the preeminent occupational lung disease in the next decade. While the increasing mortality of asthma in industrialized countries could be attributable to the increased reliance upon beta agonists in the treatment of this disease, the underlying causes of asthma remain poorly understood.
Anti-sense oligonucleotides have received considerable theoretical consideration as potential useful pharmacological agents in human disease. Their practical application in actual models of human disease, however, has been somewhat elusive. One important impediment to their effective application has been a difficulty in finding an appropriate route of administration to deliver them to their site of action. Many in vivo experiments were conducted by administering anti-sense oligonucleotides directly to specific regions of the brain. These applications, however, necessarily have limited clinical utility due to their invasive nature.
The systemic administration of anti-sense oligonucleotides also presents significant problems, not the least being an inherent difficulty in targeting disease-involved tissues. In contrast, the lung is an excellent target for the direct administration of anti-sense oligonucleotides, and provides a non-invasive and a tissue-specific route. The delivery of anti-sense agents to the lung has been relatively undeveloped.
Adenosine may constitute an important mediator in the lung for various diseases, including bronchial asthma. Its potential role was suggested by the finding that asthmatics respond favorably to aerosolized adenosine with marked bronchoconstriction whereas normal individuals do not. An asthmatic rabbit animal model, the dust mite allergic rabbit model for human asthma, responded in a similar fashion to aerosolized adenosine with marked bronchoconstriction whereas non-asthmatic rabbits showed no response. More recent work with this animal model suggested that adenosine-induced bronchoconstriction and bronchial hyperresponsiveness in asthma may be mediated primarily through the stimulation of adenosine receptors. Adenosine has also been shown to cause adverse effects, including death, when administered therapeutically for other diseases and conditions in subjects with previously undiagnosed hyper reactive airways.
A handful of medicaments have been available for the treatment of respiratory diseases and conditions, although in general they all have limitations. Theophylline, an important drug in the treatment of asthma, is a known adenosine receptor antagonist which was reported to eliminate adenosine-mediated bronchoconstriction in asthmatic rabbits. A
selective adenosine A, receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX) was also reported to inhibit adenosine-mediated bronchoconstriction and bronchial hyperresponsiveness in allergic rabbits. The therapeutic and preventative applications of currently available adenosine A, receptor-specific antagonists are, nevertheless, limited by their toxicity.
Theophylline, for example, has been widely used in the treatment of asthma, but is associated with frequent, significant toxicity resulting from its narrow therapeutic dose range. DPCPX
is far too toxic to be useful clinically. The fact that, despite decades of extensive research, no specific adenosine receptor antagonist is available for clinical use attests to the general toxicity of these agents.
Anti-sense oligonucleotides have received considerable theoretical consideration for their potential use as pharmacological agents in human disease. Finding practical and effective applications of these agents in actual models of human disease, however, have been few and far between, particularly because they had to be administered in large doses.
Another important consideration in the pharmacologic application of these molecules is their route of administration. Many in vivo applications have involved the direct administration of anti-sense oligonucleotides to limited regions of the brain. Such applications, however, have limited clinical utility due to their invasive nature.
The systemic administration of anti-sense oligonucleotides as pharmacological agents has been found to have also significant problems, not the least of which being a difficulty in targeting disease-involved tissues. That is, the necessary dilution of the anti-sense oligonucleotide in the circulatory system makes extremely difficult to attain a therapeutic dose at the target tissue by intravenous or oral administration. The bioavailability of orally administered anti-sense oligonucleotides is very low, of the order of less than about 5 % .
Anti-sense oligonucleotides have been used in therapy by many, including the present inventor, who in his previous work successfully treated various diseases and conditions by direct administration of these agents to the lung. In many instances, other workers have had to face the difficulties associated with the delivery of DNA molecules to a desired target. Thus, the route of administration may be of extreme importance for treating generalized diseases and conditions as well as those which are localized.
Accordingly, there is a need for effective ways to implement anti-sense therapy, particularly those which are highly effective for the treatment or diseases and conditions which are of a complex nature. Examples of the latter are those diseases and conditions which are associated with complex pathways and multiple endogenous agents which either alone, or in combination with one another, result in pathological conditions to the subject.
This invention relates to an agent, comprising an anti-sense oligonucleotide hybridizing to two or more mRNAs, or multiple target anti-sense oligos (MTA oligos), such as those that correspond to target genes, genomic flanking regions, the initiation codon, intron-exon borders, and the like, and the entire sequence of RNAs, including the coding region of mRNA
and non-coding RNA segments such as the 5' cap or end and the 3' end, e.g.
poly-A segment, and RNAs encoding proteins known to be associated with one or more diseases or conditions and mixtures thereof. The mRNAs, for example, may encode polypeptide(s) such as transcription factors, stimulating and activating factors, interleukins, interleukin receptors, chemokines, chemokine receptors, endogenously produced specific and non-specific enzymes, immunoglobulins, antibody receptors, central nervous system (CNS) and peripheral nervous and non-nervous system receptors, CNS and peripheral nervous and non-nervous system peptide transmitters, adhesion molecules, defensines, growth factors, vasoactive peptides and receptors, and binding proteins; or those mRNA which correspond to an oncogene. The present agent contains less than or about 15 % adenosine (A), and in many cases is completely devoid of adenosine, and is also presented as a composition, which may be in the form of a capsule or cartridge, various formulations, and a kit provided with a delivery device and instructions for its use. The anti-sense-oligos of the invention may have their adenosine content reduced by substitution with an adenosine-like binding substitute such as universal base.

The kit may also have other therapeutic agents, and ingredients for the composition. The agent also may be provided operatively linked to a vector and/or in a transfected host cell.
The agent, composition and formulation of the invention may be applied to the treatment of a disease or condition associated with the presence of an mRNA
corresponding to at least one target gene, genomic flanking regions or proteins, by administration to a subject afflicted with the disease or condition of an amount of the MTA oligo of this invention effective to reduce the production or availability, or to increase the degradation, by the subject of at least one of the target mRNA. In a preferred embodiment, the agent may be administered in an amount effective to reduce the production or availability, or to increase the degradation of at least two of the target mRNAs. Typical diseases and conditions of this invention are those associated with impaired respiration and inflammation, including lung diseases, ailments and conditions that have a negative effect on the lungs of a subject. Examples of diseases and conditions, which may be treated preventively, prophylactically and therapeutically with the agent of this invention, are pulmonary vasoconstriction, inflammation, allergic rhinitis, acute asthma, allergies, asthma, impeded respiration, respiratory distress syndrome, pain, cystic fibrosis, pulmonary hypertension, pulmonary vasoconstriction, emphysema, chronic obstructive pulmonary disease (COPD), and cancers such as leukemias, lymphomas, carcinomas, and the like, e.g. colon cancer, breast cancer, lung cancer, pancreatic cancer, hepatocellular carcinoma, kidney cancer, melanoma, hepatic metastases, etc., as well as all types of cancers which may metastasize or have metastasized to the lung(s), including breast and prostate cancer. The present agents) is (are) also suitable for administration before, during and after other treatments, including radiation, chemotherapy, antibody therapy, phototherapy and cancer, and other types of surgery. Alternatively, the present agent may be effectively administered preventively, prophylactically or therapeutically, and in conjunction with other therapies, or by itself for conditions without known therapies or as a substitute for therapies that have significant negative side effects.
The composition of this invention may be administered by transdermal or systemic routes, including by, but not exclusively, oral, intracavitary, intranasal, intraanal, intravaginal, transdermal, intradermal, intrabuccal, intravenous, subcutaneous, intramuscular, intratumor, intraglandular, by inhalation, intraarterial, intravascular in general, into the ear, intracranial, intrathecal, intraorgan including via a shunt to, for example, the liver or other organs, by implantation and intraocular administration to a human or any other animal, including vertebrates, such as mammals. The treatment of this invention may be prophylactic or therapeutic. In a preferred embodiment, the present agents are administered directly into the respiratory system of a subject, so that the agent has direct access to the lungs, in an amount effective to reduce or inhibit the effect in the lung of the targeted diseases or conditions.

The agent of this invention may be produced by selecting two or more targets such as genes, genomic flanking regions, intron-exon borders, and the like, or the entire sequence of RNAs, including non-coding RNAs, and RNAs encoding proteins known to be associated with at least one disease or condition; obtaining RNAs selected from the group consisting of RNAs corresponding to the genes and genomic flanking regions, and RNAs encoding the target proteins; selecting a segment of a first RNA which is at least about 60%, preferably about 80 % , and still more preferably about 90 % and even about 100 % homologous to a segment of at least a segment of a second RNA; and synthesizing one or more anti-sense oligonucleotide(s) to the one or more RNA segments. The target RNA includes every segment of precursor and spliced mRNAs and other RNA molecules, including the 5'- and 3'-ends, and the coding portions as well as overlapping segments juxtaposed over the coding and non-coding sequences. In a preferred form of the invention, the two or more targets may be located in the same molecule. For instance, in the case of a mRNA encoding a protein with multiple subunits, MTA oligos may be found in segments of the RNA which encode different protein subunits.
Also provided are MTA oligos which are produced by the method of the invention.
This invention arose from a desire by the inventor to improve on his own prior discovery, and those of others, that anti-sense oligonucleotides may be utilized therapeutically in the treatment of diseases or conditions which have multiple contributing pathways. The inventor reasoned that he could improve on his prior success in attenuating or enhancing the effects of one specific pathway by designing anti-sense oligonucleotides directed to a specific target associated with a disease or condition. He, thus, set out to attempt a novel and unobvious strategy directed to multiple targets. In so doing, he overcame numerous obstacles, particularly the extensive searching and selection necessary to obtain targets as well as their locating the desired sequences, be it genomic DNA, RNAs or proteins involved in specific diseases.
Thereafter, he exemplified the invention by application to some specific diseases or conditions, and provided various preferred embodiments and specifically designed multiple targeted anti-sense oligonucleotide (MTA oligo) sequences.
The mufti-targeted anti-sense (MTA) oligonucleotides of this invention have the capacity to attenuate the expression of more than one target mRNA, or to enhance or attenuate the activity of one or more pathways. By means of example, the present method may be practiced by first identifying all possible desadenosine (desA) anti-sense sequences of about 7, about 10, about 12, about 15, about 18, about 21 to about 28, about 30, about 35, about 40, about 45, about 50, about 60 or more mononucleotides in a target mRNA. This may be attained by searching for segments that are 7 or more nucleotides long within a target sequence which are low in, or lack, thymidine (T), a nucleotide which is complementary to adenosine (A). This search typically results in about 10 to 30 such desT segments, i. e.
naturally lacking thymidine, or segments with low T content, e. g. up to and including about 15 % T, from which anti-sense oligonucleotides of varying lengths may be designed for a typical target mRNA of average length, i. e. about 1800 nucleotides long. Thereafter, the sense sequence for each strictly complementary desA anti-sense sequence obtained for a specific target may be then deduced. The thus deduced sense sequence may be then used to search for sequences of preferred secondary targets. Alternatively, one or more sequence data bases, e. g., GENBANK, and the like, may be searched for alternative secondary sequences.Thus, the targeting may be undertaken in several manners, one being the selection of specific targets associated with one or more related diseases. Alternatively, a primary target may be selected first, and an anti-sense oligonucleotide found, preferably a desA
oligonucleotide and, then, secondary, tertiary or more targets searched for. In a typical search, either the list of preferred secondary targets or of a data base, multiple instances of homologous secondary targets of interest are identified. That is, the present technology is directed to finding the instances where there are natural homologies between primary, secondary, and greater sequences, and utilizing the finding for the therapeutic treatment of specific diseases or conditions associated with the target macromolecules from which the MTAs are obtained.
The present technology relies on the design of anti-sense oligos targeted to mRNAs associated with ailments involving lung airway pathology(ies), and on their modification to reduce the occurrence of undesirable side effects caused by their release of adenosine upon breakdown, while preserving their activity and efficacy for their intended purpose. In this manner, the inventor targets a specific gene to design one or more anti-sense oligonucleotide(s) (oligos) that selectively binds) to the corresponding mRNA, and then reduces, if necessary, their content of adenosine via substitution with universal base or an adenosine analog incapable of activating adenosine A,, A~ or A3 receptors. Based on his prior experience in the field, the inventor reasoned that in addition to "downregulating" specific genes, he could increase the effect of the agents) administered by either selecting segments of RNA that are devoid, or have a low content, of thymidine (T) or, alternatively, substitute one or more adenosine(s) present in the designed oligonucleotide(s) with other nucleotide bases, so called universal bases, which bind to thymidine but lack the ability to activate adenosine receptors and otherwise exercise the constricting effect of adenosine in the lungs, etc.
Given that adenosine (A) is a nucleotide base complementary to thymidine (T), when a T appears in the RNA, the anti-sense oligo will have an A at the same position. For consistency's sake, all RNAs and 3 5 oligonucleotides are represented in this patent by a single strand in the 5' to 3' direction, when read from left to right, although their complementary sequences) is (are) also encompassed within the four corners of the invention. In addition, all nucleotide bases and amino acids are represented utilizing the recommendations of the IUPAC-IUB Biochemical Nomenclature Commission, or by the known 3-letter code (for amino acids).
The method of the present invention may be used to treat ailments associated with reduced airway function in a subject, whatever its cause. The adenosine content of the anti-sense agents) of the invention have a reduced A content to prevent its liberation upon in vivo degradation of the agent{s). Examples of airway diseases that may be treated by the method of the present invention include cystic fibrosis, asthma, pulmonary hypertension and vasoconstriction, chronic obstructive pulmonary disease (COPD), chronic bronchitis, respiratory distress syndrome, lung cancer and Lung metastatic cancers and other airway diseases, including those with inflammatory response.
Anti-sense oligos to the adenosine A,, A2a, A2b, and A3 receptors, CCR3 (chemokine receptors), bradykinin 2B, CAM (vascular cell adhesion molecule), and eosinophii receptors, among others, have been shown to be effective in down-regulating the expression of their genes. Some of these act to alleviate the symptoms or reduce respiratory ailments and/or inflammation, for example, by "down regulation" of the adenosine A,, Ate, Azb, and/or A3 receptors and CCR3, bradykinin 2B, VCAM (vascular cell adhesion molecule) and eosinophil receptors. These agents are preferably administered directly into the respiratory system, e.g., by inhalation or other means, so that they may reach the lungs without widespread systemic dissemination. This permits the use of substantially lower doses of the agent of the invention as compared with those administered by the prior art, systemically or by other generalized routes and, consequently, reduce undesirable side effects resulting from the agent's widespread distribution in the body. The agents) of this invention has (have) been shown to reduce the amount of receptor protein expressed by the tissue. These agents, thus, rather than merely interacting with their targets, e.g. a receptor, lower the number of target proteins that other drugs may interact with. In this manner, the present agents) affords) extremely high efficacy with low toxicity.
The adenosine receptors discussed above are mere examples of the high power of the inventor's technology. In fact, a large number of genes may be targeted in a similar manner by the present agent(s), to reduce or down-regulate protein expression. By means of example, if the target disease or condition is one associated with impeded or reduced breathing, bronchoconstriction, chronic bronchitis, puhnonary bronchoconstriction and/or hypertension, chronic obstructive pulmonary disease (COPD), allergy, asthma, cystic fibrosis, respiratory distress syndrome, cancers, which either directly or by metastasis afflict the lung, the present method may be applied to a list of potential target mRNAs, which includes the targets listed in Table 1 below, among others.

Table 1: Pulmonary Disease or Condition (Asthma/Inflammation) Targets NfxB Transcription FactorInterleukin-8 Receptor (IL-8 R) Interleukin-5 Receptor Interleukin-4 Receptor (IL-4R) (IlrSR) Interleukin-3 Receptor Interleukin-1(3 (IL-1(3) (IL-3R) Interleukin-1/3 ReceptorEotaoin (IL-l~iR) Tryptase Major Basic Protein ~i2-adreneigic Receptor Endothelin Receptor A
Kinase Endothelin Receptor B Preproendothelin Bradykinin B2 Receptor IgE (High Affinity Receptor) (B2BR) Interleukin-1 (IL-1) Interleukin 1 Receptor (IL-1 R) Interleukin-9 (IL-9) Interleukin-9 Receptor (IL-9 R) Interleukin-11 (IL-11) Interleukin-11 Receptor (IL-11 R) Inducible Nitric Oude Cyclooxygenase (COX) Synthase Intracellular Adhesion Molecule 1 (ICAM-1) Vascular Cellular Adhesion Molecule (VCAM) Rantes Endothelial Leukocyte Adhesion Molecule (SLAM-1) Cycloozygenase-2 (COX-2)GM-CSF, Endothelin-1 Monocyte Activating FactorNeutrophil Chemotactic Factor Neutrophil Elastase Defensin 1,2,3 Muscarinic AcetylcholinePlatelet Activating Factor Receptors Tumor Necrosis Factor 5-lipoxygenase a Phosphodiesterase IV Substance P

Substance P Receptor Histamine Receptor Chymase CCR-1 CC Chemokine Receptor Interleukin-2 (IL-2) Interleukin-4 (IL-4) Interleukin-12 (IL-12) Interleukin-5 (IL-5) Interleukin-6 (IL-6) Interleukin-7 (IL-7) Interleukin-8 (IL-8) Interleukin-12 Receptor (IL-12R) Interleukin-7 Receptor Interleukin-1 (IL-1) (IL-7R) Interleukin-14 Receptor Interleukin-14 (IL-14R) CCR-2 CC Chemokine ReceptorCCR-3 CC Chemokine Receptor CCR-4 CC Chemokine ReceptorCCR-5 CC Chemokine Receptor Prostanoid Receptors GATA-3 Transcription Factor Neutrophil Adherence MAP Kinase Receptor Interleukin-15 (IL-15) Interleukin-15 Receptor (IL-15R) Interleukin-11 (IL-11) Interleukin-11 Receptor (IL-11R) NFAT Transcription FactorsSTAT 4 Table 1: Pulmonary Disease or Condition (Astluna/Inflammation) Targets (Cont'ed) MIP-1 a MCP-2 Cyclophillin (A, B, etc.)Phospholipase Basic Fibroblast Growth Metalloproteinase Factor CSBP/p38 MAP Kinase Tryptase Receptor PDG2 Interleukin-3 (IL-3) Interleukin-10 (IL-10) Cyclosporin A
-Binding Protein FK506-Binding Protein a4 p1 Selectin Fibronectin a4 p7 Selectin cMad CAM-1 LFA-1 (CDlla/CD18) Selectin C3bi PSGL-1 E-Selectin P-Selectin CD-34 L-Selectin p150,95 Mac-1 (CDIIb/CD18) Fucosyl transferase VLA-4 CD-18/CDlla CDllb/CD18 ICAM2 and ICAM3 CSa CCR3 (Eotaxin Receptor) CCRl, CCR2, CCR4, CCRS

Transcription Factor Protein kinase C Cysteinyl Leukotriene Receptor Tachykinnen Receptors IxB
(tach R) Kinase &

Interleukin-2 Receptor (e.g., (IL-2R) Substance P, &

Receptors) STAT 6 c-mas NF-Interleukin-6 (NF-IL-6)Interleukin-10 Receptor (IL-lOR) Interleukin-3 (IL-3) Interleukin-2 Receptor (IL-2R) Interleukin-13 (IL-13) Interleukin-12 Receptor (IL-12R) Interleukin-14 (IL-14) Interleukin-6 Receptor (IL-6R) Interleukin-16 (IL-16) Interleukin-13 Receptor (IL-13R) Medullasin Interleukin-16 Receptor (IL-16R) Adenosine A, Receptor Tryptase-I
(A, R) Adenosine AZb Receptor Adenosine (A~, R) A3 Receptor (A3 R) (3 Tryptase Adenosine A~, Receptor IgE
(A2, R) Receptor (3 Subunit (IgE
R
~3) Fc-epsilon receptor CD23IgE
antigen Receptor a Subunit (IgE
R
a) IgE Receptor Fc Epsilon Receptor (IgERFc ~ R) Substance P Receptor Histidine decarboxylase Tryptase-1 Prostaglandin D SynthaseEosinophil Cationic Protein Eosinophil Derived NeurotoxinEosinophil Peroxidase Endothelial Nitric OxideEndothelial Synthase Monocyte Activating Factor Neutrophil Oxidase FactorCathepsin G

Macrophage Inflammatory Interleukin-8 Protein-1- Receptor a Subunit (IL-8 R
a) Alpha/Rantes Receptor Substance P

Endothelin Receptor ET-BEndothelin ETA
Receptor The oligos of this invention may be obtained by first selecting fragments of a target nucleic acid having at least 4 contiguous nucleic acids selected from the group consisting of G and C, and then obtaining a first oligonucleotide 4 to 60 nucleotides long which comprises the selected fragment and has a C and G nucleic acid content of up to and including about 15 % . The latter step may be conducted by obtaining a second oligonucleotide 4 to 60 nucleotides long comprising a sequence which is anti-sense to the selected fragment, the second oligonucleotide having an adenosine base content of up to and including about 15 % . This SS method may also comprise, when the selected fragment comprises at least one thymidine base, substituting an adenosine base in the corresponding nucleotide of the anti-sense fragment with a universal base selected from the group consisting of heteroaromatic bases which bind to a thymidine base but have antagonist activity and less than about 0.3 of the adenosine base agonist activity at the adenosine AI, A2b and A3 receptors, and heteroaromatic bases which have no activity or have an agonist activity at the adenosine A~ receptor. The analogue heteroaromatic bases may be selected from all pyrimidines and purines, which may be substituted by O, halo, NH2, SH, SO, SOZ, 503, COOH and branched and fused primary and secondary amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkenoxy, acyl, cycloacyl, arylacyl, alkynoxy, cycloalkoxy, aroyl, arylthio, arylsulfoxyl, halocycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkynylcycioallcyl, haloaryl, alkylaryl, alkenylaryl, alkynylaryl, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, which may be further substituted by O, halo, NHZ, primary, secondary and tertiary amine, SH, SO, SOZ, S03, cycloalkyl, heterocycloalkyl and heteroaryl. The pyrimidines and purines may be substituted at all positions as is known in the art, but preferred are those which are substituted at positions 1, 2, 3, 4, 7 and/or 8. More preferred are pyrimidines and purines such as theophylline, caffeine, dyphylline, etophylline, acephylline piperazine, bamifylline, enprofylline and xantine having the chemical formula p R1~N/ i !C/N~ 3 II
i~r,,~3~C~f~~
O N H
R ~' wherein R' and R2 are independently H, alkyl, alkenyl or alkynyl and R3 is H, aryl, dicycloalkyl, dicycloalkenyl, . dicycloalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, O
cycloalkyl, O-cycloalkenyl, O-cycloalkynyl, NH2-alkylamino-ketoxyallcyloxy-aryl, mono and dialkylaminoalkyl-N-alkylamino-S02 aryl, among others.
When no segments having the desired T content were found or where desirable segments contained T, the inventor proposed to reduce the adenosine content of the anti-sense oligos corresponding to the thymidines (T) present in the target RNA to less than about 15 % , or fully eliminated A from the oligonucleotide sequence as a means for preventing their breakdown products from freeing adenosine into the lung tissue environment and, thereby, aggravating the subject's ailment and/or countering the beneficial effect of the administered agent.
By means of example, the NfxB transcription factor may be selected as a primary target and searched for desthymidine (desT) segments. When a number of desT segments are found, the anti-sense segments may be deduced, and perhaps about 20 or even more desA
anti-sense sequences obtained. These anti-sense sequences represent, when possible, all desA anti-sense sequences found within the mRNA of this primary target, and may be utilized to start the search for homologous sequences within a preferred list of secondary targets such as the one shown iri Table 1 above or Table 2 below, or within a sequence data base, such as GENBANK.
For each of the about 20 original desA anti-sense sequences found for NFx transcription factor, typically about 10 to 30 homologous sequences may be found among the other members of the group shown in Table 1 above (secondary, tertiary, and the like targets). In some instances, the search produces a homology for the primary target with, not only secondary targets (homology between primary target and sequence from one other target mRNA), but with tertiary targets (homology between primary target and sequences from, e. g.
three other target mRNA), as well. The latter case, however, is more rare. When this occurs, the anti-sense oligos found are said to be 100% homologous. More typically, however, the sequences found contain some non-fully homologous nucleotides within the secondary or tertiary or quaternary sequences. In many cases, this mismatch would suffice to render the anti-sense oligonucleotide less active or even inactive against the target(s). In some instances, the presence of even one non-homologous nucleotide may be sufficient to reduce the activity of an anti-sense oligonucleotide. When the so called "homologous" sequences obtained have mismatches, acceptable are up to about 40 % , preferably no more than about 30 % , more preferable no more than 20% , still more preferable no more than 10% mismatched nucleotides. In some instances the higher % mismatches are acceptable, and the oligos still are active since the non-homologous nucleotide may be "fixed" or replaced with a "Universal" base that may base-pair with similar or equal affinity with two or more of the four nucleotide present in natural DNA:
A, G, C, and T. This "fixing" step generates a further novel sequence, different from the one found in nature, that permits the anti-sense oligonucleotide to bind, preferably equally well, with the primary target, the secondary target, the tertiary target, etc.
As the NfxB transcription factor is selected as a target, its mRNA or DNA are searched for low thymidine (T) or desthymidine (desT) fragments. Only desT segments of the mRNA
or DNA are selected which, in turn, will produce desA anti-sense as their complementary strand. When a number of RNA desT segments are found, the sequence of the anti-sense segments may be deduced. Typically, about 10 to 30 and even larger numbers of desA anti-sense sequences may be obtained. These anti-sense sequences may include some or all desA
anti-sense oligonucleotide sequences corresponding to desT segments of the mRNA of the target, such as anyone of those shown in Table 1 above or Table 2 below. When this occurs, the anti-sense oligonucleotides found are said to be 100% A-free. For each of the original desA
anti-sense oligonucleotide sequences corresponding to the target gene, e.g.
the NFxB

transcription factor, typically about 10 to 30 sequences may be found within the target gene or RNA which have a low content of thymidine (RNA). In accordance with this invention, the selected fragment sequences may also contain a small number of thymidine (RNA) nucleotides within the secondary or tertiary or quaternary sequences. In some cases, a large adenosine content W ay suffice to render the anti-sense oligonucleotide less active or even inactive against the target. In accordance with this invention, these so called "non-fully desA" sequences may preferably have a content of adenosine of less than about 15 % , more preferably less than about % , and still more preferably less than 5 % , and some even less than 2 %
adenosine. In some instances a higher content of adenosine is acceptable and the oligonucleotides are still active, 10 particularly where the adenosine nucleotide may be "fixed" or replaced with a "Universal"
base that may base-pair with similar or equal affinity to two or more of the four nucleotide present in natural DNA: A, G, C, and T. A universal base is defined in this patent as any compound, more commonly an adenosine analogue, having the capacity to hybridize to thymidine, preferably having substantially reduced, or substantially lacking, ability to bind adenosine receptors. Alternatively, adenosine analogs which do not activate adenosine receptors, such as the adenosine A,, AZ b and/or A3 receptors, most preferably A, receptors, may be used. One example of a universal base is a-deoxyribofuranosol-(5-nitroindole), and an artisan will know how to select others. This "fixing" step generates a further novel sequence, different from the one found in nature, that permits the anti-sense oligonucleodde to bind, preferably equally well, with the target RNA. An example of a universal base is 2-deoxyribosyl-(S-nitroindole). Other examples of universal bases are 3-nitropyrrole-2'-deoxynucleoside, 5-vitro-indole, 2-deoxyribosyl-(5-nitroindole), 2-deoxyribofuranosyl-{5-nitroindole), 2'-deoxyinosine, 2'-deoxynebularine, 6H, 8H-3,4-dihydropyrimido [4,5-c]
oxazine-7-one and 2-amino-6-methoxyaminopurine. In addition to the above, Universal bases which may be substituted for any other base although with somewhat reduced hybridization potential, include 3-nitropyrrole 2'-deoxynucleoside 2-deoxyribofuranosyl-(5-nitroindole), 2'-deoxyinosine and 2'-deoxynebularine (Glen Research, Sterling, VA). More specific mismatch repairs may be made using "P" nucleotide, 6H, 8H-3, 4-dihydropyrimido[4,5-c]
[1,2] oxazin-7-one, which base pairs with either guanine (G) or adenine (A) and "K"
nucleotide, 2-amino-6-methoxyaminopurine, which base pairs with either cytidine (C) or thymidine (T), among others. Others which are known in the art are also suitable. See, for example, Loakes, D. and Brown, D. M., Nucl .Acids Res. 22:4039-4043 (1994);
Ohtsuka, E. et al., J. Biol. Chem.260(5):2605-2608 {1985); Lin, P.K.T. and Brown, D.
M., Nucleic Acids Res. 20(19):5149-5152 (1992; Nichols, R. et al., Nature 369(6480): 492-4.93 (1994);
Rahmon , M. S. and Humayun, N. Z., Mutation Research 377 (2): 263-8 (1997);
Amosova, O., et al., Nucleic Acids Res. 25 {!0): 1930-1934 (1997); Loakes D. & Brown, D. M., Nucleic Acids Res. 22 (20): 4039-4043 (1994), the entire sections relating to universal bases and their preparation and use in nucleic acid binding is inceorporated herein by reference.
When non-fully desT sequences are found in the naturally occurring target, they typically are selected so that about 1 to 3 universal base substitutions will suffice to obtain a S 100% "desA" anti-sense oligonucleotide. Thus, the present method provides either anti-sense oligonucleotides to different targets which are low in, or devoid of, A
content, as well as anti sense oligonucleotides where one or more adenosine nucleotides, e. g. about 1 to 3, or more, may be "fixed" by replacement with a "Universal" base. Universal bases are known in the art and need not be listed herein. An artisan will know which bases may act as universal bases, and replace them for A.
The present approach to the design of anti-sense oligonucleotide approach is also applicable to a variety of other diseases or conditions, including other inflammatory diseases, such as cystic fibrosis, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary hypertension, cancers, including those which metastasize to the lung, such as breast cancer, colon cancer, respiratory distress syndrome, prostate cancer, pancreatic cancer, kidney cancer, lymphomas, melanomas, hepatocellular carcinomas, etc.
As used herein, the term "treat" or "treating" asthma or other respiratory and inflammatory conditions or diseases refers to a treatment which decreases the likelihood that the subject administered such treatment will manifest symptoms of a respiratory or inflammatory lung disease or other lung conditions. The term "down-regulate"
refers to inducing a decrease in production, secretion or availability (and thus a decrease in concentration) of the targeted intracellular protein.
The present invention is concerned primarily with the treatment of vertebrates, and within this group, of mammals, including human and non-human simians, wild and domesticated animals, marine and land animals, household pets, and zoo animals, for example, felines, canines, equines, pachiderms, cetaceans, and still more preferably to human subjects.
One particularly suitable application of this technology is for veterinary purposes, and includes all types of small and Iarge animals in the care of a veterinarian, including wild animals, marine animals, household animals, zoo animals, and the like. Targeted genes and proteins are preferably mammalian, and the sequences targeted are preferably of the same species as the subject being treated. Although in many instances, targets of a different species are also suitable, particularly those segments of the target RNA or gene that display greater than about 45 % homology, preferably greater than about 85 % homology, still more preferably greater than about 95 % homology, with the recipient's sequence. A preferable group of agents is composed of des-A anti-sense oligos. Another preferred group is composed of non-fully desA
oligonucleotides, where one or more adenosine bases are replaced with universal bases.

WO 99/1388b PCT/US98/19419 The terms "anti-sense" oligonucleotides generally refers to small, synthetic oligonucleotides, resembling single-stranded DNA, which in this patent are applied to the inhibition of gene expression by inhibition of a target messenger RNA (mRNA).
See, Milligan, J. F. et al., J. Med. Chem. 36(14), 1923-1937 (1993), the relevant portion of which is hereby incorporated in its entirety by reference. The present agents inhibit gene expression of target genes, such as those of the adenosine A1 Ate, A2b; or A3 receptors, CCR3 (chemical receptor 320, also known as the eotaxin receptor), VCAM (vascular cell adhesion molecule), eonophil receptor, bradykinin 2B receptor, and many others listed in Table 1 above. This is generally attained by hybridization of the anti-sense oligonucleotides to coding (sense) sequences of a targeted messenger RNA (mRNA), as is known in the art. The exogenously administered agents of the invention decrease the levels of mRNA and protein encoded by the target gene and/or cause changes in the growth characteristics or shapes of the thus treated cells. See, Milligan et al. (1993); Helene, C. and Touhne, J. Biochim.
Biophys. Acta 1049, 99-125 (1990); Cohen, J. S. D., Ed., Oligodeoxynucleotides as Anti-sense Inhibitors of Gene Expression; CRC Press: Boca Raton, FL (1987), the relevant portion of which is hereby incorporated in its entirety by reference. As used herein, "anti-sense oligonucleotide" is generally a short sequence of synthetic nucleotide that ( 1 ) hybridizes to any segment of a mRNA encoding a targeted protein under appropriate hybridization conditions, and which (2) upon hybridization causes a decrease in gene expression of the targeted protein.
The terms "des-adenosine" (desA) and "des-thymidine" (desT) refer to oligonucleotides substantially lacking either adenosine (desA) or thymidine (desT). In some instances, the des T sequences are naturally occurring, and in others they may result from substitution of an undesirable nucleotide (A) by another one lacking its undesirable activity. In the present context, the substitution is generally accomplished by substitution of A with a "universal base" , as is known in the art.
The mRNA sequence of the targeted protein may be derived from the nucleotide sequence of the gene expressing the protein. For example, the sequence of the genomic human adenosine A, receptor and that of the rat and human adenosine Ag receptors are known. See, US Pat. No. 5,320,962; Zhou, F., et al., Proc. Nat' 1 Acad. Sci. (USA) 89 :7432 (1992);
Jacobson, M.A., et al., U.K. Pat. Appl. No. 9304582.1. The sequence of the adenosine A~, receptor gene is also known. See, Salvatore, C. A., Luneau, C. J., Johnson, R.
G. and Jacobson, M., Genomics (1995), the relevant portion of which is hereby incorporated in its entirety by reference. The sequences of many of the exemplary target genes are also known.
See, GenBank, NIH. The sequences of those genes whose sequences are not yet available may be obtained by isolating the target segments applying technology known in the art. Once the sequence of the gene, its RNA and/or the protein are known, an anti-sense oligonucleotides WO 99/1388b PCT/US98/I9419 may be produced according to this invention as described above to reduce the production of the targeted protein in accordance with standard techniques.
In one aspect of this invention, the anti-sense oligonucleotide has a sequence which specifically binds to a portion or segment of an mRNA molecule which encodes a protein S associated with a disease or condition associated with impeded breathing, lung inflammation, airway obstruction, bronchitis, and the like. One effect of this binding is to reduce or even prevent the translation of the corresponding mRNA and, thereby, reduce the available amount of target protein in the subject's lung.
In one preferred embodiment of this invention, the phosphodiester residues of the anti-sense oligonucleotide are modified or substituted. Chemical analogs of oligonucleotides with modified or substituted phosphodiester residues, e.g., to the methylphosphonate, the phosphotriester, the phosphorothioate, the phosphorodithioate, or the phosphoramidate, which increase the in vivo stability of the oligonucleotide are particularly preferred. The naturally occurring phosphodiester linkages of oligonucleotides are susceptible to some degree of degradation by cellular nucleases. Many of the residues proposed herein, on the contrary, are highly resistant to nuclease degradation. See Milligan et al., and Cohen, J.
S. D., supra. In another preferred embodiment of the invention, the oligonucleotides may be protected from degradation by adding a " 3'-end cap" by which nuclease-resistant linkages are substituted for phosphodiester linkages at the 3' end of the oligonucleotide. See, Tidd, D. M.
and Warenius, H.M., Be. J. Cancer 60: 343-350 (1989); Shaw, J.P. et al., Nucleic Acids Res.
19: 747-750 (1991), the relevant section of which are incorporated in their entireties herein by reference.
Phosphoramidates, phosphorothioates, and methylphosphonate linkages all fiuiction adequately in this manner for the purposes of this invention. The more extensive the modification of the phosphodiester backbone the more stable the resulting agent, and in many instances the higher their RNA affinity and cellular permeation. See Milligan, et al., supra. Thus, the number of residues which may be modified or substituted will vary depending on the need, target, and route of administration, and may be from 1 to all the residues, to any number in between.
Many different methods for replacing the entire phosphodiester backbone with novel linkages are known. See, Millikan et al, supra. Preferred backbone analogue residues include phosphorothioate, methylphosphonate, phosphotriester, thioformacetal, phosphorodithioate, phosphoramidate, formacetal boranophosphate, 3'-thioformacetal, 5'-thioether, carbonate, 5'-N-carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite., 2'-O methyl, sulfoxide, sulfide, hydroxylamine, methylene(methylimino) (MMI), and methyleneoxy(methylimino) (MOMI) residues. Phosphorothioate and methylphosphonate-modified oiigonucleotides are particularly preferred due to their availability through automated oligonucleotide synthesis. See, Millikan et al, supra. Where appropriate, the agent of this invention may be administered in the form of their pharmaceutically acceptable salts, or as a mixture of the anti-sense oligonucleotide and its salt. In another embodiment of this invention, a mixture of different anti-sense oligonucleotides or their pharmaceutically acceptable slats is administered.
S The agents of this invention have the capacity to attenuate the expression of one target mRNA and/or to enhance or attenuate the activity of one pathway. By means of example, the present method may be practiced by identifying all possible deoxyribonucleotide segments which are low in thymidine (T) or deoxynucleotide segments low in adenosine (A) of about 7 or more mononucleotides, preferably up to about 60 mononucleotides, more preferably about 10 to about 36 mononucleotides, and still more preferably about 12 to about 21 mononucleoddes, in a target mRNA or a gene, respectively. This may be attained by searching for mononucleotide segments within a target sequence which are low in, or lack thymidine (RNA), a nucleotide which is complementary to adenosine, or that are low in adenosine (gene), that are 7 or more nucleotides long. In most cases, this search typically results in about 10 to 30 such sequences, I. e. naturally lacking or having less than about 40%
adenosine, anti-sense oligonucleotides of varying lengths for a typical target mRNA of average length, i. e., about 1800 nucleotides long. Those with high content of T or A, respectively, may be fixed by substitution of a universal base for one or more As.
The agents) of this invention may be of any suitable length, including but not limited to, about 7 to about 60 nucleotides long, preferably about 12 to about 45, more preferably up to about 30 nucleotides long, and still more preferably up to about 21, although they may be of other lengths as well, depending on the particular target and the mode of delivery. The agents) of the invention may be directed to any and all segments of a target RNA. One preferred group of agents) includes those directed to an mRNA region containing a junction between an intron and an exon. Where the agent is directed to an intron/exon junction, it may either entirely overlie the junction or it may be sufficiently close to the junction to inhibit the splicing-out of the intervening exon during processing of precursor mRNA to mature mRNA, e.g. with the 3' or 5' terminus of the anti-sense oligonucleotide being positioned within about, for example, within about 2 to 10, preferably about 3 to S, nucleotide of the intron/exon junction. Also preferred are anti-sense oligonucleotides which overlap the initiation codon, and those near the 5' and 3' termini of the coding region.
This mufti-targeted anti-sense (MTA) oligonucleotide approach is, thus, applicable to a variety of other diseases or conditions, including other inflammatory diseases, such as cystic fibrosis, chronic obstructive pulmonary disease, chronic bronchitis, etc..
Other specific diseases or conditions to which this technology is effectively applied are pulmonary hypertension, and cancers.

Table 2 below provides a number of targets to which mufti-targeted anti-sense (MTA) oligonucleotides are effectively applied. Others may also be targeted.
Table 2: Cancer Targets Transforming Therapy Oncogenes Targets ras thymidylate synthetase src thymidylate synthetase myc dihydrofolate reductase bcl-2 thymidine kinase deoxycytidine Icinase ribonucleotide reductase A group of preferred targets for the treatment of cancers are genes associated with different types of cancers, or those generally known to be associated with malignancies, whether they are regulatory or involved in the production of RNA and/or proteins. Examples are transforming oncogenes, including, but not limited to, ras, src, myc, and bcl-2, among others. Other targets are those to which present cancer chemotherapeutic agents are directed to, such as various enzymes, primarily, although not exclusively, thymidylate synthetase, dihydrofolate reductase, thymidine kinase, deoxycytidine kinase, ribonucleotide reductase, and the like.
The present technology is extremely important for the treatment of diseases or conditions such as cancer given that traditional cancer therapies are fraught with the unresolved problem of selectively killing cancer cells while preserving normal living cells from the devastating effects of treatments such as chemotherapy, radiotherapy, and the like. The present technology provides the ability of simultaneously attenuating or enhancing multiple pathways.
This approach provides a significant advantage for the treatment of cancer because it permits the selection of a combination of multiple pathways, including primary, secondary and possibly tertiary targets, which are not generally expressed simultaneously in normal cells. Thus, the present agent may be administered to a subject to cause a selective increase in toxicity within tumor cells that, for instance, express all three targets while normal cells that may expresses only one or two of the targets will be significantly less affected or even spared.
This invention thus provides an agent, comprising an anti-sense oiigonucleotide to two or more mRNAs selected from the group consisting of RNAs corresponding to target genes, to genomic flanking regions, the initiation origin, intron-exon borders, and the like, or the entire sequence of precursor RNAs, including the coding region of mRNAs, non-coding RNA

segments, the 5'-end and the 3'-end, e.g. poly-A segment and oligos targeted to the juxta-section between coding and non-coding regions, and RNAs encoding proteins known to be associated with one or more diseases or conditions or mixtures thereof.
The agents administered in accordance with this invention are preferably designed to be anti-sense to target genes and/or mRNAs related in origin to the species to which it is to be administered. When treating humans, the agents are preferably designed to be anti-sense to a human gene or RNA. The agents of the invention encompass oligonucleotides which are anti-sense to naturally occurring DNA and/or RNA sequences, fragments thereof of up to a length of one (1) base less than the targeted sequence, preferably at least about 7 nucleotides long, oligos having only over about 0.02 % , more preferably over about 0.1 % , still more preferably over about 1 % , and even more preferably over about 4 % adenosine nucleotides, and up to about 30 % , more preferably up to about 1 S % , still more preferably up to about 10 % and even more preferably up to about 5 % , adenosine nucleotide, or lacking adenosine altogether, and oligos in which one or more of the adenosine nucleotides have been replaced with so-called 1 S universal bases, which may pair up with thymidine nucleotides but fail to substantially trigger adenosine receptor activity. Examples of human sequences and fragments, which are not limiting, of anti-sense oligonucleotide of the invention are the following fragments as well as shorter segments of the fragments and of the full gene or mRNA coding sequences, exons and intron-exon junctions encompassing preferably 7, 10, 15, 18 to 21, 24, 27, 30, n-1 nucleotides for each sequence, where n is the sequence's total number of nucleotides.
These fragments may be selected from any portion of the longer oligo, for example, from the middle, 5'- end, 3'- end or starting at any other site of the original sequence. Of particular importance are fragments of low adenosine nucleotide content, that is, those fragments containing less than or about 30 % , preferably less than or about 15 % , more preferably less than or about 10 % , and even more preferably less than or about 5 % , and most preferably those devoid of adenosine nucleotide, either by choice or by replacement with a universal base in accordance with this invention. The agent of the invention includes as a most preferred group sequences and their fragments where one or more adenosines present in the sequence have been replaced by a universal base {B), as exemplified here. Similarly, also encompassed are all shorter fragments of the B-containing fragments designed by substitution of B(s) for adenosine(s) (A(s)) contained in the sequences, fragments thereof or segments thereof, as described above. A
limited list of sequences and fragments is provided below.
Some of the examples of anti-sense oligonucleotide sequence fragments target the initiation codon of the respective gene, and in some cases adenosine is substituted with a universal base adenosine analogue denoted as "B", which lacks ability to bind to the adenosine A, and/or A3 receptors. In fact, such replacement nucleotide acts as a "spacer". Many of the examples shown below provide one such sequence and many fragments overlapping the initiation codon, preferably wherein the number of nucleotides n is about 7, about 10, about 12, about 15, about 18, about 21 and up to about 28, about 35, about 40, about 50, about 60.
In one embodiment, at least one of the mRNAs to which the MTA oligo of the invention is targeted encodes a protein such as transcription factors, stimulating and activating factors, intracellular and extracellular receptors and peptide transmitters in general, interleukins, interleulcin receptors, chemolanes, chemoki~ receptors, endogenously produced specific and non-specific enrymes, immunoglobulins, antibody receptors, central nervous system (CNS) and peripheral nervous and non-nervous system receptors, CNS and peripheral nervous and non-nervous system peptide transmitters, adhesion molecules, defensines, growth factors, vasoactive peptides and receptors, and binding proteins, among others; or the mRNA
is corresponding to an oncogene and other genes associated with various diseases or conditions.
Examples of target proteins are eotaxin, major basic protein, preproendothelin, eosinophil cationic protein, P-selectin, STAT 4, MIP-la, MCP-2, MCP-3, MCP-4, STAT 6, c-mas, NF-IL-6, cyclophillins, PDG2, cyclosporin A-binding protein, FKS-binding protein, fibronectin, LFA-1 (CDIIa/CD18), PECAM-1, C3bi, PSGL-1,CD-34, substance P, p150,95, Mac-1 (CDllb/CD18), VLA-4, CD-18/CDlla, CDIIb/CD18, CSa, CCRl, CCR2, CCR4, CCRS, and LTB-4, among others. Others are, however, suitable, as well.
In another embodiment, at least one of the mRNAs to which the MTA oligo is targeted encodes intracellular and extracellular receptors and peptide transmitters such as sympathomimetic receptors, parasympathetic receptors, GABA receptors, adenosine receptors, bradykinin receptors, insulin receptors, glucagon receptors, prostaglandin receptors, thyroid receptors, androgen receptors, anabolic receptors, estrogen receptors, progesterone receptors, receptors associated with the coagulation cascade, adenohypophyseal receptors, adenohypophyseal peptide transmitters, and histamine receptors (HisR), among others.
However others are also contemplated.
The encoded sympathomimetic receptors and parasympathomimetic receptors include acetylcholinesterase receptors (AcChaseR) acetylcholine receptors (AcChR), atropine receptors, muscarinic receptors, epinephrine receptors (EpiR), dopamine receptors (DOPAR), and norepinephrine receptors (NEpiR), among others. Further examples of encoded receptors are adenosine A, receptor, adenosine AZB receptor, adenosine A3 receptor, endothelin receptor A, endothellin receptor B, IgE high affinity receptor, muscarinic acetylcholine receptors, substance P receptor, histamine receptor, CCR-1 CC chemokine receptor, CCR-2 CC
chemolcine receptor, CCR-3 CC chemokine receptor (Eotaxin Receptor), interleukin-1[3 receptor (IL-1(3R), interleukin-1 receptor (IL-1R), interleukin-lei receptor (IL-l~iR), interleukin-3 receptor (IL-3R), CCR-4 CC chemolcine receptor, cysteinyl leukotriene receptors, prostanoid receptors, GATA-3 transcription factor receptor, interleukin-1 receptor (IL-1R), interleukin-4 receptor (IL-4R), interleukin-5 receptor (IL-SR), interleukin-8 receptor (IL-8R), interleukin-9 receptor (IL-9R), interleukin-11 receptor (IL-11R), bradykinin B2 receptor, sympathomirnetic receptors, parasympathomimetic receptors, GABA
receptors, adenosine receptors, bradykinin receptors, insulin receptors, glucagon receptors, prostaglandin receptors, thyroid receptors, androgen receptors, anabolic receptors, estrogen receptors, progesterone receptors, receptors associated with the coagulation cascade, adenohypophyseal receptors, and histamine receptors (HisR). Others are also contemplated even though not listed herein.
The encoded enzymes for development of the MTA oligos of the invention include synthetases, kinases, oxidases, phosphatases, reductases, polysaccharide, triglyceride, and protein hydrolases, esterases, elastases, and , polysaccharide, triglyceride, lipid, and protein synthases, among others. Examples of target enzymes are tryptase, inducible nitric oxide synthase, cyclooxygenase (Cox), MAP kinase, eosinophil peroxidase, X32-adrenergic receptor 1 S kinase, leukotriene c-4 synthase, S-lipooxygenase, phosphodiesterase IV, metalloproteinase, tryptase, CSBP/p38 MAP kinase, neutrophil elastase, phospholipase A2, cyclooxygenase 2 (Cox-2), fucosyl transferase, chymase, protein kinase C, thymidylate synthetase, dihydrofolate reductase, thymidine kinase, deoxycytidine kinase, and ribonucleotide reductase, among others. Any enzyme associated with a disease or condition , however, is suitable as a target for this invention.
Suitable encoded factors for application of this invention are, among others, NficB
transcription factor, granulocyte macrophage colony stimulating factor (GM-CSF), AP-1 transcription factor, GATA-3 transcription factor, monocyte activating factor, neutrophil chemotactic factor, granulocyte/macrophage colony-stimulating-factor (G-CSF), NFAT
transcription factors, platelet activating factor, tumor necrosis factor a (TNF a), and basic fibroblast growth factor (BFGF). Additional factors are also within the invention even though not specifically mentioned.
Suitable adhesion molecules for use with this invention include intracellular adhesion molecules 1 (ICAM-1), 2 (ICAM-2) and 3 (ICAM-3), vascular cellular adhesion molecule (VCAM), endothelial leukocyte adhesion molecule-1 (SLAM-1), neutrophil adherence receptor, mad CAM-1, and the like. Other known and unknown factors (at this time) may also be targeted herein.
Among the cytokines, lymphokines and chemokines preferred are interleukin-1 (IL-1), interleukin-lei (IL-1)interleukin-3 (IL,-3), interleukin-4 (IL-4), interleukin-5 (IL-S), interleukin 8 (IL-8), interleukin-9 (IL-9), interleukin-11 (IL-11),CCR-5 CC chemokine, and Rantes.
Others, however, may also be targeted, as they are known to be involved in specific diseases or conditions to be treated, or for their generic activities, such as inflammation.
Examples of defensins for the practice of this invention are defensin 1, defensin 2, and defensin 3, and of selectins are a4(31 selectin, a4~i7 selectin, LFA-1 selectin, E-selectin, P-selectin, and L-selectin. Examples of oncogenes, although not an all inclusive list, are ras, src, myc, and bcl-2. Others, however, are also suitable for use with this invention.
The agents administered in accordance with this invention are preferably designed to be anti-sense to target genes and/or mRNAs related in origin to the species to which it is to be administered. When treating humans, the agents are preferably designed to be anti-sense to a human gene or RNA. The agents of the invention encompass oligonucleotides which are anti-sense to naturally occurring DNA and/or RNA sequences, fragments thereof of up to a length of one (1) base less than the targeted sequence, preferably at least about 7 nucleotides long, oligos having only over about 0.02 % , more preferably over about 0.1 % , still more preferably over about 1 % , and even more preferably over about 4 % adenosine nucleotides, and up to about 30 % , more preferably up to about 15 % , still more preferably up to about 10 % and even more preferably up to about 5 % , adenosine nucleotide, or lacking adenosine altogether, and oligos in which one or more of the adenosine nucleotides have been replaced with so-called universal bases, which may pair up with thymidine nucleotides but fail to substantially trigger adenosine receptor activity. Examples of human sequences and fragments, which are not limiting, of anti-sense oligonucleotide of the invention are the following fragments as well as shorter segments of the fragments and of the full gene or mRNA coding sequences, exons and intron-exon junctions encompassing preferably 7, 10, 15, 18 to 21, 24, 27, 30, n-1 nucleotides for each sequence, where n is the sequence's total number of nucleotides.
These fragments may be selected from any portion of the longer oligo, for example, from the middle, S'- end, 3'- end or starting at any other site of the original sequence. Of particular importance are fragments of low adenosine nucleotide content, that is, those fragments containing less than or about 30 % , preferably less than or about 15 % , more preferably less than or about 10 % , and even more preferably less than or about 5%, and most preferably those devoid of adenosine nucleotide, either by choice or by replacement with a universal base in accordance with this invention. The agent of the invention includes as a most preferred group sequences and their fragments where one or more adenosines present in the sequence have been replaced by a universal base (B), as exemplified here. Similarly, also encompassed are all shorter fragments of the B-containing fragments designed by substitution of B(s) for adenosine(s) (A(s)) contained in the sequences, fragments thereof or segments thereof, as described above. A
limited list of sequences and fragments is provided below.
Some of the examples of anti-sense oligonucleotide sequence fragments target the initiation codon of the respective gene, and in some cases adenosine is substituted with a universal base adenosine analogue denoted as "B", which lacks ability to bind to the adenosine A, and/or A3 receptors. In fact, such replacement nucleotide acts as a "spacer". Many of the examples shown below provide one such sequence and many fragments overlapping the initiation codon, preferably wherein the number of nucleotides n is about 7, about 10, about S 12, about 1S, about 18, about 21 and up to about 28, about 3S, about 40, about 50, about 60.
5'--GGCGGCCTGG AAAGCTGAGA TGGAGGGCGG CATGGCGGGC ACAGGCfGGG C TGCTfTfCT
TTTCTGGGCC
TCTGTGGTCT GTTTTTTTCr GGCCCTGCTG GGGCGCfCTC CGCCGCCCGC CTGGCTCCCG GBGCCCBTGB
TGGGCBTGCC
GTGGTTCTTG CCCTCCITfG GCTGCCGTGC CCGCfCCCCG GCCfCCfGGC GGGTGGCCGT TGGGCCCGTG
TTCCCCTGGG
IO GCCTGGGGCf CCCTTCTCfC GCCCTTCTTG CfGGGCCfCT GCTGCTGCTG GTGCfGTGGC CCCCGTACA
CCGAGGAGCC
CATGATGGGC ATGCCACAGA CGACAGGCGT BCBCCGBGGB GCCCHTGHTG GGCBTGCCBC BGBCGBCBGG C
GGC GCC GTG
CCG CGT CTT GGT GGC GGC GG GTT CGC GCC CGC GCG GGG CCC CfC CGG TCC GTT CGC GCC
CGC GCG GGG CCC CTC
CGG TCC CGG GTC GGG GCC CCC CGC GGC C GCC TCG GGG CTG GGG CGC TGG TGG CCG GG
CCG CGC CTC CGC CTG
CCG CTT CTG GCT GGG CCC CGG GCG CCC CCf CCC CTC TTG CrC GGG TCC CCG TG ACA GCG
CGT CCT GTG TCT CCA
1 S GCA GCA TGG CCG GGC CAG CTG GGC CCC BCB GCG CGT CCT GTG TCf CCB GCB GCB
TGG CCG GGC CBG CTG GGC
CCC ACA GAG CAG TGC TGT TGT TGG GCA TCf TGC CTT CCC AGG G BCB GBG CB TGC TGT
TGT TGG GCB TCT TGC CTT
CCC BGG GCC CTT TTC TGG TGG GGT GGT GCT GTT GTT GGG CIT TCT TCT GTT CCC BCB
GBG CBG TGC TGT TGT TGG
GCB TCT TGC CTT CCC BGG GCC CTT TTC TGG TGG GGT GGT GCT GTT GTT GGG C TTT CIT
CfG TTC CC TTT CCC CTG
GGT CIT CC CTC CTG CTC TTT TTT C ATT TGC TCf CCT ATT ACf TTC TGT GTC CAT TTT
TTC ATT AAC CGA GCT GT
2O BTT TGC TCT CCT BTT BCr TTC TGT GTC CBT TTT TTC BTT BBC CGB GCT GT GCC TGT
GTC TGT CCr CCT GCT TCG TTC
CTC TCG TTC CTG CIT GGT GCC CIT GCC G GTC CfG CfC CfC CGG GCT GTG G GTC GTG
GCC CTG GCr CCG GCr GGT
GGG CTC CCC TGG CCT TCG CTG GCf GGC GGC GTG C GGG TCT TGC TCT GGG CCr GGC TGT
GGC CGT GGT TGG GGG
TCT TC GCT GCC TCC GTT TGG GTG GC TCT CTG AAT ATT GAC CfT CCf CCA TGG CGG TCC
TGC TTG GAT TCr CCC
GA TCT CrG BBT BTT GHC CIT CCf CCH TGG CGG TCC TGC T'fG GHT TCT CCC GB GCC TTT
CCf GGT TCT CiT GTT GTT
2 S TTT GGG GTT TGG CTT ACA GTA GAG TAG GGG ATT CCA TGG CAG GAG CCA TCT TCr TCA TGG ACT CC TTC AAG GAG
ACC TTA GGT TTC TGA GGG ACT GCT AAC ACG CCA TCT GGA GC BCB GTB GBG TBG GGG BTT
CCB TGG CBG GBG CCB
TCT TCT TCB TGG BCf CC TTC BHG GBG BCC TTB GGT TTC TGB GGG BCT GCT BBC BCG CCB
TCT GGB GC GTT GTT
TTT GGG GTT TGG CTT GCC TTT CCT GGT TCT CIT BCB GTB GBG THG GGG BTT CCB TGG
CBG GBG CCB TCf TCT TCB
TGG BCT CC TTC BHG GBG BCC TTB GGT TTC TGB GGG BCr GCT BBC BCG CCB TCT GGB GC
GCC TGT GTC TGT CCT
3O CCT GCT TCG TTC CPC TCG TTC CfG CTT GGT GCC CIT GCC G GTC CTG CTC CTC CGG
GCT GTG G GTC CTC GCC CTG
GCf CCG GCf GGT GGG CTC CCC TGG CCT TCG CTG GCT GGC GGC GTG C CCC BGB BCG BGB
CCC GGB CCG BCB GGC
CGT GGT TGG GGG TCf TC GCT GCC TCC GTT TGG GTG GC GAT CfC TGA ATA TTGA CCT TCC
ATG GCG GTC CTG CTT
GGA GBT CTC TGB BTB TTGB CCT TCC BTG GCG GTC CTG CTT GGB TCT GGG GTG TCC TGG
CCf TCG TGG TTC CrC TTC
CTT CGT TTG CCG TCC GCG GGG GCC CCC GGG CCT GGC TGC GCT CCf GCC CCG CCT CTT
TCC CGG GCT CIT GCG CI'G
3 S GGG GGT GCr CC CGT GTG TTT GCG CCC TC CTC CTG GTC GCG CTT GTC GTT TTG GGG
CCG GCT TTG CCC GCC TCC
CGG CGC CfG GCC CGG CC TTC CfG GGC TGC GTG CGC GTT CTG TTC TTC TTC CTG GCT CTG
GGG TGT CCT GGC CTT
CGT GGT TCC TCT TCC TTC GTT TGC CGT CCG CGG GGG CCC CCG GGC CT GGC TGC GCT CCT
GCC CCG CCT CTT TCC
CGG GCT C1T GCG CfG GGG GGT GCT CCC GTG TGT TTG CGC CCT CCT CCf GGT CGC GCf TGT CGT TTT GG GGC CGG
CTT TGC CCG CCf CCC GGC GCC TGG CCC GGC CTT CCf GGG CTG CGT GCG CGT TCT GTT
Crr CTT CCT GGC GCA GGA

CfC CGG AAC GCA GGA
CAG AGG TGC C GC BGG BGB CBG GGC BGG GCG BTC BGG BGC BGC GTG BGC CBB BGG BGG
HCC BTC GGG BBC GCB
GCT CCG GBB CGC HGG BCB GBG GTG CC TCf GCC CTG TCC GCC GGC TCf TCG GTG GCT CGG
CCC CGC TCC TTG TCT
TGC CGC GGG TTG GTT CCT GGG CCT GGT TCf TGC GGG CGT TTC GGT CfG CTG GCT GGT
CTG GGC CCG CGG TGC GGC
GGG TGG CIT GCT GTT CTG CCT GGG CTC TCC CCT CfC CTC CTT TTC TCC CTT CCr CPG
TCT TGC CTC CTT CCT CTG
4S GGT CCT CIT GGC CTG GGC GCT CIT CCC CTC GGG CGG CTG CGG GCG CTC GTG CTG CCf GGT CCG CTC CCT GGG GGT
GCT CCT TCC CTT TCC CCG CrC GTG GGG TTT GCG GGG CTG GGC TGC CCT GGG GGG TCT
GGG CCT TTT GGG GTC GGC
TGG CTG CfG CTT CGG GCC GCC TGG GCf TCC CTG TGC CCC TTT CCT CfG CTG GGT CCC
CCT CCC GTT CCA AGC TGC
ACC GCA CAG ACC GGC GCf ACA GGA CAG AGC CAG GCA AGC ACC CAT GGG GAT CCA GGC
CCA GCT GTT CCB BGC
TGC BCC GCB CBG BCC GGC GCf BCH GGB CBG BGC CBG GCB BGC BCC CBT GGG GBT CCB
GGC CCB GCT G
SO CTCAGTGGCC CCCAAAAGGA TGAGTAATAC ATGCGCCACG ATGATCATAT CCrIITfACT
ATGAGGCCGT GTCTGTCGTG

TCTTTCCTTT GCTCTTGGTG TGTCTTTGCT GTGCCCTGCC TCTCTGCCCG TGTCTGTCGT GTCTTTCCTT
TGCTCTTGGT
GTGTCTTTGC TGTGCCCTGC CTCTCTGCC CGTGTCTGTC GTGTCTTTCC TTTGCTCTTG GTGTGTCTTT
GCTGTGCCCT
GCC1'CTCTGC -GGGGGTGGCT TCCTGCCGCG TCTCTGGGCC GTCCCGTCCC TCGGCCCCGC GCCGCGCTCG
GCTCCTCTCC
CTCTGGCCCG GCTCGGGGCG GGGCGGGGCG GTGGGCGGGC GGCGCTGCCC TGCGCGCGGC GCTG(iCCCCT
GCTGGCCGTC
S GGCTGCGCGC TGCTGGCTGC CCTGCTGGCC GCGCCGGGGC CTGTCCGCCT CTGCGGGCGC TGTCTCCTGG
CTTGTCTTCC
GGCTCTTCTG CTGGGGTGGG GCTGGGCGGC CGGCCCGGTG CTGGGGCTCC TCGGGGGGGG GGGCTCTTCC
GGGCTGTCTC
CCTCCGGGGC GGGGGTTTCT GGCCGTGGGG GTCTTGCCTG GCCTCCGGGC TCCTGCTTGT CTTGCCTTCC
TTCTCTGGTC
GGTTGTGGCT CGGGGCTCCG TGGGTCCCTG GCGCCCGTTT GTGTTTTGTC TTTTCCCCTG GCGTCCCTGT
GCCCCTCTCC
TCTCCTTCCT CTGCTTCTCG CTCTCCTTTG TGGGGCCCTC CCTGCTGCTC TTGGTTTTGG GCTITTTZ'I'C
TCTTCCTCCT
I O TTTTCGTGCG TGGGCCTCC GCACGCCTCT TGCCACCTCC TGCGCAGGGC AGCGCCTTGG
GGCCAGCGCC GCTCCCGGCG
CGGCCAGCAG GGCAGCCAGC AGCGCGCAGC CGACGGCCAG CATGCTTCCT CCTCGGCTAC CACTCCATGG
TCCCGCAGAG
GCGGACAGGC GCBCGCCTC TTGCCBCCTC CTGCGCBGGG CBGCGCCTTG GGGCCBGCGC CGCTCCCGGC
GCGGCCBGCB
GGGCBGCCBG CBGCGCGCBG CCGBCGGCCB GCBTGCTTCC TCCTCGGCTB CCBCTCCBTG GTCCCGCBGB
GGCGGBCBGG
C GCTGCCCGGC GGGGTGTGCG CTTGGCGCTC CCGTGCTCGG TTCTCTGTCT CCCGGTCCCC CTTGCCTGGC
GTCTCGGGCC
I S TTCGTCCTCT TCCTCTTCTT CCTTCCGCTC CGTGGGGGCT GCTTGGTGGG GGCCTGTGCCT
CGGGGTCCCG GGGCTTCTGG
CCCTTGCCGT TCATGGTGGC TAGGTGGGGC GTTCBTGGTG GCTBGGTGGG GC GGG GTG GGT BGG CCG
TGT CTG GGGGTT
GGC CBT GTT GGT TGC CTCT TGG TGG TGC GCC GGG CGCG TCT TGG CTT TCT TCT CCT TCG
GGC CCT CGG GCC GGT
GCT TGT GGGCT CCT CCC GGG CGG CCT CCC CGG GCG GGG GCT TCT TGGCG CTG GCG GGG
GGG CCT CCTGCT CTG
TGG CTG GGC GTT CCT TGG TGT TCT GGG TGGTGG CGG GCG TGG TGG CCT CTG TGGGGG CCC
GCG GCT GCB GGG

CTG GGGGTT GGC CAT GTT
GGT TGC CGGG CCC GCG GCT GCA GGG G ACAGGGGCTG TAATCTTCATC TGCAGGTGGC
ATGCCAGTGA AATTTAGATC
ATCAAAATCC CACATCTGTG GATCTGTAAT ATTTGACATG TCCTCTTCAG TTTCAGCAAT GGTTTGATCT
AACTGAAGCA
CCGGCCAGGB CBGGGGCTGT BBTCTTCBTC TGCBGGTGGC BTGCCBGTGB BBTTTBGBTC BTCBBBBTCC
CBCBTCTGTG
GBTCTGTBBT BTTTGBCBTG TCCTCTTCBG TTTCBGCBB TGGTTTGBTC TBBCTGBBGC BCCGGCCBGG
TGGCTCGGTG

CTCTTTCTCT TTGTTCGGGG
GTTCTTGTGG CGGGCTGCTT GTCTCGTTCC GCCCTGTCGG GCGGGAAGCC TCTCTCCTCT CCCCAGATC
CGCGACAGGC
CGCAGGCAAG AACCAGCGCA ACCAGGGCGC GTCCGCACAG ACTTGGAGGC GGCTGCATGC TGCTACCTGC
TCCAGAAGCG
TCCGGTGGCC GCCGCGCC CTGTCGGGCG GGBBGCCTCT CTCCTCTCCC CBGBTCCGCG BCBGGCCGCB
GGCBBGBBCC
BGCGCBBCCB GGGCGCGTCC GCBCBGBCTT GGBGGCGGCT GCBTGCTGCT BCCTGCTCGGGCG
GGBBGCCTCCG

CGGGTCCTGC CGTCCTGTCT
CCTTTTCTTT TGCTGTCTTG TCTTCCCGTC TCTGCTTT GTCTGTCCTC CCCGTCTCCT CCCACTGCTT
CTCCCGGGGG
CTTCCCCGGC TTCGGGTGGC CGGTGTCCCG GGCTCCGGCG CGGCGGCGGC TTCGGCfGCG GGTGGGTGGC
GCGGGCTGCC
GGGTCCGCGC GGCGCCTGGG CCCTTGTGCT GCTTTTTGCT TGTTCCGTTC TGGCTGCTCC GGTCTGTGTT
GTGGTTGTTT
TGTTTCTTCT TGGGTGTGGG CCTTGCGGTT TTGGCTGTGG GCCCTTTGGG GCCTTGGCTT CTGGCTCGTC
TGTCCTCCCC

CTCCGGCGCG GCGGCGGCTT
CGGCTGCGGG TGGGTGGCGC GGGCTGCCGG GTCCGCGCGG CGCCTGGGCC CTTGTGCTGC TTTTTGCTTG
TTCCGTTCTG
GCTGCTCCGG TCTGTGTTGT GGTTGTTTTG TTTCfTCTTG GGTGTGGGCC TTGCGGTTTT GGCTGTGGGC
CCTTTGGGGC
CTTGGCTTCT GGCTCCAT CCACATGATT GCTTAGATTT GTGCTGTATC TCTCAGGATT ATCACTGATT
ACACATCCAA
CCAGTGCCAG CCAAAAGGAT GCCCTGAGGC AAAGGGTTTC CATCTTGAGG CAAATTTGAG GACBTCCBC
BTGBTTGCTT

BBGGBTGCCC TGBGGCBBBG
GGTTTCCBTC TTGBGGCBBB TTTGBGGBGGGCTBBGBT GBTCCBCBTC BCTBCCBCGT TGCCCBCCBC
BGBGGTCBCC
BCBBTGBCCG TGTBGGCBGC TGCCCBBBGG BCBBTTTGCC BGGCTGGTTG CBCGBBCTGB TTGGGTTCCG
BGGTGTTBGT
GGBGBTGTTT GGGGBGBGGT CTGBGTCCBC CGGGBGGBCG TTBTCCBTTT CGBBGCTBGG CGGTBBBGCC
CTBCTBTCTG
TBCBCBBCCC CCCTCTGCBG CBGBGTCCTG TCGTGGCGCC TGGGGCTCBG GGTCCGGGC TAAGATGATC
CACATCACTA

TTTGCCAGGC TGGTTGCACG
AACTGATTGG GTTCCGAGGT GTTAGTGGAG ATGTTTGGGG AGAGGTCTGA GTCCACCGGG AGGACGTTAT
CCATTTCGAA
GCTAGGCGGT AAAGCCCTAC TATCTGTACA CAACCCCCCT CTGCAGCAGA GTCCTGTCGT GGCGCCTGGG
GCTCAGGGTC
CGTCCTGTCG TGGCGCCTGG GGCTCTTCTT TTGTGGGCTC TTTGGTGGCT GTGGCTGTGG TCTCTGTGGT
TGCTGCCCTG
GGTCTGGGGG TGTGGCCTTG GGGCCGTCCT CTGGCTCCTC CTCGTGGGCC CCC GGTGBCBTTG
BGCBTGTCGG
SO CGCGGTCCCG TTBBGBGTGG GCCCGCCAGC CCAGCCACTC CACTTGGGGG CGGGTGGCCA
GCACGAACAG CACCCAGAGG
AAGGGGGGCG GCCCAGAAGG GCAGCCCGCA GGCCAGGATC AGGTCTGCTG CGGCCGGAGA TAATGGCATT
CACCACGCGG
CGGCCCAGCG CACGCCGCGC ATCCGGCCCG GGTTCTGACC TGCAGCCCCC GTCTCCTTGG CATTCCTGGG
CCCCAGTCAC
TCCTCTCCCT GCCCCCCTTG CTGGGGCAGG GACGGGGTG BCBTTGBGCB TGTCGGCGCG GTCCCGTTBB
GBGTGGGCCC
GCCAGCCCAG CCACTCCACT TGGGGGCGGG TGGCCAGCAC GAACAGCACC CAGAGGAAGG GGGGCGGCCC
AGAAGGGCAG

CCCGCAGGCC AGGATCAGGT CTGCTGCGGC CGGAGATAAT GGCATTCACC ACGCGGCGGC CCAGCGCACG
CCGCGCATCC
GGCCCGGGTT CTGACCTGCA GCCCCCGTCT CCTTGGCATT CCTGGGCCCC AGTCACTCCT CTCCCTGCCC
CCCTTGCTGG
GGCAGGGACG GCCGTGTTGT CBGTGGTGCT GCCCGTTTGB GGTBTGGCGC TCCBCCHBTT CCCTTTTCTC
CTTGI~ITI'CC
GTTTCTCTTG CCGTCTGTGG TT-3' (SEQ. 1D N0:2409) 5'-CTT GCT CCT GCiG GGC CTC CTG GTC CCT CTG GCT G TT CCC GGC CCT GGB CTG GGG
CBG GGG CCG CGT BGG CGC
GGC TCG CCB GGB CGG GCB GCG CCB GCB GCB GCB GGC TCB GCB TCC TGG CCB CGG BBT
TCC GGT GTG CGG GGC
CTG GTG CC CCT GGG CCT CGG GTG CTG CCT GT GCG CTG CCT TCT TCT CCT GG GTC CTC
GCC GGG GCC CTT GCT GCC
CTG GCT GT GCC CTG GGG GTC TGG GTT CGG CTG T CCC CBG CBG GBC CBG TCC CBT CCB
CBG CGT GTG BTG BGT BGC
I O CBT TCT CCT GCB GCC GBG GGG CGC GGG CGB GCB TCG C TTT GGG CTT TTC TCC TTT
GGT T TGB GCG CCB GCiB CCG
CGC BCH GCB GCB GGG CGC GGG CGB GCB TCG CBG CGG CGG GCB GGG GGGCTCCCGC
CGCGBGBGGT TBTGGGCTCC
CBGGBCCBCC CGCBCCGCGC GGBCGTTTBC BTTCGCCHCG CBGTGCGCGG CCGBCBTGBC GBBGTTGGGC
GCBBTCBGGG
TGGCGCCGCB GBBGTGGCCT CCGCGCBGCT GCBGGGBCBC CBTGBBGGGC CBCGCGTGGG GCCGCGCTCG
CCGGCCCCCC
BCBBTCTCCG BGGCCBGCGC GGTGCCCCCC BGCBGCBBGG CCGGCBGGBC BCBGGCGBGG BGBCBCGCGB
GTCGGCGGCC
IS GBGGGTCBTG GTGGGGCTGG GGCTCCGGGG TCTCTGCCCC TCCGTGCTGG TGGGGCTGGG GCTCCGGGG
TCTCTGCCCC
TCCGTGCCGC GTGGGGCCGC GCTCGCCGGC CCCCCCCTGC CGGGTGGGCT CCCGCCGCGC GCCGGCCTGC
CGGCCCCTCG
TGGGTCCTGC TGGCCGGGTC CGGGTCCCGG GGGTGGGGCG CGBGTCGGCG GCCGBGGGTC CCCTCCBCBT
CTGCTCTGBC
CTGCTGGBCT CTGGBTCTGB BGBTBCGCCB TGTBGGGGCG GGBGTGGGGC CTGCTCTCCC GGCCTCCGBT
GBTCTCCCCT
GCCTCBGCCC CBGTGGGTBG GBGBBBGGCC BGCBGBBGCB GGBGTGGCTG CBTCTTTCCT GGTGGGGCCT
GCTCTCCCGG

BGCBBCCTCB TCBGCTCTTG
CCTGGBGTGG CTCBGCCTGG GCCTGCBGGG CCBCCBGGBG HBTGGCBGCB BGGBTGGCGB GGGTCCTCBT
GGCTGGGGTC
BCBGBTCCTC TBGCTBGGCB GGGTGBCCBG BGBGGGC GGG TCC TCB TGG CTG GGG GCC TGG GCC
TGC BGG GCC GCT
CTT GCC TGG BGT GGC TC GCC CBG BGT CTT CCC TGG T CGCTGCBBTC TGCTCCGGGG
CTGCBGCBBC CTCBTCBGCTC
TTGCCTGGBGTG GCTCBGCCTGG GCCTGCBGGG CCBCCBGGBGB BTGGCBGCBBG GBTGGCGBGGG
TCCTCBTGGC

TTT CCT TTG CGG
TC TTG GCC CGG GCT CCG GGT G CCC GCC CGC CCG CCG GCC GCC GC CCC GCC GGG CTG
TCC CCG CCC CGC CCC GGC
CCG GGG CGC GGG GG CGG CCC TCC CGC CCC TCT GG GCC GGC GCG GGC GTC GG CCG CTC
GCG CCT GGG GTT CCC
TCT CCT CCC CCT GTG C GCC TGC CTC TTG CTC TTCTGC GTC CGC TGC CTT CTC CC CTC
TCC TCG GCC GTT GCC TGT
GC TGT CCG TCC TGT CGC CCT TCC GTG GTG C TGT TGT CTC TTC TGC CCT C GGT GTG CTG
GTG CTG GTG GTG GTG

TCT TGG TTG CCC TTT CTT
CTC GTG GTG CCT CTC CTC CCT GGC TTG GTC GT TGT CTG GGG TGG TGC TCC TCT CCC TTT
CCC TGC TGG CCG TTT
GT CCT GTT TTC TGT CTT CCT CT TTC CTC CTG TTT CTC CGT TTG GCT TGC TGC TTG CGG
GGC TGT CTC C CTT GCC
CCT GTG GGC TTT CCC TGG TCC GGT CTT CTC CTT GGG GGT C GCC CTT CTT GGT GGG
CTGGCT CGT CTG TCT TTT TCC
TTC C TGG GGG TGG CCG TTG TGG GCG GTG TGG TCC GCC T TGC CTC TGC TGG TCT TTC -CTCGGTBGBC GCGCTCGBBC

CBGGGBGBBG TBGGCTTGCB
GCBGGBCTCC CBGGBGGGTG BCBGCBGCCB GTBGBGCTBC CTCGTCCTTC BTGGTBCCGT CGGTGTGGTG
GCBCGGGCTG
TGTGTGBBGG CGBGCTGGGC CCCGTCTGCT GCTCCTCGTG CCGCCTCGTC CTTCA TGG TA CCGTCGGTGT
GGTGGCCTCG
GGTGGGCCGG TGGTGGGGCG CGCGCGCTCG CGTGGCTCCG GCTCTTCTTT CCCGGCTCCGT CGGCCCGGGG
GCCTTGGTCT

TCBCCCBCCG

GBGBGBBBBT CBTGBGCBBB
TBBTCCBTTC TGBBBBBBBG GGBTCBBBBB CCTCCCGTTC CCCGTTCGCC TGGCGCGCGC TGCGGGTTCC
TCGTGGGTTT
CTCCCCGCCG TTCTCCGGTC TGTTGCCTTT GTGGGCTTCT TGTCTTTTTG GCTGTTCTTT TCCTGCTTGG
CGTCTTTTCC
TTTCTTTGTG CTCGGTTGTG GGTCCGCTGG TCCTTTGCCC TGTGTGTTTC TGCTGCCCGT TCGCCTGGCG
CGCGCTGCGG
GTTCCTCGTG GGTTTCTCCC CGCCGTTCTC CGGTCTGTTG CCTTTGTGGG CTTCTTGTCT TTTTGGCTGT

GTTTCTGCTG GGBGCTGBTB
CTGCBGATTT CBGBGGGBBG BBCCCTGBTB CTCBCCBGCT TCBGCTCTGG BGCBCBBGBG BBBGBGCBGC
BGGGGGBGBG
GBBGBBGCBG CBTCTTCCCB GBGBGGCTGC CTGBGCBBBT GCTGGTTTTC CTTTCCBGTC TTGGGTTTTB
TBBCTCCCBG
BBGGCBBGBG BGGGGCBBGG CGTTTTCTTC TCTCGCTGGT TTTCCTTTCC TGGCAGTGGG TGGGGGTGGG
GGTGGGGTGG
CTTCCTTGTT CCTGGGGGTG TCCTCTTGCT CTGGGCTTTT CTCCCCTTTT CCTTCCTGTC TGTTTTCCTG
GGGCTCTCCT
SO CTGTCTCTGT GTCCTTGCCC TGGCCCTCTT CCCTCTCCTG TCTCCTGTCC CTGTGTTCCG
CCCGTCTTCC CTCTCCTGAC
CTCCTTTTCC TCCGCTGGGT GGGGCCCTGC CTGTTCTCTG CTCCCTGGCT TGGGGTTTCT TCTGTGTGTC
TTCTTCCTCT
GTTGGCTGGC TTTCTCCTTC TTTTGTCTTC CTGGGTGCCC CTTCTTCCTT TCTTGGGTCC TTGGTGCTTG
GGCTGGG

WO 99/1388b PC'TNS98/19419 GCGTCTTGGG GTGCBGGGCC CBTCCTGCTG CGCCTGGGCG CTGCTGTGCG TCCGTCTGCT GGGGGGCCGG
GGTGGCTGGG
CCCTGCTTGC CGCACGACCC CGGGCCGACC CGAGGCTCGG GGGGCTGTGT TCTGGCGCTG GTGGGCTTGG
GCCCCTCTGG
GGGCTGGGTT TCCTGCTGCG CCTGGGCGCT GGCGTCTTGG GGTGCGGGGC CGGGGGGCCG GGGGGCCGCT
GTTCGTGGGC
CTGGGGGTGC CTGTGGCTGC CGGTTGCCCC GGTTGGTGGC GCCGTCCTGC TGCCGGTCGT TGGCTGGGTC
CCCCCGCCCG
S TTTCCTGGGG TCCGCGTGGG GTGCTCCGGT TCCTCGTGCC GCTGCTGCCT TGTCTTTCCG GCCGTGGCGG
CGTGGTGGTC
CGCCCCCCCT GGCCTTCTGC TCGGGGTCTG GCTGGTTGCC GGTGCCCTTG GCGGCGGTCT TCTTCCTGGT
GGCTCTGGGC
CCGGCCGGTC TCGGGCGTCT CGTGTTCGCT CTTGTGCTGT TCCGGCCGCT CCTTCCTCTT CCGCCGCCGC
CGCTCCCCGC
CCGCTCGTCG CCCTGGCCCG GCCTCCTCCT GGCCGCTGTC TCGGGCGGCG GCCTTGGCGC TCCGTTTGGG
GCTGCCTCTG
GCGCTTCCGG CCCTCGGCCT GGGCGCTCTC TTCCGCCTGT GCTGGTGGCC CTCGTGGGCC CCTCCTGGCC
TCCGGTGTCC
I O TGTGGTCCCC CGGCTGGTGG CCGGGCCGGT TGGGCGGGCG TGGGCGCCGG CGGGTCCTCC
GGGCTGCCCT TCTCCGCCGG
GGGTCCCGCG CTCCTGCTGT TCCCTGGGCT CTTCTGCCTC TCTCCTGGGT GGGTGCTGGG TGCCGGGGTC
TCCGGGCTTG
CCCCGCGCTG CTGGGCGTTC TGCGGTCTTG GGGTTGTCTG TGGCCCCGCT CGTGTCGCCC TCCGTCGCCC
GTCGCCGGCC
TCGTCCCCTC CTGGGTGCGC GGCGGGCTGG TCCTGGCGTT TTGCTCCTTC CTGGGCGTCT TGGGGTGCBG
GGCCCBTCCT
GCTGCGCCTG GGCGCTGCTG TGCGTCCGTC TGCTGGGGGG CCGGGGTGGC TGGGCCCTGC TTGCCGCACG
ACCCCGGGCC
I S GACCCGAGGC TCGGGGGGCT GTGTTCTGGC GCTGGTGGGC TTGGGCCCCT CTGGGGGCTG
GGTTTCCTGC TGCGCCTGGG
CGCTGGCGTC TTGGGGTGCG GGGCCGGGGG GCCGGGGGGC CGCTGTTCGT GGGCCTGGGG GTGCCTGTGG
CTGCCGGTTG
CCCCGGTTGG TGGCGCCGTC CTGCTGCCGG TCGTTGGCTG GGTCCCCCCG CCCGTTTCCT GGGGTCCGCG
TGGGGTGCTC
CGGTTCCTCG TGCCGCTGCT GCCTTGTCTT TCCGGCCGTG GCGGCGTGGT GGTCCGCCCC CCCTGGCCTT
CTGCTCGGGG
TCTGGCTGGT TGCCGGTGCC CTTGGCGGCG GTCTTCTTCC TGGTGGCTCT GGGCCCGGCC GGTCTCGGGC
GTCTCGTGTT

GTCGCCCTGG CCCGGCCTCC
TCCTGGCCGC TGTCTCGGGC GGCGGCCTTG GCGCTCCGTT TGGGGCTGCC TCTGGCGCTT CCGGCCCTCG
GCCTGGGCGC
TCTCTTCCGC CTGTGCTGGT GGCCCTCGTG GGCCCCTCCT GGCCTCCGGT GTCCTGTGGT CCCCCGGCTG
GTGGCCGGGC
CGGTTGGGCG GGCGTGGGCG CCGGCGGGTC CTCCGGGCTG CCCTTCTCCG CCGGGGGTCC CGCGCTCCTG
CTGTTCCCTG
GGCTCTTCTG CCTCTCTCCT GGGTGGGTGC TGGGTGCCGG GGTCTCCGGG CTTGCCCCGC GCTGCTGGGC
GTTCTGCGGT

CCTCCTGGGT GCGCGGCGGG
CTGGTCCTGG CGTTTTGCTC CTTCCTGG CTGCCCCBGT TTTTGBTCCT CBCBTGCCGT GGGGBGGBCB
BTGGCTGCCT
CCCCGGGGTT TCTGCTGCTT GCTGCTTCTT TCCCGTCTCC CTTCTTTCCC GTCTCCTTTT TGCCTCTTTG
GGTTCCTGTT
GTTTCTGGCC TGCTTGGTGG CGGCTTGTGC GTTTCCTCTC TCTTCTCTTG GGTCTCCGCT TCTCGTCCTG
CCTTTTCCTG
TCTCTGTCGC GCCGTTCCTC CTCCGGCGTC CTCCTGCCCT GTGCTGTTTG CCTCGGGTGG TGCGGGTCCC
GGTGCTCCCC

TGTGGTGGGC TCTTCTGTGG
CCTGTGGGGC TGTTGGTGTC TCTGTGGGCG TGTGCTGGGT CTTGGGGCTT CCTCCCTTGT GCTGGGTGCG
GCCTCCCCGC
CCCCCTTCTG GGCCGGTGGC CTGGCTCCTT GTGGGCGCTT CTGGCTCTTG CCCTGTCCTT CTTCGCCTCG
TGGCTGCTGG
GCTGC-3' (SEQ. ID N0:2410) Hag a~n n Factor Related Anti-sense Oli~~nuc]eotide 3 S 5'-CCT CCT TCC TGG TCT GTC TGC CBG BCB BBT TTG GGB BGT GBB CBG TTT TGG BBC
CBT GTT TCC CBG TCT CTG BGC
TGT GGC GCC CTG CTG CTC TTT CTG CT TCC CTT GGT GGG TTG GGC C GCT GGT TGT TCT
GGG GTT C TTG CTG CCC
CTT CTG TCC C TGT TTG CTG GTG TCT GCG C 5'- CCC CBB CBG BBG BBG CBG BCB BBT
TTG GGB BGT GBB CBG TTT TGG
BBC CBT GTT TCC TGT GCG CTC GGC CTG GTC CCG G GGG TCT CCT CTT GTT GTT GC TTG
CGC CTC CTG CTG GGG GT
CC CTC TGT TCT TGT TTT GGG GGC GGG CCC GGC CGT TGT CTT G GTT TGG GGG TTT CCG
TTG GGG TTC TCC TGG

CTG GGG CCT TGC GCT GTC
TTT GGT G 5'-GCB CCG TCC BGT GBT GGT GCG GTB CTT GTC GCT GCB GCG CTC GGC CTG
GTC CCG GBG BGC GCG CGG
GCC GGG GGC TGC TGG G GGT TGG CCC GGG GTG CCC C GCC GCT GGG TGC CCT CGT CCT
CTG CGG TC GTG TCT CCT
GGC TCT GGT TCC CC GCT GCG CCC GTT GTC CTC TGG GGT GGC CTT C GCT CCC GGG TCT
GGT TCT TGT GT TGG GGG
TCC CTT TTT GGG CCT GTT GT GGC GTG GCT TGT GTG TTC GGT TTC TGC CCT GTC CTC CGG
CGT CCC CGG BGC CTC

GGB BCB GBG CCC CGB GCB
GGB CCB GGB GTG CGG GCB GCG CGG GCC GGG GGC TGC TGG GBG CCB TBG CGB GGC TGB G
CCT CTT TTC TGT TTT
TCC C CTC TGC CTT TGT TTG GGT TCG CTT CCT TTC TGC TTC TTC C CTG TGT CTC CTG
TCT CCG CTT TTT TCT TC GTC
TTT GTT GTT TTC TCT TCC TTG CTG BGC BBG BTB TCT BGB TTC TGG GGT GGT CTC GBT
TTT BBBB GCT TGB GBB GCT
GCB BBC BTT BTC CBB BGT BTB TTT GBG GCT CCB BGG BTC BCG BCC BTC TTC CCB GGC
BTT TTB BGT TGC TGT CGT
SO BBG TGB GBG CTG BGB GBB BCT GTG BBG CBB TCB TGB CTT CBB GBG TTC TTT TCB CCC
GTT CTT GGC TTC TTC TGT
C CGT TGG CTT CTC GTT GTC CC TGT GGG CTT CTC GTT GTC CC CCC TTC GGG GGC TGG
TGG GGC CGT CCT TGC CTG
CTG G GTT CTT GGC TTC TTC TGT CCG T TGG CTT CTC GTT GTC CC TGT GGG CTT CTC GTT
GTC CC CCC TTC GGG

GGC TGG TGG GGC CGT CCT TGC CTG CTG G TTT TCT CTT TCG CTT TCT TIT CGT CTC CTG
TTC CTC CTT TT TTG CTG
TTT TTT CTC CTT CTT CTC TCC TIT CTT TTC TTT TCT CTT TCG CTT TCT TTT CGT CTC
CTG TTC CTC CTT TT TTG CTG
TTT TTT CTC CTT CTT CTC TCC TIT CTT TfC CTC TGT CTT GTT CTG GTC CTT CGT GGG
GCT CTG TGT CGC GTG G GTG
CGG CCG TGG CC GGC GGB CCB GGB GTT GGB GCB GGB GCB GGB CGG GCB GGC GGC TCB TGT
TfG GBT CGG CBG GBG
S GCB CTC CTC TGG TTG GCT TCC TTC GCC GGC BCB TGC TBG CBG GBB GBB CBG BGG GGG
BBG CBG TTG GGB GGT GBG
BCC CBT TBB THG GTG TCG B TCCCTGTTTC CCCCCTTTCG TTCTGCGTTT GCCTTTGGCG
TTIITfGTTT GTT'ITCTCTC
TCCGTCTTTC TTCTCCCCT GTGGGBBTTT CTGTGGGGBT GGCBTBCBCG TBGGCBGCTC CBBGBGCTBG
CBBBCTCBBB
TGCBGBBGCB TCCTCBTGGC TCTGBBBCGG TGGGAATTTC TGTGGGGBTG GCATACACGT AGGCAGCTCC
AAGAGCTAGC
AAACTCAAAT GCAGAAGCATC CTCATGGCTC TGAAACG GGGGGTGGCT TCCTGCCGCG TCTCTGGGCC
GTCCCGTCCC
I O TCGGCCCCGC GCCGCGCTCG GCTCCTCTCC CTCTGGCCCG GCTCGGGGCG GGGCGGGGCG
GTGGGCGGGC GGCGCTGCCC
TGCGCGCGGC GCTGGCCCCT GCTGGCCGTC GGCTGCGCGC TGCTGGCTGC CCTGCTGGCC GCGCCGGGGC
CTGTCCGCCT
CTGCGGGCGC TGTC!'CCTGG CTTGTCTTCC GGCTCTTCTG CTGGGGTGGG GCTGGGCGGC CGGCCCGGTG
CTGGGGCTCC

GCCTCCGGGC
TCCTGCTTGT CTTGCCTTCC TTCTCTGGTC GGTTGTGGCT CGGGGCTCCG TGGGTCCCTG GCGCCCGTTT
GTGTTTTGTC
I S TTTTCCCCTG GCGTCCCTGT GCCCCTCTCC TCTCCTTCCT CTGCTTCTCG CTCTCCTfTG
TGGGGCCCTC CCTGCTGCTC
TTGGTITTGG GC'I"I7Z1'1'fC TCTTCCTCCT TTTTCGTGCG TGGGCCTCC GCACGCCTCT
TGCCACCTCC TGCGCAGGGC
AGCGCCTTGG GGCCAGCGCC GCTCCCGGCG CGGCCAGCAG GGCAGCCAGC AGCGCGCAGC CGACGGCCAG
CATGCTTCCT
CCTCGGCTAC CACTCCATGG TCCCGCAGAG GCGGACAGGC GCBCGCCTC TTGCCBCCTC CTGCGCBGGG
CBGCGCCTTG
GGGCCHGCGC CGCTCCCGGC GCGGCCBGCB GGGCBGCCBG CBGCGCGCBG CCGBCGGCCB GCBTGCTTCC
TCCTCGGCTH

GCBCTGBCBT CTBBGTTCTT
TBGCBCTCCT TGGCBBBBCT GCBCCTTCBC BCBGBGCTGC BGBBBTCBGG BBGGCTGCCB BGBGBGCCBC
GGCCBGCTTG
GBBGTCBTGT TTBCBCBCBG TGBGBTGGTT CCTTCCGGGC TTGTGTGCTC TGCTGTCTCT TGGTTCCTTC
CGGTGGTTTC
TTCCTGGCTC TTGTCCTTTC TCTTGG CCCT TGGC CGGGBGTGGG GGTCCTGGBC GGCBCTGBBG
GCBTCCBGGG
CTCCCTTCCB GTCCTTCT"fG TCCGCTGCCB GCBCCCCTfC BTTCCBGBGG CTGBTGGCCT CCBCCBGGGB
CBTGBTTBGG

GGGTTTTCGG TCTGGGTGGG
CTTTCCTCCT GGGGCTGCTG CTGGGCTCTT CTTTTTGTTT CTGGCCTGGT GCTCTCTCGT GCCCTTTCCC
TTGGGTGTCT
TGTTTTTGTG GCCTCCBCCB GGGBCBTG GTCTTTGTIT CTGGGCTCGT GCCCCBTCCC GGCTfCTCTC
TGGTTCCGTC
CTCTGTGGTG TTTGGCCCTG CTTCCTTTTG CCTGTTGAGG GGGCAGCAGT TGGGCCCCAA AGGCCCTCTC
GTTCACCTTC
TGGCACGGAGTT GCATCCCCATA GTCAAACTCT GTGGTCGTGT CATAGTCCTC TGTGGTGTTT
GGAGTTTCCA TCCCGGCTTC

BGTTGCBTCC
CCBTBGTCBB BCTCTGTGGT CGTGTCBTBG TCCTCTGTGG TGTTTGGBGT TfCCBTCCCG GCTTCTCTCT
GGTTCCBBGG GB
GGGCBCGGGG CBGTGGGCGG GCBBTGTBGG CBBBGCBGCB GGGTGTGGTG TCCGBGGBBT BTGGGGBGGC
BGBTGCBGGB
GCGCBGBGGG CBGTBGCBBT GBGGBTGBCB GCGBGGCGTG CCGCGGBGBC CTTCBTGGTB CCTGTGGBGB
GGCTGTCGGB
GGGGGTGTGG TGTCCGCTTG GCGGTTCTTT CGGGTGTTTC TTCTCTGGGT TGGCCTGCTG CTCGTCGTGGT
CGCTCCGCTC

GBTGTTTGTT BCCBBBGCBT
CBBGBBTBGC TTTGCTBTCT BBGGBTCHCB TCTBGBCBTB GGBBBBCGCT GTBGGTCBGBB BGBTGTGCTT
BCCTTCBCBC
BGBGCTGCBG BBBTCBGGBBGG CTGCCBBGBGBG CCBCGGCCBGC TTGGBGTCBT GTTTBCBCHC
BGTGBGGTGC

TITCTCTTGG
CCCTTGGCCC CTTGBGCBGG BBGCTCTGGG GCBGGGBGCT GGCBGGGCCC BGGGGGGTGG CTTCCTGCBC
TGTCCBGBGT

CCBGCCBTGG GTCTGGGTGG
GGCTGGGCTG CBGGCTCCGG GCGGTCCBGCCBTGGGTCTG GGGGCTGGG CTGCBGGCTC CGGGCGGGCG
GGTGCGGGCT
GCGTGCTGGG GGCTGCCCCG CAGGCCCTGC GGTCCBGCCB TGGGTCTGGG GGCTGGGCTG CBGGCTCCGG
GCGGGCGGGT
GCGGGCTGCG TGCTGGGGGC TGCCCCGCAG GCCCTGC GCBCCGCCTG GBGCCCTGGG GCCCCCCTGT
CTTCTTGGGG
BGCGCCTCCT CGGCCBGCTC CBCGTCCCGG BTCBTGCTTT CBGTGCTCBT GGTGTCCTTT CCBGGGGBGB
GBGGGGCTGG

CTTGGGGCCT CTTCCCTCTG
GGGGCCGTCT CTCTCCCTCT CTTGCGTCTC TCTCTlTCTC TCTCTCTCTT CCCCTTTCCC GCTCTTTCTG
TCTCGGTGTC
TGGTTTTCTC TCTCCGCTGG CTGCCTGTCT GGCCTGCGCT CTTGGCCTGT GCTGTTCCTC CTCCGGTTCC
TGTCCTCTCT
GTCTGTCGCC CCCTCTGGGG TCTCCCTCTG GGTGGTGGTC TTGTTGCTTG GGCTGGGCTC CGTGTCTCCB
GTGCTCBTGG
TGTCCGCTGB GGGBGCGTCT GCTGGCGCTG GTCCTCTGCTGTC CTTGCTGGTG CTCBTGGTGT

SO CCTGTCTTCT TGGGGCCTCT TCCCTCTGGG GGCCGTCTC TCTCCCTCTC TTGCGTCTCT CTCTTTCTCT
CTCTCTCTTC
CCCTTTCCCG CTCTTTCTGT CTCGGTGTCT GGTTTTCTCT CTCCGCTGGC TGCCTGTCTG GCCTGCGCTC
TTGGCCTGTG
CTGTTCCTCC TCCGGTTCCT GTCCTCTCTG TCTGTCGCCC CCTCTGG(iGT CTCCCTCTGG CGTGGTGGTC
TTGTTGCTTG
GGCTGGGCTC CGTGTCTCCB GTGCTCBTGG TGTCCGCTGB GGGBGCGTCT GCTGGC CTGCTGBGGC
TTGGGTCTCC
GGGCGBTTCT CTGCBGBBGB TGCTCBBBGG GCTCCGGCBG TTCCTCCTTG BTCTGGTCGCT GTCGTBCCBG
TCGGHCCBGT

BBTTCBGBTC BTCBTTGGCT CCTBTTTCTT CTGCBBBCBG CTGBGTGGBG BCBBGBBBBB BGBCTGCCBB
GGCCBCGBGG
BTTTTCBTGT TGGBTTTTGC GBCGGBCBGT CCCGCGGGGT GCTGAGTTTC TCTGGTTCCT CCGBGCGCBC
GTGGTCGCTC
CGCGTTTCTC TGGTTCCTCC GGTCCCGCGG GGTGCTGTCT GGTCGCTGTC GTGGCTTGGG TCTCCGGGCG
GTTTCCTTCC
TTTTCCGC CGGCCCTTCT CACTGGAGGC ACCGGGCAGT CCTCCATGGG AGGGTTGGGC TTGGCCGGGG
CTGCCCGGTG
S CCTCCTCTTG GCTGGTCCCT CGTTGTCCTT GGGCCCCGC TCCCGCTGCT CGGCCTCCGT GTTCTTTGGC
CTCTTGCTCC
GCCTGCTGTC TTGTCCCGTC CCCTCCTCGC TTGCGTTTCC CTCTTCCTTG TCTTCCAGGC CTTCCTCCGC
TTCCGCTGCT
GGGGCCCGCG CCGGGGGGGC GCTCGGCTCC GCGGCTTCCT CCCCGGCTGG GGGGTCCTGG TCTCCGGGGC
CTGCGGCTCG
CGGGCTCGGG GCTGCGTGCG CCGCGCGCGG CGTCCGCGGT GGGTGGCGCT GTCCCGCCGT GGTGTGTCTC
CGTTCTCGTC
CTGCGCCGTC CTGGTCTGCC CGTGGGGTCC TGGGCGTGGT GGGGGGCGTC TGGTGCCTCG TCTGCCCCGT
GGGGCTTCGG
I O GCTCGGGGCT GTTCGTCCCC CCTGCCGCTC TGTGGCCTCC GGGGCTCCTC GTTTTCGCTG
CTTCGGGTGT CCTTCTCGGC
GTGTGGCCCC GGGTCCCGGC CCTGCTGGGC TGGGCGGGGT CGCTGCCCTG GGCTTCTGGC CCGTCTGGTT
GTCTGTCGGT
GCTTGTCTCG GGTTTCTGGC CTCTGTGCTG GGCGCTTCTC TGCCTCCTGC TCCGCCCTCC TGGTGGCTCG
GCTGGGGGTG
CCCGTGCGGG GGTGGGTGTG GGGTGTTTTC GGGGTCCTCC CCTTCCC GTT TCA TCT TGG CTT TAT
CCTCT CCC CTT GTT
CCT CCC CTCT CCT GCT CTG GRG TCT CCT C TTC CCT CCC TCC CCT GCC GTG TTG TCT GTG
GGT GTC GTT TCG CTC
I S TTG TTG CCC TGG GCC CTT CCC TGC TGG GGG GGA GTT TCA TCT TGG GTT TCB TCT
TGG CTT TBT CCTCT CCC CTT
GTT CCT CCC CTCT CCT GCT CTG GRG TCT CCT C TTC CCT CCC TCC CCT GCC GTG TTG TCT
GTG GGT GTC GTT TCG
CTC TTG TTG CCC TGG GCC CTT CCC TGC TGG GGG GGB GTT TCB TCT TGG GGG GGB GTT
TCB TCT TGG CTT T
CCGTGTTGTC BGTGGTGCTG CCCGTTTGBG GTBTGGCGCT CCBCCBBTTC CCTTTTCTCC TTGTTTTCCG
TTTCTCTTGC
CGTCTGTGGT T-3' (SEQ. ID N0:2411) 20 ~~, Receptor Anti-sense Oligonucleotide Fragments 5'-GAT GGA GGG CGG CAT GGC GGG-3' (FRAG. NO: 1657) (SEQ ID N0:1670) 5'-G CGG GTC GCC GG-3' (FRAG. NO: 1658) (SEQ ID N0:16?1) 5'-GGC GGG CBC BGG C-3' (P'RAG. NO: 1659) (SEQ ID N0:1672) 5'-GGC GGG CBC-3' (FRAG. NO: 1660) (SEQ ID N0:1673) 2S 5'-GC GGC CTG G-3' (FRAG. NO: 1661) (SEQ ID N0:1674) 5'-GGB GGG CGG C-3' (FRAG. NO: 1662) (SEQ ID N0:1675) 5'-GBT GGB GGG-3' (P'RAG. NO: 1663) (SEQ ID N0:1676) 5'-GG CTG GGC-3' (FRAG. NO: 1664) (SEQ ID N0:1677) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG.1) (SEQ. ID NO: 11) 3O 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 2) (SEQ. ID NO: 12) 5'-GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 3) (SEQ. ID NO: 13) 5'-GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 4) (SEQ. ID NO: 14) 5'-C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG S) (SEQ. ID NO: 15) 5'-CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 6) (SEQ. ID NO: 16) 3 S 5'-TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 7) (SEQ. ID NO: 17) 5'-G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 8) (SEQ.
ID NO: 18) S'-GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 9) (SEQ.
ID NO: 19) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 10) (SEQ.
ID NO: 20) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 11) (SEQ. ID
NO: 21) 4O 5'-AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 12) (SEQ.
ID NO: 22) 5'-GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 13) (SEQ. ID
NO: 23) 5'-C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 14) (SEQ. ID NO:
24) 5'-TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG IS) (SEQ. ID NO:
ZS) 5'-GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 16) (SEQ. m NO: 26) 4S 5'-A GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 17) (SEQ. ID NO:
27) 5'-GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 18) (SEQ. >D NO: 28) 5'-AT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 19) (SEQ. ID NO: 29) 5'-T GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 20) (SEQ. ID NO: 30) 5'-GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 21) (SEQ. ID NO: 31) SO 5'-GA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 22) (SEQ. ID NO: 32) 5'-A GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 23) (SEQ. ID NO: 33) 5'-GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 24) (SEQ. ID NO: 34) 5'-GG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 25) (SEQ. ID NO: 35) 5'-G CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 26) (SEQ. ID NO: 36) SS 5'-CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 27) (SEQ. ID NO: 37) 5'-GG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 28) (SEQ. ID NO: 38) 5'-G CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 29) (SEQ. ID NO: 39) 5'-CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 30) (SEQ. ID NO: 40) WO 99/13886 PCT/tJS98/19419 5'-AT GGC GGG CAC AGG CTG GGC-3' (FRAG 31) (SEQ. ID NO: 41) 5'-T GGC GGG CAC AGG CTG GGC-3' (FRAG 32) (SEQ. ID NO: 42) 5'-GGC GGG CAC AGG CTG GGC-3' (FRAG 33) (SEQ. ID NO: 43) 5'-GC GGG CAC AGG CTG GGC-3' (FRAG 34) (SEQ. ID NO: 44) S 5'-C GGG CAC AGG CTG GGC-3' (FRAG 35) (SEQ. ID NO: 45) 5'-GGG CAC AGG CTG GGC-3' (FRAG 36) (SEQ. ID NO: 46) 5'-GG CAC AGG CTG GGC-3' (FRAG 37) (SEQ. ID NO: 47) 5'-G CAC AGG CTG GGC-3' (FRAG 38) (SEQ. ID NO: 48) 5'-CAC AGG CTG GGC-3' (FRAG 39) (SEQ. ID NO: 49) I O 5'-AC AGG CTG GGC-3' (FRAG 40) (SEQ. ID NO: 50) 5'-C AGG CTG GGC-3' (FTtAG 41) (SEQ. ID NO: 51) S'-AGG CTG GGC-3' (FRAG 42) (SEQ. ID NO: 52) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 43) (SEQ. ID NO: 53) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG
44) (SEQ. ID NO: 54) I S 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 45) (SEQ. ID NO: 55) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG
46) (SEQ. ID NO: 5~
5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 47) (SEQ. ID NO: 57) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 48) (SEQ. ID NO: 58) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 49) (SEQ. ID NO: 59) 2O 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 50) (SEQ. ID NO: 60) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 51) (SEQ. ID NO: 61) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 52) (SEQ.
ID NO: 62) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 53) (SEQ.
ID NO: 63) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 54) (SEQ. ID
NO: 64) 2S 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 55) (SEQ.
ID NO: 65) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 56) (SEQ. ID
NO: (~
5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3'(FRAG 57) (SEQ. ID NO:
67) S'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 58) (SEQ. ID NO:
68) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 59) (SEQ. ID NO:
69) 3O 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 60) (SEQ. ID NO:
70) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 61) (SEQ. ID NO: 71) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 62) (SEQ. ID NO: 72) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 63) (SEQ. ID NO: 73) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CGG -3' (FRAG 64) (SEQ. ID NO: 74) 3 S S'-GGC GGC CTG GAA AGC TGA GAT GGA GGG CG -3' (FRAG 65) (SEQ. ID NO: 75) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG C -3' (FRAG 66) (SEQ. ID NO: 76) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GGG -3' (FRAG 67) (SEQ. ID NO: 77) 5'-GGC GGC CTG GAA AGC TGA GAT GGA GG -3' (FRAG 68) (SEQ. ID NO: 78) 5'-GGC GGC CTG GAA AGC TGA GAT GGA G -3' (FRAG 69) (SEQ. ID NO: 79) 4O 5'-GGC GGC CTG GAA AGC TGA GAT GGA -3' (FRAG 70) (SEQ. ID NO: 80) 5'-GGC GGC CTG GAA AGC TGA GAT GG -3' (FRAG 71) (SEQ. ID NO: 81) 5'-GGC GGC CTG GAA AGC TGA GAT G -3' (FRAG 72) (SEQ. ID NO: 82) 5'-GGC GGC CTG GAA AGC TGA GAT -3' (FRAG 73) (SEQ. ID NO: 83) 5'-GGC GGC CTG GAA AGC TGA GA-3' (FRAG 74) (SEQ. ID NO: 84) 4S 5'-GGC GGC CTG GAA AGC TGA G-3' (FRAG 75) (SEQ. ID NO: 85) 5'-GGC GGC CTG GAA AGC TGA-3' (FRAG 76) (SEQ. ID NO: 8~
5'-GGC GGC CTG GAA AGC TG-3' (FRAG 77) (SEQ. ID NO: 87) 5'-GGC GGC CTG GAA AGC T-3' (FRAG 78) (SEQ. ID NO: 88) 5'-GGC GGC CTG GAA AGC-3' (FRAG 79) (SEQ. ID NO: 89) SO 5'-GGC GGC CTG GAA AG-3' (FRAG 80) (SEQ. ID NO: 90) 5'-GGC GGC CTG GAA A-3' (FRAG 81) (SEQ. ID NO: 91) 5'-GGC GGC CTG GAA-3' (FRAG 82) (SEQ. ID NO: 92) 5'-GGC GGC CTG GA-3' (FRAG 83) (SEQ. ID NO: 93) 5'-GGC GGC CTG G-3' (FRAG 84) (SEQ. ID NO: 94) SS 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 85) (SEQ. ID NO: 95) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG
86) (SEQ. ID NO: 9~
5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG
87) (SEQ. ID NO: 97) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG
88) (SEQ. 1D NO: 98) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 89) (SEQ. ID NO: 99) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 90) (SEQ. ID NO: 100) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 91) (SEQ. ID NO: 101) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 92) (SEQ. ID NO: 102) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 93) (SEQ.
ID NO: 103) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 94) (SEQ.
ID NO: 104) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 95) (SEQ. ID
NO: 105) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 96) (SEQ. ID
NO: 106) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 97) (SEQ. ID
NO: 107) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 98) (SEQ. ID NO:
108) S 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 99) (SEQ. ID
NO: 109) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 100) (SEQ. ID NO:
110) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 101) (SEQ. ID NO:
111) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 102) (SEQ. ID NO:
112) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 103) (SEQ. ID NO: 113) I O 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 104) (SEQ. ID NO:
114) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 105) (SEQ. m NO: 115) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CGG -3' (FRAG 106) (SEQ. ID NO: 116) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG CG -3' (FRAG 107) {SEQ. ID NO: 117) 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG C -3' (FRAG 108) (SEQ. ID NO: 118) I S 5'-GC GGC CTG GAA AGC TGA GAT GGA GGG -3' (FRAG 109) (SEQ. ID NO: 119) 5'-GC GGC CTG GAA AGC TGA GAT GGA GG -3' (FRAG I 10) (SEQ. ID NO: 120) 5'-GC GGC CTG GAA AGC TGA GAT GGA G -3' (FRAG 111) (SEQ. ID NO: 121) 5'-GC GGC CTG GAA AGC TGA GAT GGA -3' (FRAG 112) (SEQ. ID NO: 122) 5'-GC GGC CTG GAA AGC TGA GAT GG -3' (FRAG 113) (SEQ. ID NO: 123) 2O 5'-GC GGC CTG GAA AGC TGA GAT G -3' (FRAG 114) (SEQ. ID NO: 124) 5'-GC GGC CTG GAA AGC TGA GAT -3' (FRAG 115) (SEQ. ID NO: 125) 5'-GC GGC CTG GAA AGC TGA GA-3' (FRAG 116) (SEQ. ID NO: 126) 5'-GC GGC CTG GAA AGC TGA G-3' (FRAG 117) (SEQ. ID NO: 127) 5'-GC GGC CTG GAA AGC TGA-3' (FRAG 118) (SEQ. ID NO: 128) 25 5'-GC GGC CTG GAA AGC TG-3' (FRAG 119) (SEQ. ID NO: 129) 5'-GC GGC CTG GAA AGC T-3' (FRAG 120) (SEQ. ID NO: 130) 5'-GC GGC CTG GAA AGC-3' (FRAG 121) (SEQ. ID NO: 131) 5'-GC GGC CTG GAA AG-3' (FRAG 122) (SEQ. ID NO: 132) 5'-GC GGC CTG GAA A-3' (FRAG 123) (SEQ. ID NO: 133) 3O 5'-GC GGC CTG GAA-3' (FRAG 124) (SEQ. ID NO: 134) 5'-GC GGC CTG GA-3' (FRAG 125) (SEQ. ID NO: 135) S'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG
126) (SEQ. ID NO: 136) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG
127) (SEQ. ID NO: 137) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG
128) (SEQ. ID NO: I38) 3 S 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG
129) (SEQ. ID NO: 139) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 130) (SEQ. ID NO: 140) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 131) (SEQ. ID NO: 141) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 132) (SEQ. ID NO: 142) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 133) (SEQ. ID NO: 143) 4O 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 134) (SEQ. ID NO: 144) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 135) (SEQ.
ID NO: 145) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 136) (SEQ. ID
NO: 146) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 137) (SEQ. ID
NO: 147) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 138) (SEQ. ID
NO: 148) 4S 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 139) (SEQ. ID
NO: 149) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 140) (SEQ. ID NO:
150) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 141) (SEQ. ID NO:
151) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 142) (SEQ. ID NO:
152) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT G -3' (FRA 143) (SEQ. ID NO: 153) SO 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 144) (SEQ. ID NO:
154) 5'-C GGC CTG GAA ACC TGA GAT GGA GGG CGG CA-3' (FRAG 145) (SEQ. ID NO: 155) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 146) (SEQ. ID NO: 151r~
5'-C GGC CTG GAA AGC TGA GAT GGA GGG CGG -3' (FRAG 147) (SEQ. ID NO: 157) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG CG -3' (FRAG 148) (SEQ. ID NO: 158) SS 5'-C GGC CTG GAA AGC TGA GAT GGA GGG C -3' (FRAG 148) (SEQ. ID NO: 159) 5'-C GGC CTG GAA AGC TGA GAT GGA GGG -3' (FRAG 150) (SEQ. ID NO: 160) 5'-C GGC CTG GAA AGC TGA GAT GGA GG -3' (FRAG 151) (SEQ. ID NO: 161) 5'-C GGC CTG GAA AGC TGA GAT GGA G -3' (FRAG 152) (SEQ. ID NO: 162) 5'-C GGC CTG GAA AGC TGA GAT GGA -3' (FRAG 153) (SEQ. ID NO: 163) 6O 5'-C GGC CTG GAA AGC TGA GAT GG -3' (FRAG 154) (SEQ. ID NO: 164) 5'-C GGC CTG GAA AGC TGA GAT G -3' (FRAG 155) (SEQ. ID NO: 16$) 5'-C GGC CTG GAA AGC TGA GAT -3' (FRAG 156) (SEQ. ID NO: 166) 5'-C GGC CTG GAA AGC TGA GA-3' (FRAG 157) (SEQ. ID NO: 16'f7 5'-C GGC CTG GAA AGC TGA G-3' (FRAG 158) (SEQ. ID NO: 168) S'-C GGC CTG GAA AGC TGA-3' (FRAG 159) (SEQ. ID NO: 169) S'-C GGC CTG GAA AGC TG-3' {FRAG 160) (SEQ. ID NO: 170) S'-C GGC CTG GAA AGC T-3' (FRAG 161) (SEQ. ID NO: 171) S'-C GGC CTG GAA AGC-3' (FRAG 162) (SEQ. 1D NO: 172) S S'-C GGC CTG GAA AG-3' (FRAG 163) (SEQ. ID NO: 173) S'-C GGC CTG GAA A-3' (FRAG 164) (SEQ. ID NO: 174) S'-C GGC CTG GAA-3' (FRAG 165) (SEQ. ID NO: 175) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG
166) (SEQ. ID NO: 176) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG
167) (SEQ. ID NO: 177) I O S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG
168) (SEQ, m NO: 178) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 169) (SEQ. m NO: 179) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 170) {SEQ. m N0:180}
S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 171) (SEQ. ID NO: 181) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 172) (SEQ. ID NO: 182) I S S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 173) (SEQ. ID NO: 183) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 174) (SEQ.
ID NO: 184) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 17S) (SEQ. >D
NO: 185) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 176) (SEQ. ID
NO: 186) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 177) (SEQ. 1D
NO: 187) ZO S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 178) (SEQ. ID
NO: 188) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 179) (SEQ. ID NO:
189) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 180) (SEQ. ID NO:
190) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 181) (SEQ. )D NO:
191) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 182) (SEQ. ID NO:
192) ZS S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 183) (SEQ. ID NO:
193) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 184) (SEQ. m NO: 194) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 185) (SEQ. ID NO: 195) 5'- GGC CTG GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 186) (SEQ. m NO: 196) S'- GGC CTG GAA AGC TGA GAT GGA GGG CGG -3' (FRAG 187) (SEQ. )D NO: 197) 3O 5'- GGC CTG GAA AGC TGA GAT GGA GGG CG -3' (FRAG 188) (SEQ. ID NO: 198) S'- GGC CTG GAA AGC TGA GAT GGA GGG C -3' (FRAG 189) (SEQ. ID NO: 199) S'- GGC CTG GAA AGC TGA GAT GGA GGG -3' (FRAG 190) (SEQ. ID NO: 200) S'- GGC CTG GAA AGC TGA GAT GGA GG -3' (FRAG 191) (SEQ. ID NO: 201) S'- GGC CTG GAA AGC TGA GAT GGA G -3' (FRAG 192) (SEQ. m NO: 202) 3S S'- GGC CTG GAA AGC TGA GAT GGA -3' (FRAG 193) (SEQ. ID NO: 203) S'- GGC CTG GAA AGC TGA GAT GG -3' (FRAG 194) (SEQ. ID NO: 204) S'- GGC CTG GAA AGC TGA GAT G -3' (FRAG 19S) (SEQ. 1D NO: 205) S'- GGC CTG GAA AGC TGA GAT -3' (FRAG 196) (SEQ. ID NO: 206) S'- GGC CTG GAA AGC TGA GA-3' (FRAG 197) (SEQ. ID NO: 207) 4O S'- GGC CTG GAA AGC TGA G-3' (FRAG 198) (SEQ. )D N0:108) S'- GGC CTG GAA AGC TGA-3' (FRAG 199) (SEQ. ID NO: 209) S'- GGC CTG GAA AGC TG-3' (FRAG 200 (SEQ. ID NO: 210) S'- GGC CTG GAA AGC T-3' (FRAG 201) (SEQ. ID NO: 211) S'- GGC CTG GAA AGC-3' (FRAG 202) (SEQ. ID NO: 212) 4S S'- GGC CTG GAA AG-3' (FRAG 203) (SEQ. ID NO: 213) S'- GGC CTG GAA A-3' (FRAG 204) (SEQ. ID NO: 214) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG
20S) (SEQ. ID NO: 215) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG
206) (SEQ. ID NO: 216) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 207) (SEQ. ID NO: 217) SO S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG
208) (SEQ. ID NO: 218) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 209) (SEQ. ID NO: 219) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 210) (SEQ. m NO: 220) 5'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 211) (SEQ. ID NO: 221) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 212) (SEQ.
ID NO: 222) SS S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 213) (SEQ. ID NO: 223) 5'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 214) (SEQ. ID
NO: 224) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 21S) (SEQ. ID
NO: 225) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 216) (SEQ. ID
NO: 226) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 217) (SEQ. ID NO:
227) C7O S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 218) (SEQ. ID
NO: 228) 5'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 219) (SEQ. m NO:
229) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 220) (SEQ. ID NO:
230) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 221) (SEQ. ID NO: 231) S'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT G -3' (FItAG 222) (SEQ. m NO: 232) 5'- GC CTG GAA AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 223) (SEQ. ID NO: 233) 5'- GC CTG GAA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 224) (SEQ. ID NO: 234) 5'- GC CTG GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 225) (SEQ. ID NO: 233) 5'- GC CTG GAA AGC TGA GAT GGA GGG CGG -3' (FRAG 226) (S'EQ.1D NO: 236) S 5'- GC CTG GAA AGC TGA GAT GGA GGG CG -3' (FRAG 227) (SEQ. iD NO: 237) 5'- GC CTG GAA AGC TGA GAT GGA GGG C -3' (FRAG 228) (SEQ. ID NO: 238) 5'- GC CTG GAA AGC TGA GAT GGA GGG -3' (FRAG 229) (S'EQ. iD NO: 239) 5'- GC CTG GAA AGC TGA GAT GGA GG -3' (FRAG 230) (SEQ. iD NO: Z40) 5'- GC CTG GAA AGC TGA GAT GGA G -3' (FRAG 231) (SEQ. ID NO: 241) 1 O 5'- GC CTG GAA AGC TOA GAT GGA -3' (FRAG 232) (SEQ. 1D NO: 242) 5'- GC CTG GAA AGC TGA GAT GG -3' (FRAG 233) (SEQ. ID NO: 243) 5'- GC CTG GAA AGC TGA GAT G -3' (FRAG 234) (SEQ. ID NO: 244) 5'- GC CTG GAA AGC TGA GAT -3' (FRAG 235) (SEQ. ID NO: 245) 5'- GC CTG GAA AGC TGA GA-3' (FRAG 236) (SLQ. ID NO: 246) 1 S 5'- GC CTG GAA AGC TGA G-3' (FRAG 237) (5'EQ. ID NO: 247) 5'- GC CTG GAA AGC TGA-3' (FRAG 238) (SEQ. ID NO: 248) 5'- GC CTG GAA AGC TG-3' (FRAG 239) (SEQ. iD NO: 249) 5'- GC CTG GAA AGC T-3' (FRAG 240) (SEQ. ID NO: 250) 5'- GC CTG GAA AGC-3' (FRAG 241) (SEQ. ID NO: 251) ZO 5'- GC CTG GAA AG-3' (FRAG 242) (SEQ. ID NO: 252) 5'- C CTG GAA AGC TGA GAT GG A GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG
243) (S~EQ. ID NO: 253) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 244) (SEQ. ID NO: 254) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 245) (SEQ. ID NO: 255) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 246) (SEQ. ID NO: 256) ZS 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 247) (SEQ. ID NO: 257) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 248) (SEQ. ID NO: 258) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 249) (SEQ.
ID NO: 259) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 250) (SEQ.
iD NO: 260) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 251) (SEQ. ID
NO: 261) 3O 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 252) (SEQ.
ID NO: 262) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 253) (SEQ. ID
NO: 263) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 254) (5'EQ. ID
NO: 264) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 255) (SEQ. ID NO:
265) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 256) (SEQ. ID NO:
2(~
3 S 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 257) (SEQ. ID NO:
267) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 258) (SEQ. ID NO: 268) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 259) (SEQ. 1D NO: 269) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 260) (SEQ. ID NO: 270) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 261) (SEQ. >D NO: 271) 4O 5'- C CTG GAA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 2b2) (SEQ. m NO: 272) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 263) (SEQ. ID NO: 273) 5'- C CTG GAA AGC TGA GAT GGA GGG CGG -3' (FRAG 264) (SEQ. ID NO: 274) 5'- C CTG GAA AGC TGA GAT GGA GGG CG -3' (FRAG 265) (SEQ. ID NO: 275) 5'- C CTG GAA AGC TGA GAT GGA GGG C -3' (FRAG 266) (SEQ. ID NO: 276) 4S 5'- C CTG GAA AGC TGA GAT GGA GGG -3' (FRAG 267) (SEQ. ID NO: 277) 5'- C CTG GAA AGC TGA GAT GGA GG -3' (FRAG 268) (SEQ. ID NO: 278) 5'- C CTG GAA AGC TGA GAT GGA G -3' (FRAG 269) (SEQ. ID NO: 279) 5'- C CTG GAA AGC TGA GAT GGA -3' (FRAG 270) (SEQ. ID NO: 280) 5'- C CTG GAA AGC TGA GAT GG -3' (FRAG 271) (SEQ. ID NO: 281) SO 5'- C CTG GAA AGC TGA GAT G -3' (FRAG 272) (5'EQ. m NO: 282) 5'- C CTG GAA AGC TGA GAT -3' (FRAG 273) (SEQ. ID NO: 283) 5'- C CTG GAA AGC TGA GA-3' (FRAG 274) (SEQ. iD NO: 284) 5'- C CTG GAA AGC TGA G-3' (FRAG 275) (SEQ. ID NO: 285) 5'- C CTG GAA AGC TGA-3' (FRAG 276) (SEQ. ID NO: 286) S S 5'- C CTG GAA AGC TG-3' (FRAG 277) (SEQ. ID NO: 287) 5'- C CTG GAA AGC T-3' (FRAG 278) (SEQ. ID NO: 288) 5'- C CTG GAA AGC-3' (FRAG 279) (SEQ. iD NO: 289) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 280) (SEQ. ZD NO: 290) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 281) (S'EQ, iD NO: 291) 6O 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 282) (SEQ. ID NO: 292) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 283) (SEQ. ID NO: 293) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 284) (SEQ.
ID NO: 294) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 285) (SEQ.
1D NO: 295) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 286) (SEQ.
ID NO: 296) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 287) (SEQ. ID
NO: 297) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 288) (SEQ. ID
NO: 298) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 289) (SEQ. ID NO:
299) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 290) (SEQ. ID NO:
300) S 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 291) (SEQ. m NO:
301) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 292) (SEQ. ID NO:
302) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 293) (SEQ. ID NO: 303) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 294) (SEQ. ID NO: 304) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 295) (SEQ. ID NO: 305) I O 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 296) (SEQ. m NO: 306) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 297) (SEQ. ID NO: 307) 5'- CTG GAA AGC TGA GAT. GGA GGG CGG CAT -3' (FRAG 298) (SEQ. ID NO: 308) 5'- CTG GAA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 299) (SEQ. ID NO: 309) 5'- CTG GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 300) (SEQ. ID NO: 310) I S 5'- CTG GAA AGC TGA GAT GGA GGG CGG -3' (FRAG 301) (SEQ. ID NO: 311) 5'- CTG GAA AGC TGA GAT GGA GGG CG -3' (FRAG 302) (SEQ. ID NO: 312) 5'- CTG GAA AGC TGA GAT GGA GGG C -3' (FRAG 303) (SEQ. ID NO: 313) 5'- CTG GAA AGC TGA GAT GGA GGG -3' (FRAG 304) (SEQ. ID NO: 314) 5'- CTG GAA AGC TGA GAT GGA GG -3' (FRAG 305) (SEQ. ID NO: 315) 2O 5'- CTG GAA AGC TGA GAT GGA G -3' (FRAG 306) (SEQ. ID NO: 316) 5'- CTG GAA AGC TGA GAT GGA -3' (FRAG 307) (SEQ. ID NO: 317) 5'- CTG GAA AGC TGA GAT GG -3' (FRAG 308) (SEQ. ID NO: 318) 5'- CTG GAA AGC TGA GAT G -3' (FRAG 309) (SEQ. ID NO: 319) 5'- CTG GAA AGC TGA GAT -3' (FRAG 310) (SEQ. ID NO: 320) 2S 5'- CTG GAA AGC TGA GA-3' (FRAG 311) (SEQ. ID NO: 321) 5'- CTG GAA AGC TGA G-3' (FRAG 312) (SEQ. ID NO: 322) 5'- CTG GAA AGC TGA-3' (FRAG 313) (SEQ. ID NO: 323) 5'- CTG GAA AGC TG-3' (FRAG 314) (SEQ. ID NO: 324) 5'- CTG GAA AGC T-3' (FRAG 315) (SEQ. ID NO: 325) 3O 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG
316) {SEQ. ID NO: 326) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 317) (SEQ. ID NO: 327) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 3l8) (SEQ. ID NO: 328) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 319) (SEQ. ID NO: 329) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 320) (SEQ.
ID NO: 330) 3S 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 321) (SEQ. ID NO: 331) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 322) (SEQ. ID
NO: 332) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 323) (SEQ. ID
NO: 333) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 324) (SEQ. ID
NO: 334) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 325) (SEQ. ID NO:
335) 4O 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 326) (SEQ. ID
NO: 336) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 327) (SEQ. ID NO:
337) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 328) (SEQ. ID NO:
338) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 329) (SEQ. ID NO: 339) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3' {FRAG 330) (SEQ. ID NO: 340) 4S 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FR.AG 331) (SEQ. ID NO:
341) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 332) (SEQ. ID NO: 342) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 333) (SEQ. ID NO: 343) 5'- TG GAA AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 334) (SEQ. ID NO: 344) 5'- TG GAA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 335) (SEQ. m NO: 345) SO 5'- TG GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 336) (SEQ. ID NO: 346) 5'- TG GAA AGC TGA GAT GGA GGG CGG -3' (FRAG 337) (SEQ. ID NO: 347) 5'- TG GAA AGC TGA GAT GGA GGG CG -3' (PRAG 338) (SEQ. ID NO: 348) 5'- TG GAA AGC TGA GAT GGA GGG C -3' (FRAG 339) (SEQ. ID NO: 349) 5'- TG GAA AGC TGA GAT GGA GGG -3' (FRAG 340) (SEQ. ID NO: 350) SS 5'- TG GAA AGC TGA GAT GGA GG -3' (FRAG 34l) (SEQ. ID NO: 351) 5'- TG GAA AGC TGA GAT GGA G -3' (FRAG 342) (SEQ. iD NO: 352) 5'- TG GAA AGC TGA GAT GGA -3' (FRAG 343) (SEQ. ID NO: 353) 5'- TG GAA AGC TGA GAT GG -3' (FRAG 344) (SEQ. >D NO: 354) 5'- TG GAA AGC TGA GAT G -3' {FRAG 345) (SEQ. ID NO: 355) C)O 5'- TG GAA AGC TGA GAT -3' (FRAG 346) (SEQ. !D NO: 356) 5'- TG GAA AGC TGA GA-3' (FRAG 347) (SEQ. iD NO: 357) 5'- TG GAA AGC TGA G-3' (FRAG 348) (SEQ. ID NO: 358) 5'- TG GAA AGC TGA-3' (FRAG 349) (SEQ. ID NO: 359) 5'- TG GAA AGC TG-3' (FRAG 350) (SEQ. ID NO: 360) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 351) (SEQ. ID NO: 361) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 352) (SEQ. ID NO: 362) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 353) (SEQ. ID NO: 363) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 354) (SEQ.
>D NO: 364) S 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 355) (SEQ.
ID NO: 365) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 356) (SEQ. ID
NO: 366) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 357) (SEQ. ID
NO: 367) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 358) (SEQ. ID
NO: 368) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 359) (SEQ. ID NO:
369) I O 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 360) (SEQ. ID
NO: 370) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 361) (SEQ. ID NO:
371) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 362) (S'EQ. ID NO:
372) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 363) (SEQ. ID NO: 373) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (PRAG 364) (SEQ. ID NO: 374) I S 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 365) (SEQ. ID NO:
375) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 366) (SEQ. ID NO: 376) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 367) (SEQ. ID NO: 377) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 368) (SEQ. ID NO: 378) 5'- G GAA AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 369) (SEQ. ID NO: 379) ZO 5'- G GAA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 370) (SEQ. ID NO: 380) 5'- G GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 371) (SEQ. ID NO: 381) 5'- G GAA AGC TGA GAT GGA GGG CGG -3' (FRAG 372) (SEQ. ID NO: 382) 5'- G GAA AGC TGA GAT GGA GGG CG -3' (FRAG 373) (SEQ. ID NO: 383) 5'- G GAA AGC TGA GAT GGA GGG C -3' (FRAG 374) (SEQ. ID NO: 384) ZS 5'- G GAA AGC TGA GAT GGA GGG -3' (FRAG 375) (SEQ. ID NO: 385) 5'- G GAA AGC TGA GAT GGA GG -3' (FRAG 376) (SEQ. ID NO: 386) 5'- G GAA AGC TGA GAT GGA G -3' (FRAG 377) (SEQ. ID NO: 387) 5'- G GAA AGC TGA GAT GGA -3' (FRAG 378) (SEQ. ID NO: 388) 5'- G GAA AGC TGA GAT GG -3' (FRAG 379) (SEQ. ID NO: 389) 3O 5'- G GAA AGC TGA GAT G -3' (FRAG 380) (SEQ. ID NO: 390) 5'- G GAA AGC TGA GAT -3' (FRAG 381) (SEQ. ID NO: 391) 5'- G GAA AGC TGA GA-3' (FRAG 382) (SEQ. ID NO: 392) 5'- G GAA AGC TGA G-3' (FRAG 383) (SEQ. ID NO: 393) 5'- G GAA AGC TGA-3' (FRAG 384) (SEQ. ID NO: 394) 3S 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 385) (SEQ. ID NO: 395) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 386) (SEQ.
ID NO: 396) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 387) (SEQ.
ID NO: 397) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 388) (SEQ.
ID NO: 398) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 389) (SEQ. ID
NO: 399) 4O 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 390) (SEQ. m NO: 400) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 391) (SEQ. ID
NO: 401) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 392) (SEQ. ID NO:
402) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 393) (SEQ. >D NO:
403) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 394) (SEQ. ID NO:
404) 4S 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 395) (SEQ. ID NO:
405) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 396) (SEQ. m NO: 406) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 397) (SEQ. ID NO: 407) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 398) (SEQ. ID NO: 408) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 399) {SEQ. ID NO: 409) SO 5'- GAA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 400) (SEQ. ID NO: 410) 5'- GAA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 401) (SEQ. ID NO: 411) 5'- GAA AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 402) (SEQ. ID NO: 412) 5'- GAA AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 403) (SEQ. ID NO: 413) 5'- GAA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 404) (SEQ. ID NO: 414) SS 5'- GAA AGC TGA GAT GGA GGG CGG C-3' (FRAG 405) (SEQ. ID NO: 415) 5'- GAA AGC TGA GAT GGA GGG CGG -3' (FRAG 406) (SEQ. ID NO: 416) 5'- GAA AGC TGA GAT GGA GGG CG -3' (FRAG 407) (SEQ. ID NO: 417) 5'- GAA AGC TGA GAT GGA GGG C -3' (FRAG 408) (SEQ. ID NO: 418) 5'- GAA AGC TGA GAT GGA GGG -3' (FRAG 409) (SEQ. ID NO: 419) E)O 5'- GAA AGC TGA GAT GGA GG -3' (FRAG 410) (SEQ. ID NO: 420) 5'- GAA AGC TGA GAT GGA G -3' (FRAG 411) (SEQ. ID NO: 421) 5'- GAA AGC TGA GAT GGA -3' (FRAG 412) (SEQ. ID NO: 422) 5'- GAA AGC TGA GAT GG -3' (FRAG 413) (SEQ. ID NO: 423) 5'- GAA AGC TGA GAT G -3' (FRAG 414) (SEQ. ID NO: 424) 5'-GAA AGC TCiA GAT -3' (FRAG 415) (SEQ. m NO: 425) 5'-GAA AGC TGA GA-3' (FRAG 416) (SEQ. m NO: 426) 5'-GAA AGC TGA G-3' (FRAG 417) (SEQ. ID NO: 427) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG
GGC-3' (FRAG 418) (SEQ. ID NO: 428) S 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG
GG-3' (FRAG 419) (SEQ. m NO: 429) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG
G-3' (FRAG 420) (SEQ. ID NO: 430) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG
-3' (FRAG 421) (SEQ. ID NO: 431) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (PRAG 422) (SEQ. ID NO: 432) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (PRAG 423) (SEQ. m NO: 433) I 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3'(FRAG
O 424) (SEQ. ID NO: 434) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG
425) (SEQ. m NO: 435) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG
426) (SEQ. ID NO: 436) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG
427) (SEQ. ID NO: 437) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG
428) (SEQ. ID NO: 438) I 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 429) S (SEQ. ID NO: 439) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 430) (SEQ. ID NO: 440) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 431) (SEQ. ID NO: 441) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 432) (SEQ. ID NO: 442) 5'-AA AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 433) (SEQ.
ID NO: 443) ZO 5'-AA AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 434) (SEQ.
ID NO: 444) 5'-AA AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 435) (SEQ.
ID NO: 445) 5'-AA AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 436) (SEQ.
ID NO: 446) 5'-AA AGC TGA GAT GGA GGG CGG CA-3' (FRAG 437) (SEQ. ID
NO: 447) 5'-AA AGC TGA GAT GGA GGG CGG C-3' (FRAG 438) (SEQ. ID
NO: 448) ZS 5'-AA AGC TGA GAT GGA GGG CGG -3' (FRAG 439) (SEQ. ID
NO: 449) 5'-AA AGC TGA GAT GGA GGG CG -3' (FRAG 440) (SEQ. ID NO:
450) 5'-AA AGC TGA GAT GGA GGG C -3' (FRAG 441) (SEQ. ID NO:
451) 5'-AA AGC TGA GAT GGA GGG -3' (FRAG 442) (SEQ. m NO: 452) 5'-AA AGC TGA GAT GGA GG -3' (FRAG 443) (SEQ. ID NO: 453) 3O 5'-AA AGC TGA GAT GGA G -3' (FRAG 444) (SEQ. ID NO: 454) 5'-AA AGC TGA GAT GGA -3' (FRAG 445) (SEQ. m NO: 455) 5'-AA AGC TGA GAT GG -3' (FRAG 446) (SEQ. ID NO: 456) 5'-AA AGC TGA GAT G -3' (FRAG 447) (SEQ. ID NO: 457) 5'-AA AGC TGA GAT -3' (FRAG 448) (SEQ. ID NO: 458) 3S 5'-AA AGC TGA GA-3' (PRAG 449) (SEQ. ID NO: 459) 5'-A AGC TGA GAT GGA GGG CG G CAT GGC GGG CAC AGG CTG
GGC-3' (FRAG 450) (SEQ. ID NO: 460) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 451) (SEQ. ID NO: 461) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 452) (SEQ. ID NO: 462) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 453) (SEQ. ID NO: 463) 4O 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 454) (SEQ. 1D NO: 464) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (PRAG 455) (SEQ. ID NO: 465) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG
456) (SEQ. ID NO: 466) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG
457) (SEQ. ID NO: 467) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG
458) (SEQ. ID NO: 468) 4S 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG
459) (SEQ. ID NO: 469) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 460) (SEQ. ID NO: 470) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 461) (SEQ. m NO: 471) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 462) (SEQ. ID NO: 472) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 463) (SEQ. ID NO: 473) SO 5'-A AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 464) (SEQ.
m NO: 474) 5'-A AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 465) (SEQ.
ID NO: 475) 5'-A AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 466) (SEQ.
ID NO: 476) 5'-A AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 467) (SEQ.
ID NO: 477) 5'-A AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 468) (SEQ.
ID NO: 478) SS 5'-A AGC TGA GAT GGA GGG CGG CA-3' (FRAG 469) (SEQ. ID
NO: 479) 5'-A AGC TGA GAT GGA GGG CGG C-3' (FRAG 470) (SEQ. ID
NO: 480) 5'-A AGC TGA GAT GGA GGG CGG -3' (FRAG 471) (SEQ. ID NO:
481) 5'-A AGC TGA GAT GGA GGG CG -3' (FRAG 472) (SEQ. m NO:
482) 5'-A AGC TGA GAT GGA GGG C -3' (FRAG 473) (SEQ. ID NO:
483) C)O5'-A AGC TGA GAT GGA GGG -3' (FRAG 474) (SEQ. ID NO: 484) 5'-A AGC TGA GAT GGA GG -3' (FRAG 475) (SEQ. ID NO: 485) 5'-A AGC TGA GAT GGA G -3' (FRAG 476) (SEQ. ID NO: 486) 5'-A AGC TGA GAT GGA -3' (FRAG 477) (SEQ. ID NO: 48'n 5'-A AGC TGA GAT GG -3' (FRAG 478) (SEQ. ID NO: 488) 5'- A AGC TGA GAT G -3' (FRAG 479) (SEQ. ID NO: 489) 5'- A AGC TGA GAT -3' (FRAG 480) (SEQ. ID NO: 490) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 481) (SEQ. ID
NO: 491) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 482) (SEQ. ID
NO: 492) S 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 483) (SEQ. iD
NO: 493) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 484) (SEQ. ID
NO: 494) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 485) (SEQ. ID NO:
495) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 486) (SEQ. ID NO:
496) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 487) (SEQ. ID NO:
497) I O 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 488) (SEQ. ID NO:
498) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 489) (SEQ. ID NO: 499) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 490) (SEQ. iD NO: 500) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 491) (SEQ. iD NO: 501) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 492) (SEQ. ID NO: 502) I S 5'- AGC TGA GAT GGA GGG CGG CAT GGC GGG -3' (PRAG 493) (SEQ. ID NO: 503) 5'- AGC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 494) (SEQ. ID NO: 504) 5'- AGC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 495) (SEQ. ID NO: 505) 5'- AGC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 496) (SEQ. ID NO: 506) 5'- AGC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 497) (SEQ. ID NO: 507) ZO 5'- AGC TGA GAT GGA GGG CGG CAT G -3' (FRAG 498) (SEQ. ID NO: 508) 5'- AGC TGA GAT GGA GGG CGG CAT -3' (FRAG 499) (SEQ. ID NO: 509) 5'- AGC TGA GAT GGA GGG CGG CA-3' (FRAG 500) (SEQ. ID NO: 510) 5'- AGC TGA GAT GGA GGG CGG C-3' (FRAG 501) (SEQ. ID NO: 511) 5'- AGC TGA GAT GGA GGG CGG -3' (FRAG 502) (SEQ. ID NO: 512) ZS 5'- AGC TGA GAT GGA GGG CG -3' (FRAG 503) (SEQ. 1D NO: 513) 5'- AGC TGA GAT GGA GGG C -3' (FRAG 504) (SEQ. ID NO: 514) 5'- AGC TGA GAT GGA GGG -3' (FRAG 505) (SEQ. ID NO: 515) 5'- AGC TGA GAT GGA GG -3' (FRAG 506) (SEQ. ID NO: 516) 5'- AGC TGA GAT GGA G -3' (FRAG 507) (SEQ. ID NO: 517) 3O 5'- AGC TGA GAT GGA -3' (FRAG 508) (SEQ. ID NO: 518) 5'- AGC TGA GAT GG -3' (FRAG 509) (SEQ. ID NO: 519) 5'- AGC TGA GAT G -3' (FRAG 510) (SEQ. ID NO: 520) 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 511) (SEQ. ID
NO: 521) 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 512) (SEQ. ID
NO: 522) 3 S 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 513) (SEQ.
ID NO: 523) 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 514) (SEQ. ID NO:
524) 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 515) (SEQ. ID NO:
525) 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 516) (SEQ. ID NO:
52~
5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 517) (SEQ. ID NO:
527) 4O 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 518) (SEQ. ID NO:
528) 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 519) (SEQ. ID NO: 529) 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 520) (SEQ. ID NO: 530) 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 521) (SEQ. ID NO: 531) 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 522) (SEQ. ID NO: 532) 4S 5'- GC TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 523) (SEQ. ID NO: 533) 5'- GC TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 524) (SEQ. ID NO: 534) 5'- GC TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 525) (SEQ. ID NO: 535) 5'- GC TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 526) (SEQ. ID NO: 536) 5'- GC TGA GAT GGA GGG CGG CAT GG -3' (FRAG 527) (SEQ. ID NO: 537) SO 5'- GC TGA GAT GGA GGG CGG CAT G -3' (FRAG 528) (SEQ. ID NO: 538) 5'- GC TGA GAT GGA GGG CGG CAT -3' (FRAG 529) (SEQ. ID NO: 539) 5'- GC TGA GAT GGA GGG CGG CA-3' (FRAG 530) (SEQ. ID NO: 540) 5'- GC TGA GAT GGA GGG CGG C-3' (FRAG 531) (SEQ. ID NO: 541) 5'- GC TGA GAT GGA GGG CGG -3' (FRAG 532) (SEQ. ID NO: 542) SS 5'- GC TGA GAT GGA GGG CG -3' (FRAG 533) (SEQ. ID NO: 543) 5'- GC TGA GAT GGA GGG C -3' (FRAG 534) (SEQ. ID NO: 544) 5'- GC TGA GAT GGA GGG -3' (FRAG 535) (SEQ. ID NO: 545) 5'- GC TGA GAT GGA GG -3' (FRAG 536) (SEQ. ID NO: 546) 5'- GC TGA GAT GGA G -3' (FRAG 537) (SEQ. ID NO: 547) GO 5'- GC TGA GAT GGA -3' (FRAG 538) (SEQ. ID NO: 548) 5'- GC TGA GAT GG -3' (FRAG 539) (SEQ. ID NO: 549) 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 540) (SEQ. ID
NO: 550) 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 541) (SEQ. ID
NO: 551) 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 542) (SEQ. ID NO:
552) 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 543) (SEQ. ID NO:
553) 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 544) (SEQ. )D NO:
554) 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 545) (SEQ. iD NO: 555 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 546) (SEQ. ID NO: 551 S 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 547) (SEQ. ID NO: 557) 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 548) (SEQ. ID NO: 558) 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 549) (SEQ. ID NO: 559) 5'- C TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 550) (SEQ. 1D NO: 560) 5'- C TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 551) (SEQ. >D NO: 561) I O 5'- C TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 552) (SEQ. ID NO: 562) 5'- C TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 553) (SEQ. ID NO: 563) 5'- C TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 554) (SEQ. ID NO: 564) 5'- C TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 555) (SEQ. iD NO: 565) 5'- C TGA GAT GGA GGG CGG CAT GG -3' (FRAG 556) (SEQ. ID NO: 5C~
I S 5'- C TGA GAT GGA GGG CGG CAT G -3' (FRAG 557) (SEQ. ID NO: 567) 5'- C TGA GAT GGA GGG CGG CAT -3' (FRAG 558) (SEQ. )D NO: 568) 5'- C TGA GAT GGA GGG CGG CA-3' (FRAG 559) (SEQ. ID NO: 569) 5'- C TGA GAT GGA GGG CGG C-3' (FRAG 560) (SEQ. ID NO: 570) 5'- C TGA GAT GGA GGG CGG -3' (FRAG 561) (SEQ. ID NO: 571) 5'- C TGA GAT GGA GGG CG -3' (FRAG 562) (SEQ. ID NO: 572) 5'- C TGA GAT GGA GGG C -3' (FRAG 563) (SEQ. ID NO: 573) 5'- C TGA GAT GGA GGG -3' (FRAG 564) (SEQ. ID NO: 574) 5'- C TGA GAT GGA GG -3' (FRAG 565) (SEQ. ID NO: 575) 5'- C TGA GAT GGA G -3' (FRAG 566) (SEQ. ID NO: 576) ZS 5'- C TGA GAT GGA -3' (FRAG 567) (SEQ. ID NO: Sm 5'- TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 568) (SEQ. ID NO:
578) 5'- TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 569) (SEQ. ID NO:
579) 5'- TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 570) (SEQ. ID NO:
580) 5'- TGA GAT GGA GGG CGG CAT GGC GG(i CAC AGG CTG -3' (FRAG 571) (SEQ. ID NO:
S81) 3O 5'- TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' {FRAG 572) (SEQ. >D NO:
582) 5'- TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 573) (SEQ. ID NO: 583) 5'- TGA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 574) (SEQ. ID NO: 584) 5'- TGA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 575) (SEQ. ID NO: 585) 5'- TGA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 576) (SEQ. ID NO: 586) 3 S 5'- TGA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 577) (SEQ. ID NO: 587) 5'- TGA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 578) (SEQ. ID NO: 588) 5'- TGA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 579) (SEQ. ID NO: 589) 5'- TGA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 580) (SEQ. ID NO: 590) 5'- TGA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 581) (SEQ. ID NO: 591) 4O 5'- TGA GAT GGA GGG CGG CAT GGC G-3' (FRAG 582) (SEQ. 1D NO: 592) 5'- TGA GAT GGA GGG CGG CAT GGC -3' (FRAG 583) (SEQ. ID NO: 593) 5'- TGA GAT GGA GGG CGG CAT GG -3' (FRAG 584) (SEQ. ID NO: 594) 5'- TGA GAT GGA GGG CGG CAT G -3' (FRAG 585) (SEQ. ID NO: 595) 5'- TGA GAT GGA GGG CGG CAT -3' (FRAG 586) (SEQ. ID NO: 596) 4S 5'- TGA GAT GGA GGG CGG CA-3' (FRAG 587) (SEQ. ID NO: 597) 5'- TGA GAT GGA GGG CGG C-3' (FRAG 588) (SEQ. )D NO: 598) 5'- TGA GAT GGA GGG CGG -3' (FRAG 589) (SEQ. ID NO: 599) 5'- TGA GAT GGA GGG CG -3' (FRAG 590) (SEQ. ID NO: 600) 5'- TGA GAT GGA GGG C -3' (FRAG 591) (SEQ. ID NO: 641) SO 5'- TGA GAT GGA GGG -3' (FRAG 592) (SEQ. )D NO: 602) 5'- TGA GAT GGA GG -3' (FRAG 593) (SEQ. ID NO: 603) 5'- TGA GAT GGA G -3' (FRAG 594) (SEQ. ID NO: 604) 5'- GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 595) (SEQ. ID NO:
605) 5'- GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 596) (SEQ. ID NO:
606) SS 5'- GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 597) (SEQ. ID NO:
607) 5'- GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 598) (SEQ. >D NO: 6~) 5'- GA GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 599) (SEQ. ID NO: 609) 5'- GA GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FR.AG 600) (SEQ. ID NO: 610) 5'- GA GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 601) (SEQ. ID NO: 611) bO 5'- GA GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 602) (SEQ. ID NO: 612) 5'- GA GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 603) (SEQ. m NO: 613) 5'- GA GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 604) (SEQ. ID NO: 614) 5'- GA GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 605) (SEQ. ID NO: 615) 5'- GA GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 606) (SEQ. ID NO: 616) 3b 5'-GA GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 607) (SEQ. ID NO: 617) 5'-GA GAT GGA GGG CGG CAT GGC GG-3' (FRAG 608) (SEQ.
iD NO: 618) 5'-GA GAT GGA GGG CGG CAT GGC G-3' (FRAG 609) (SEQ.
ID NO: 619) 5'-GA GAT GGA GGG CGG CAT GGC -3' (FRAG 610) (SEQ.
ID NO: 620) S 5'-GA GAT GGA GGG CGG CAT GG -3' (FRAG 611) (SEQ.
ID NO: 621) 5'-GA GAT GGA GGG CGG CAT G -3' (FRAG 612) (SEQ.
ID NO: 622) 5'-GA GAT GGA GGG CGG CAT -3' (FRAG 613) (SEQ. ID
NO: 623) 5'-GA GAT GGA GGG CGG CA-3' (FRAG 614) (SEQ. ID
NO: 624) 5'-GA GAT GGA GGG CGG C-3' (FRAG 615) (SEQ. ID NO:
625) I 5'-GA GAT GGA GGG CGG -3' (PRAG 616) (SEQ. ID NO:
O 626) 5'-GA GAT GGA GGG CG -3' (PRAG 617) (SEQ. ID NO:
627) S'-GA GAT GGA GGG C -3' (FRAG 618) (SEQ. ID NO:
628) 5'-GA GAT GGA GGG -3' (FRAG 619) (SEQ. >D NO: 629) 5'-GA GAT GGA GG -3' (FRAG 620) (SEQ. ID NO: 630) I 5'-A GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' S (FRAG 621) (SEQ. ID NO: 631) 5'-A GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 622) (SEQ. 1D NO: 632) 5'-A GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 623) (SEQ. ID NO: 633) 5'-A GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 624) (SEQ. ID NO: 634) 5'-A GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG
625) (SEQ. ID NO: 635) ZO 5'-A GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG
626) (SEQ. ID NO: 636) 5'-A GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG
627) (SEQ. ID NO: 637) 5'-A GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG
628) (SEQ. >D NO: 638) 5'-A GAT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG
629) (SEQ. ID NO: 639) 5'-A GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 630) (SEQ. ID NO: 640) ZS 5'-A GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 631) (SEQ. ID NO: 641) 5'-A GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 632) (SEQ. ID NO: 642) 5'-A GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 633) (SEQ. ID NO: 643) 5'-A GAT GGA GGG CGG CAT GGC GG-3' (FRAG 634) {SEQ.
ID NO: 644) 5'-A GAT GGA GGG CGG CAT GGC G-3' (FRAG 635) (SEQ.
ID NO: 645) 3O 5'-A GAT GGA GGG CGG CAT GGC -3' (FRAG 636) (SEQ.
ID NO: 646) 5'-A GAT GGA GGG CGG CAT GG -3' (FRAG 637) (SEQ.
ID NO: 647) 5'-A GAT GGA GGG CGG CAT G -3' (FRAG 638) (SEQ.
ID NO: 648) 5'-A GAT GGA GGG CGG CAT -3' (FRAG 639) (SEQ. ID
NO: 649) 5'-A GAT GGA GGG CGG CA-3' (FRAG 640) (SEQ. ID NO:
650) 3S 5'-A GAT GGA GGG CGG C-3' (FRAG 641) (SEQ. ID NO:
651) 5'-A GAT GGA GGG CGG -3' (FRAG 642) (SEQ. ID NO:
652) 5'-A GAT GGA GGG CG -3' (FRAG 643) {SEQ. ID NO:
653) 5'-A GAT GGA GGG C -3' (FRAG 644) (SEQ. ID NO: 654) 5'-A GAT GGA GGG -3' (FRAG 645) (SEQ. ID NO: 655) 4O 5'-GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 646) (SEQ. ID NO: 656) 5'-GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 647) (SEQ. ID NO: 657) 5'-GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 648) (SEQ. ID NO: 658) 5'-GAT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG
6) (SEQ. ID NO: 659) 5'-GAT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG
650) (SEQ. ID NO: 660) 4S 5'-GAT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG
651) (SEQ. ID NO: 661) 5'-GAT GGA GGG CGG CAT GGC GGG CAC AGG -3' {FRAG
652) (SEQ. ID NO: 662) 5'-GAT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 653) (SEQ. ID NO: 663) 5'-GAT GGA GGG CGG CAT GGC GGG CAC A-3' {FRAG 6S4) (SEQ. ID NO: 664) 5'-GAT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 655) (SEQ. ID NO: 665) SO 5'-GAT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 636) (SEQ. ID NO: 666) S'-GAT GGA GGG CGG CAT GGC GGG C-3' (FRAG 657) (SEQ.
ID NO: 667) 5'-GAT GGA GGG CGG CAT GGC GGG -3' (FRAG 658) (SEQ.
ID NO: 668) 5'-GAT GGA GGG CGG CAT GGC GG-3' (FRAG 659) (SEQ.
ID NO: 669) 5'-GAT GGA GGG CGG CAT GGC G-3' (FRAG 660) (SEQ.
ID NO: 670) SS 5'-GAT GGA GGG CGG CAT GGC -3' (FRAG 661) (SEQ.
ID NO: 671) 5'-GAT GGA GGG CGG CAT GG -3' (FRAG 662) (SEQ. ID
NO: 672) 5'-GAT GGA GGG CGG CAT G -3' (FRAG 663) (SEQ. ID
NO: 673) 5'-GAT GGA GGG CGG CAT -3' (FRAG 664) (SEQ. ID NO:
674) 5'-GAT GGA GGG CGG CA-3' (FRAG 665) (SEQ. ID NO:
675) E)O5'-GAT GGA GGG CGG C-3' (FRAG 666) (SEQ. ID NO:
676) 5'-GAT GGA GGG CGG -3' (FRAG 667) (SEQ. ID NO: 677) 5'-GAT GGA GGG CG -3' (FRAG 668) (SEQ. ID NO: 678) 5'-GAT GGA GGG C -3' (FRAG 669) (SEQ. ID NO: 679) 5'-AT GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 670) (SEQ. ID NO: 680) 5'- AT GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 671) (SEQ. ID NO: 681) 5'- AT GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 672) (SEQ. ID NO: 682) 5'- AT GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 673) (SEQ. ID NO: 683) 5'- AT GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 674) (SEQ. ID NO: 684) S 5'- AT GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 675) (SEQ. ID NO: 685j 5'- AT GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 676) (SEQ. ID NO: 686) 5'- AT GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 677) (SEQ. ID NO: 687) 5'- AT GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 678) (SEQ. ID NO: 688) 5'- AT GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 679) (SEQ. ID NO: 689) I O 5'- AT GGA GGG CGG CAT GGC GGG CA-3' (FRAG 680) (SEQ. ID NO: 690) 5'- AT GGA GGG CGG CAT GGC GGG C-3' (FRAG 681) (SEQ. ID NO: 691) 5'- AT GGA GGG CGG CAT GGC GGG -3' (FRAG 682) (SEQ. iD NO: 692) 5'- AT GGA GGG CGG CAT GGC GG-3' (FRAG 683) (SEQ. ID NO: ~3) 5'- AT GGA GGG CGG CAT GGC G-3' (FRAG 684) (SEQ. ID NO: 694) I S 5'- AT GGA GGG CGG CAT GGC -3' (FRAG 685) (SEQ. ID NO: 695) 5'- AT GGA GGG CGG CAT GG -3' (FRAG 686) (SEQ. ID NO: 696) 5'- AT GGA GGG CGG CAT G -3' (FRAG 687) (SEQ. ID NO: 697) 5'- AT GGA GGG CGG CAT -3' (FRAG 688) (SEQ. ID NO: 698) 5'- AT GGA GGG CGG CA-3' (FRAG 689) (SEQ.1D NO: 699) ZO 5'- AT GGA GGG CGG C-3' (FRAG 690) (SEQ. ID NO: 700) 5'- AT GGA GGG CGG -3' (FRAG 691) (SEQ. ID NO: 701) 5'- AT GGA GGG CG -3' (FRAG 692) (SEQ. ID NO: 702) 5'- T GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 693) (SEQ. ID NO: 703) 5'- T GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 694) (SEQ. iD NO: 704) ZS 5'- T GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 695) (SEQ. ID NO: 705) 5'- T GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 696) (SEQ. ID NO: ?06) 5'- T GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 697) (SEQ. ID NO: 707) 5'- T GGA GGG CGG CAT GGC GGG CAC AGG C3' (l:RAG 698) (SEQ. ID NO: 708) 5'- T GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 699) (SEQ. ID NO: 709) 3O 5'- T GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 700) (SEQ. ID NO: 710) 5'- T GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 701) (SEQ. ID NO: 711) 5'- T GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 702) (SEQ. ID NO: 712) 5'- T GGA GGG CGG CAT GGC GGG CA-3' (FRAG 703) (SEQ. ID NO: 713) 5'- T GGA GGG CGG CAT GGC GGG C-3' (FRAG 704) (SEQ. ID NO: 714) 3 S 5'- T GGA GGG CGG CAT GGC GGG -3' (FRAG 705) (SEQ. ID NO: 715) 5'- T GGA GGG CGG CAT GGC GG-3' (FRAG 706) (SEQ. ID NO: 716) 5'- T GGA GGG CGG CAT GGC G-3' (FRAG 707) (SEQ. ID NO: 717) 5'- T GGA GGG CGG CAT GGC -3' (FRAG 708) (SEQ. ID NO: 718) 5'- T GGA GGG CGG CAT GG -3' (FRAG 709) (SEQ. ID NO: 719) 4O 5'- T GGA GGG CGG CAT G -3' (FRAG 710) (SEQ. ID NO: 720) 5'- T GGA GGG CGG CAT -3' (FRAG 7l i) (SEQ. ID NO: 721) 5'- T GGA GGG CGG CA-3' (FRAG 712) (SEQ. ID NO: 722) 5'- T GGA GGG CGG C-3' (FRAG 713) (SEQ. >D NO: 723) 5'- T GGA GGG CGG -3' (FRAG 714) (SEQ. ID NO: 724) 4S 5'- GGA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 715) (SEQ. ID NO: 725) 5'- GGA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 716) (SEQ. ID NO: 726) 5'- GGA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 717) (SEQ. ID NO: 727) 5'- GGA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 718) (SEQ. m NO: 728) 5'- GGA GGG CGG CAT GGC GGG CAC AGG CT-3' (l;RAG 719) (SEQ. ID NO: 719) SO 5'- GGA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 720) (SEQ. ID NO: 730) 5'- GGA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 721) (SEQ. ID NO: 731) 5'- GGA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 722) (SEQ. ID NO: 732) 5'- GGA GGG CGG CAT GGC GGG CAC A-3' (FRAG 723) (SEQ. ID NO: 733) 5'- GGA GGG CGG CAT GGC GGG CAC-3' (FRAG 724) (SEQ. ID NO: 734) SS 5'- GGA GGG CGG CAT GGC GGG CA-3' (FRAG 725) (SEQ. ID NO: 735) .
5'- GGA GGG CGG CAT GGC GGG C-3' (FRAG 726) (SEQ. ID NO: 736) 5'- GGA GGG CGG CAT GGC GGG -3' (FRAG 727) (SEQ. ID NO: 737) 5'- GGA GGG CGG CAT GGC GG-3' (FRAG 728) (SEQ. ID NO: 738) 5'- GGA GGG CGG CAT GGC G-3' (FRAG 729) (SEQ. ID NO: 739) E)O 5'- GGA GGG CGG CAT GGC -3' (FRAG 730) (SEQ. ID NO: 740) 5'- GGA GGG CGG CAT GG -3' (FRAG 731) (SEQ. ID NO: 741) 5'- GGA GGG CGG CAT G -3' (FRAG 732) (SEQ. ID NO: 742) 5'- GGA GGG CGG CAT -3' (FRAG 733) (SEQ. ID NO: 743) 5'- GGA GGG CGG CA-3' (FRAG 734) (SEQ. ID NO: 744) 5'- GGA GGG CGG C-3' (FRAG 735) (SEQ. ID NO: 745) 5'- GA GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 736) (SEQ. ID NO: 746) 5'- GA GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 737) (SEQ. ID NO: 747) 5'- GA GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 738) (SEQ. >D NO: 748) S 5'- GA GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 739) (SEQ. ID NO: 749) 5'- GA GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 740) (SEQ. ID NO: 750) 5'- GA GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 741) (SEQ. ID NO: 751) 5'- GA GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 742) (SEQ. ID NO: 752) 5'- GA GGG CGG CAT GGC GGG CAC AG-3' (FRAG 743) (S~Q. ID NO: 753) I O 5'- GA GGG CGG CAT GGC GGG CAC A-3' (FRAG ?44) (SEQ. ID NO: 754) 5'- GA GGG CGG CAT GGC GGG CAC-3' (FRAG 745) (SEQ. ID NO: 755) 5'- GA GGG CGG CAT GGC GGG CA-3' (FRAG 746) (SEQ. ID NO: 756) 5'- GA GGG CGG CAT GGC GGG C-3' (FRAG 747) (SEQ. ID NO: 757) 5'- GA GGG CGG CAT GGC GGG -3' (FRAG 748) (SEQ. ID NO: 758) I S 5'- GA GGG CGG CAT GGC GG-3' (FRAG 749) (SEQ. ID NO: 759) 5'- GA GGG CGG CAT GGC G-3' (FRAG 750) (SEQ. ID NO: 760) 5'- GA GGG CGG CAT GGC -3' (FRAG 751) (SEQ. ID NO: 761) 5'- GA GGG CGG CAT GG -3' (FRAG 752) (SEQ. ID NO: 762) 5'- GA GGG CGG CAT G -3' (FRAG 753) (SEQ. ID NO: 763) ZO 5'- GA GGG CGG CAT -3' (FRAG 754) (SEQ. m NO: 764) 5'- GA GGG CGG CA-3' (FR.AG 755) (SEQ. ID NO: 765) 5'- A GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 756) (SEQ. ID NO: 766) 5'- A GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 757) (SEQ. ID NO: 767) 5'- A GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 758) (SEQ. ID NO: 768) ZS 5'- A GGG CGG CAT GGC GGG CAC AGG CTG 3' (FRAG 759) (SEQ. ID NO: 769) 5'- A GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 760) (SEQ. ID NO: 770) 5'- A GGG CGG CAT GGC GGG CAC AGG C-3' (FR.AG 761) (SEQ. ID NO: 771) 5'- A GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 762) (SEQ. ID NO: 772) 5'- A GGG CGG CAT GGC GGG CAC AG-3' (FRAG 763) (SEQ. ID NO: 773) 3O 5'- A GGG CGG CAT GGC GGG CAC A-3' (FRAG 764) (SEQ. ID NO: 774) 5'- A GGG CGG CAT GGC GGG CAC-3' (FRAG 765) (SEQ. ID NO: 775) 5'- A GGG CGG CAT GGC GGG CA-3' (FRAG 766) (SEQ. ID NO: 776) 5'- A GGG CGG CAT GGC GGG C-3' (FRAG 767) (SEQ. ID NO: 777) 5'- A GGG CGG CAT GGC GGG -3' (FRAG 768) (SEQ. ID NO: 778) 3S 5'- A GGG CGG CAT GGC GG-3' (FRAG 769) (SEQ. ID NO: 779) 5'- A GGG CGG CAT GGC G-3' (FRAG 770) (SEQ. ID NO: 780) 5'- A GGG CGG CAT GGC -3' (FRAG 771) (SEQ. ID NO: 781) 5'- A GGG CGG CAT GG -3' (FRAG 772) (SEQ. ID NO: 782) 5'- A GGG CGG CAT G -3' (FRAG 773) (SEQ. ID NO: 783) 4O 5'- A GGG CGG CAT -3' (FRAG 774) (SEQ. >D NO: 784) 5'- GGG CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 775) (SEQ. ID NO: 785) 5'- GGG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 776) (SEQ. ID NO: 786) 5'- GGG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 777) (SEQ. ID NO: 787) 5'- GGG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 778) (SEQ. ID NO: 788) 4S 5'- GGG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 779) (SEQ. ID NO: 789) 5'- GGG CGG CAT GGC GGG CAC AGG C-3' (FRAG 780) (SEQ. ID NO: 790) 5'- GGG CGG CAT GGC GGG CAC AGG -3' (FRAG 781) (SEQ. ID NO: 791) 5'- GGG CGG CAT GGC GGG CAC AG-3' (FRAG 782) (SEQ. ID NO: 792) 5'- GGG CGG CAT GGC GGG CAC A-3' (FRAG 783) (SEQ. ID NO: 793) SO 5'- GGG CGG CAT GGC GGG CAC-3' (FRAG 784) (SEQ. m NO: 794) 5'- GGG CGG CAT GGC GGG CA-3' (FRAG 785) (SEQ. ID NO: 795) 5'- GGG CGG CAT GGC GGG C-3' (FRAG 786) (SEQ. ID NO: 796) 5'- GGG CGG CAT GGC GGG -3' (FRAG ?87) (SEQ. ID NO: 797) 5'- GGG CGG CAT GGC GG-3' (FRAG 788) (SEQ. ID NO: 798) SS 5'- GGG CGG CAT GGC G-3' (FRAG 789) (SEQ. ID NO: 799) 5'- GGG CGG CAT GGC -3' (FRAG 790) (SEQ. ID NO: 800) 5'- GGG CGG CAT GG -3' (FRAG 791) (SEQ. ID NO: 801) 5'- GGG CGG CAT G -3' (FRAG 792) (SEQ. ID NO: 802) 5'- GG CGG CAT GGC GGG CAC AG G CTG GGC-3' (FRAG 793) (SEQ. ID NO: 803) 6O 5'- GG CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG 794) (SEQ. ID NO: 804) 5'- GG CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG 795) (SEQ. ID NO: 805) 5'- GG CGG CAT GGC GGG CAC AGG CTG -3' (FRAG 796) (SEQ. ID NO: 806) 5'- GG CGG CAT GGC GGG CAC AGG CT-3' (FRAG 797) (SEQ. ID NO: 807) 5'- GG CGG CAT GGC GGG CAC AGG C-3' (FRAG 798) (SEQ. ID NO: 808) 5'- GG CGG CAT GGC GGG CAC AGG -3' (FRAG 799) (SEQ. ID NO: 809) 5'- GG CGG CAT GGC GGG CAC AG-3' (FRAG 800) (SEQ. ID NO: 810) 5'- GG CGG CAT GGC GGG CAC A-3' (FRAG 801) (SEQ. ID NO: 811) 5'- GG CGG CAT GGC GGG CAC-3' (FRAG 802) (SEQ. ID NO: 812) S 5'- GG CGG CAT GGC GGG CA-3' (FRAG 803) (SEQ.
ID NO: 813) 5'- GG CGG CAT GGC GGG C-3' (FRAG 804) (SEQ.
ID NO: 814) S'- GG CGG CAT GGC GGG -3' (FRAG 805) (SEQ.
ID NO: 815) S'- GG_CGG CAT GGC GG-3' (FRAG 806) (SEQ.
1D NO: 816) 5'- GG CGG CAT GGC G-3' (FRAG 807) (SEQ.
ID NO: 817) I 5'- GG CGG CAT GGC -3' (FRAG 808) (SEQ. ID
O NO: 818) 5'- GG CGG CAT GG -3' (FRAG 809) (SEQ. ID
NO: 819) 5'- G CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG 810) (SEQ. >D NO: 820) 5'- G CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG
811) (SEQ. ID NO: 821) 5'- G CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG
812) (SEQ. ID NO: 822) I 5'- G CGG CAT GGC GGG CAC AGG CTG -3' (FRAG
S 813) (SEQ. ID NO: 823) 5'- G CGG CAT GGC GGG CAC AGG CT-3' (FRAG
814) (SEQ. ID NO: 824) 5'- G CGG CAT GGC GGG CAC AGG C-3' (FRAG
815) (SEQ. ID NO: 825) 5'- G CGG CAT GGC GGG CAC AGG -3' (FRAG 816) (SEQ. ID NO: 826) 5'- G CGG CAT GGC GGG CAC AG-3' (FRAG 817) (SEQ. ID NO: 827) ZO 5'- G CGG CAT GGC GGG CAC A-3' (FRAG 818) (SEQ. ID NO: 828) 5'- G CGG CAT GGC GGG CAC-3' (FRAG 819) (SEQ.
ID NO: 829) 5'- G CGG CAT GGC GGG CA-3' (FRAG 820) (SEQ.
ID NO: 830) 5'- G CGG CAT GGC GGG C-3' (FRAG 821) (SEQ.
ID NO: 831) 5'- G CGG CAT GGC GGG -3' (FRAG 822) (SEQ.
ID NO: 832) 2S 5'- G CGG CAT GGC GG-3' (FRAG 823) (SEQ.
ID NO: 833) 5'- G CGG CAT GGC G-3' (FRAG 824) (SEQ. ID
NO: 834) 5'- G CGG CAT GGC -3' (FRAG 825) (SEQ. ID
NO: 835) 5'- CGG CAT GGC GGG CAC AGG CTG GGC-3' (FRAG
826) (SEQ. ID NO: 836) 5'- CGG CAT GGC GGG CAC AGG CTG GG-3' (FRAG
827) (SEQ. ID NO: 837) 3O 5'- CGG CAT GGC GGG CAC AGG CTG G-3' (FRAG
828) (SEQ. ID NO: 838) 5'- CGG CAT GGC GGG CAC AGG CTG -3' (FRAG
829) (SEQ. ID NO: 839) 5'- CGG CAT GGC GGG CAC AGG CT-3' (FRAG 830) (SEQ. ID NO: 840) 5'- CGG CAT GGC GGG CAC AGG C-3' (FRAG 831) (SEQ. ID NO: 841) 5'- CGG CAT GGC GGG CAC AGG -3' (FRAG 832) (SEQ. ID NO: 842) 3 5'- CGG CAT GGC GGG CAC AG-3' (FRAG 833) S (SEQ. ID NO: 843) 5'- CGG CAT GGC GGG CAC A-3' (FF,AG 834) (SEQ. ID NO: 844) 5'- CGG CAT GGC GGG CAC-3' (FRAG 835) (SEQ.
ID NO: 845) 5'- CGG CAT GGC GGG CA-3' (FRAG 836) (SEQ.
ID NO: 846) 5'- CGG CAT GGC GGG C-3' (FRAG 837) (SEQ.
ID NO: 847) 40 5'- CGG CAT GGC GGG -3' (FRAG 838) (SEQ.
ID NO: 848) 5'- CGG CAT GGC GG-3' (FRAG 839) (SEQ. ID
NO: 849) 5'- CGG CAT GGC G-3' (FRAG 840) (SEQ. iD
NO: 850) 5'- GG CAT GGC GGG CAC AGG C TG GGC-3' (FRAG
841) (SEQ. ID NO: 851) 5'- GG CAT GGC GGG CAC AGG CTG GG-3' (FRAG
842) (SEQ. ID NO: 852) 4S 5'- GG CAT GGC GGG CAC AGG CTG G-3' (FRAG
843) (SEQ. ID NO: 853) 5'- GG CAT GGC GGG CAC AGG CTG -3' (FRAG
844) (SEQ. ID NO: 854) 5'- GG CAT GGC GGG CAC AGG CT-3' (FRAG 845) (SEQ. ID NO: 855) 5'- GG CAT GGC GGG CAC AGG C-3' (FRAG 846) (SEQ. ID NO: 856) 5'- GG CAT GGC GGG CAC AGG -3' (FRAG 847) (SEQ. ID NO: 857) SO 5'- GG CAT GGC GGG CAC AG-3' (FRAG 848) (SEQ.
ID NO: 858) 5'- GG CAT GGC GGG CAC A-3' (FRAG 849) (SEQ.
ID NO: 859) 5'- GG CAT GGC GGG CAC-3' (FRAG 850) (SEQ.
ID NO: 860) 5'- GG CAT GGC GGG CA-3' (FRAG 851) (SEQ.
ID NO: 861) 5'- GG CAT GGC GGG C-3' (FRAG 852) (SEQ.
ID NO: 862) SS 5'- GG CAT GGC GGG -3' (FRAG 853) (SEQ. ID
NO: 863) 5'- GG CAT GGC GG-3' (FRAG 854) (SEQ. ID
NO: 864) 5'- G CAT GGC GGG CAC AGG CTG GGC-3' (FRAG
855) (SEQ. ID NO: 865) 5'- G CAT GGC GGG CAC AGG CTG GG-3' (FRAG
856) (SEQ. ID NO: 866) 5'- G CAT GGC GGG CAC AGG CTG G-3' (FRAG
857) (SEQ. ID NO: 867) 6O 5'- G CAT GGC GGG CAC AGG CTG -3' (FRAG 858) (SEQ. ID NO: 868) 5'- G CAT GGC GGG CAC AGG CT-3' (FRAG 859) (SEQ. ID NO: 869) 5'- G CAT GGC GGG CAC AGG C-3' (FRAG 860) (SEQ. ID NO: 870) 5'- G CAT GGC GGG CAC AGG -3' (FRAG 861) (SEQ. ID NO: 871) 5'- G CAT GGC GGG CAC AG-3' (FRAG 862) (SEQ.
ID NO: 872) 5'-G CAT GGC GGG CAC A-3' (FRAG 863) (SEQ.
1D NO: 873) 5'-G CAT GGC GGG CAC-3' (PRAG 864) (SEQ.
)~ NO: 874) 5'-G CAT GGC GGG CA-3' (FRAG 865) (SEQ.
ID NO: 875) 5'-G CAT GGC GGG C-3' (FRAG 866) (SEQ.
ID NO: 876) S 5'-G CAT GGC GGG -3' (FRAG 867) (SEQ.
ID NO: 877) 5'-CAT GGC GGG CAC AGG CTG GGC-3' (FRAG
868) (SEQ. ID NO: 878) 5'-CAT GGC GGG CAC AGG CTG GG-3' (FRAG
869) (SEQ. ID NO: 879) 5'-CAT GGC GGG CAC AGG CTG G-3' (FRAG
870) (SEQ. ID NO: 880) 5'-CAT GGC GGG CAC AGG CTCi -3' (PRAG
871) (SEQ. ID NO: 881) 1 5'-CAT GGC GGG CAC AGG CT-3' (FRAG 872) O (SEQ. ID NO: 882) 5'-CAT GGC GGG CAC AGG C-3' (FRAG 873) (SEQ. iD NO: 883) 5'-CAT GGC GGG CAC AGG -3' (FRAG 874) (SEQ. m NO: 884) 5'-CAT GGC GGG CAC AG-3' (FRAG 875) (SEQ.
lD NO: 885) 5'-CAT GGC GGG CAC A-3' (FRAG 876) (SEQ.
ID NO: 886) 1 5'-CAT GGC GGG CAC-3' (FRAG 877) (SEQ.
S ID NO: 887) 5'-CAT GGC GGG CA-3' (FRAG 878) (SEQ.
ID NO: 888) 5'-CAT GGC GGG C-3' (FRAG 879) (SEQ. ID
NO: 889) 5'-AT GGC GGG CAC AGG CTG GGC-3' (FRAG
880) (SEQ. LD NO: 890) 5'-AT GGC GGG CAC AGG CTG GG-3' (FRAG
881) (SEQ. ID NO: 891) ZO 5'-AT GGC GGG CAC AGG CTG G-3' (FRAG 882) (SEQ. ID NO: 892) 5'-AT GGC GGG CAC AGG CTG -3' (FRAG 883) (SEQ. ID NO: 893) 5'-AT GGC GGG CAC AGG CT-3' (FRAG 884) (SEQ. ID NO: 894) 5'-AT GGC GGG CAC AGG C-3' (FRAG 885) (SEQ. ID NO: 895) 5'-AT GGC GGG CAC AGG -3' (FRAG 886) (SEQ.
ID NO: 896) ZS 5'-AT GGC GGG CAC AG-3' (FRAG 887) (SEQ.
ID NO: 897) 5'-AT GGC GGG CAC A-3' (FRAG 888) (SEQ.
m NO: 898) 5'-AT GGC GGG CAC-3' (FRAG 889) (SEQ.
ID NO: 899) 5'-AT GGC GGG CA-3' (FRAG 890) (SEQ. ID
NO: 900) 5'-T GGC GGG CAC AGG CTG GGC-3' (FRAG
891) (SEQ. )~ NO: 901) 5'-T GGC GGG CAC AGG CTG GG-3' (FRAG 892) (SEQ. )~ NO: 902) 5'-T GGC GGG CAC AGG CTG G-3' (FRAG 893) (SEQ. ID NO: 903) 5'-T GGC GGG CAC AGG CTG -3' (FRAG 894) (SEQ. ID NO: 904) 5'-T GGC GGG CAC AGG CT-3' (FRAG 895) (SEQ. ID NO: 905) 5'-T GGC GGG CAC AGG C-3' (FRAG 896) (SEQ.
ID NO: 906) 3S 5'-T GGC GGG CAC AGG -3' (P'RAG 897) (SEQ.
ID NO: 907) 5'-T GGC GGG CAC AG-3' (FRAG 898) (SEQ.
ID NO: 908) 5'-T GGC GGG CAC A-3' (FRAG 899) (SEQ.
ID NO: 909) 5'-T GGC GGG CAC-3' (FRAG 900) (SEQ. ID
NO: 910) 5'-GGC GGG CAC AGG CTG GGC-3' (FRAG 901) (SEQ. ID NO: 911) 4O 5'-GGC GGG CAC AGG CTG GG-3' (FRAG 902) (SLQ. ID NO: 912) 5'-GGC GGG CAC AGG CTG G-3' (FRAG 903) (SEQ. ID NO: 913) 5'-GGC GGG CAC AGG CTG -3' (FRAG 904) (SEQ. ID NO: 914) 5'-GGC GGG CAC AGG CT-3' (FRAG 905) (SEQ.
ID NO: 915) 5'-GGC GGG CAC AGG C-3' (FRAG 906) (SEQ.
ID NO: 916) 4S 5'-GGC GGG CAC AGG -3' (FRAG 907) (SEQ.
ID NO: 917) 5'-GGC GGG CAC AG-3' (FRAG 908) (SEQ.
ID NO: 918) 5'-GGC GGG CAC A-3' (FRAG 909) (SEQ. ID
NO: 919) 5'-GC GGG CAC AGG CTG GGC-3' (FRAG 910) (SEQ. ID NO: 920) 5'-GC GGG CAC AGG CTG GG-3' (FRAG 911) (SEQ. ID NO: 921) SO 5'-GC GGG CAC AGG CTG G-3' (FRAG 912) (SEQ. ID NO: 922) 5'-GC GGG CAC AGG CTG -3' (FRAG 913) (SEQ.
TD NO: 923) 5'-GC GGG CAC AGG CT-3' (FRAG 914) (SEQ.
ID NO: 924) 5'-GC GGG CAC AGG C-3' (FRAG 915) (SEQ.
ID NO: 925) 5'-GC GGG CAC AGG -3' (FRAG 916) (SEQ.
ID NO: 926) SS 5'-GC GGG CAC AG-3' (FRAG 917) (SEQ. ID
NO: 927) 5'-C GGG CAC AGG CTG GGC-3' (FRAG 918) (SEQ. ID NO: 928) 5'-GGG CAC AGG CTG GG-3' (FRAG 919) (SEQ.
ID NO: 929) 5'-C GGG CAC AGG CTG G-3' (FRAG 920) (SEQ.
iD NO: 930) 5'-C GGG CAC AGG CTG -3' (FRAG 921) (SEQ.
ID NO: 931) E)O5'-C GGG CAC AGG CT-3' (FRAG 922) (SEQ.
ID NO: 932) 5'-C GGG CAC AGG C-3' (FRAG 923) (SEQ.
ID NO: 933) 5'-C GGG CAC AGG -3' (FRAG 924) (SEQ.
)D NO: 934) 5'-GGG CAC AGG CTG GGC-3' (FRAG 925) (SEQ.
m NO: 935) 5'-GGG CAC AGG CTG GG-3' (FRAG 926) (SEQ.
ID NO: 936) 5'- GGG CAC AGG CTG G-3' (FRAG 927) (SEQ. ID NO: 937) 5'- GGG CAC AGG CTG -3' (FRAG 928) (SEQ. ID NO: 938) 5'- GGG CAC AGG CT-3' (FRAG 929) (SEQ. ID NO: 939) 5'- GGG CAC AGG C-3' (FRAG 930) (SEQ. ID NO: 940) S 5'- GG CAC AGG CTG GGC-3' (FRAG 931) (SEQ. ID NO: 941) 5'- GG CAC AGG CTG GG-3' (FRAG 932) (SEQ. ID NO: 942) 5'- GG CAC AGG CTG G-3' (FRAG 933) (SEQ. ID NO: 943) 5'- GG CAC AGG CTG -3' (FRAG 934) (SEQ. ID NO: 944) 5'- GG CAC AGG CT-3' (FRAG 935) (SEQ.1D NO: 945) I O 5'- G CAC AGG CTG GGC-3' (FRAG 936) (SEQ. ID NO: 946) 5'- G CAC AGG CTG GG-3' (FRAG 937) (SEQ. ID NO: 947) 5'- G CAC AGG CTG G-3' (FRAG 938) (SEQ. ID NO: 948) 5'- G CAC AGG CTG -3' (FRAG 939) (SEQ. ID NO: 949) 5'- CAC AGG CTG GGC-3' (FRAG 940) (SEQ. ID NO: 950) I S 5'- CAC AGG CTG GG-3' (FRAG 941) (SEQ. ID NO: 951) 5'-CAC AGG CTG G-3' (FRAG 942) (SEQ. ID NO: 952) 5'-AC AGG CTG GGC-3' (FRAG 943) (SEQ. ID NO: 953) 5'-AC AGG CTG GG-3' (FRAG 944) (SEQ. ID NO: 954) 5'-C AGG CTG GGC-3' (FRAG 945) (SEQ. ID NO: 955) 2O 5'-TTT TCC TTC CTT TGT CTC TCT TC (FRAG 946) (SEQ. ID NO: 956) 5'-GCT CCC GGC TGC CTG (FRAG 947) (SEQ. ID NO: 957) 5'-CTC GGC CGT GCG GCT CTG TCG CTC CCG GT (FRAG 948) (SEQ. ID NO: 958) 5'-CCG CCG CCC TCC GGG GGG TC (FRAG 949) (SEQ. ID NO: 959) 5'-TGC TGC CGT TGG CTG CCC (FRAG 950) (SEQ. iD NO: 960) 2S 5'-CTT CTG CGG GTC GCC GG (FRAG 951) (SEQ. ID NO: 961) 5'-TGC TGG GCT TGT GGC (FRAG 952) (SEQ. ID NO: 962) 5'-GGC CTC TCT TCT GGG (FRAG 953) (SEQ. ID NO: 963) 5'-CCT GGT CCC TCC GT (FRAG 954) (SEQ. ID NO: 964) 5'-GGT GGC TCC TCT GC (FRAG 955) (SEQ. >D NO: 965) 3O 5'-GCT TGG TCC TGG GGC TGC (FRAG 956) (SEQ. >D NO: 966) 5'-TGC TCT CCT CTC CTT (FRAG 957) (SEQ. iD NO: 967) 5'-TGC TTT TCT TTT CTG GGC CTC TGT GGT CTG TTT TTT TCT G GCC CTG CTG GGG CGC
TCT CC GCC GCC CGC CTG
GCT CCC GGB GCC CBT GBT GGG CBT GCC GTCi GTT CTT GCC CTC CTT TGG CTG CCG TGC
CCG CTC CCC GGC CTC CTG

CTT CTT GCT GGG CCT C TGC
TGC TGC TGG TGC TGT GGC CCC C GTA CAC CGA GGA GCC CAT GAT GGG CAT GCC ACA GAC
GAC AGG C GTB CBC
CGB GGB GCC CBT GBT GGG CBT GCC HCB GBC GHC BGG C-3' (FRAG. NO. 1665) (SEQ. ID
N0:1678) 5'-CTG GGC CTC-3' (FRAG 1666) (SEQ. ID NO: 1679) 5'-GCC GCC CGC CTG-3' (P'RAG 1667) (SEQ. ID NO: 1680) 4O 5'-GC CCG CTC CCC GGC-3' (FRAG 1668) (SEQ. ID NO: 1681) 5'-CBCCGBGGBGCCC-3' (FRAG 1669) (SEQ. ID NO: 1682) 5'-TGC TTT TCT TTT CTG GGC CTC-3' (IrRAG 958) (SEQ. ID NO: 968) 5'-TGT GGT CTG TTT TTT TCT G-3' (FRAG 959) (SEQ. ID NO: 969) 5'-GCC CTG CTG GGG CGC TCT CC-3' (FRAG 960) (SEQ. ID NO: 970) 4S 5'-GCC GCC CGC CTG GCT CCC-3' (FRAG 961) (SEQ. ID NO: 971) 5'-GGB GCC CBT GBT GGG CBT GCC-3' (FRAG 962) (SEQ. 1D NO: 972) 5'-GTG GTT CTT GCC CTC CTT TGG CTG-3' (FRAG 963) (SEQ. ID NO: 973) 5'-CCG TGC CCG CTC CCC GGC-3' (FRAG 964) (SEQ. ID NO: 974) 5'-CTC CTG GCG GGT GGC CGT TG-3' (FRAG 965) (SEQ. ID NO: 975) SO 5'-GGC CCG TGT TCC CCT GGG-3' (FRAG 966) (SEQ. ID NO: 976) 5'-GCC TGG GGC TCC CTT CTC TC-3' (FRAG 967) (SEQ. ID NO: 977) 5'-GCC CTT CTT GCT GGG CCT C-3' (FRAG 968) (SEQ. ID NO: 978) 5'-TGC TGC TGC TGG TGC TGT GGC CCC C-3' (FRAG 969) (SEQ. ID NO: 979) 5'-GTACACCGAGGAGCCCATGATGGGCATGCCACAGACGACAGGC-3' (FRAG 970) (SEQ. ID NO: 980) SS 5'-GTBCBCCGBGGBGCCCBTGBTGGGCBTGCCBCBGBCGBCBGGC-3' (FRAG 971) (SEQ. ID NO:
981) 5'-GGC GCC GTG CCG CGT CTT GGT GGC GGC GG GTT CGC GCC CGC GCG GGG CCC CTC CGG
TCC GTT CGC GCC CGC
GCG GGG CCC CTC CGG TCC CGG GTC GGG GCC CCC CGC GGC C GCC TCG GGG CTG GGG CGC
TGG TGG CCG GG CCG

CGC CTC CGC CTG CCG CTT CTG GCT GGG CCC CGG GCG CCC CCT CCC CTC TTG CTC GGG
TCC CCG TG ACA GCG CGT
CCT GTG TCT CCA GCA GCA TGG CCG GGC CAG CTG GGC CCC BCB GCG CGT CCT GTG TCT
CCB GCB GCB TGG CCG GGC
CBG CTG GGC CCC-3' (FRAG. NO: 1670) (SEQ. n) N0:1683) 5'-GCGCGTCCTG-3' (FRAG. NO: 1671) (SEQ. ID N0:1684) S 5'-GCT GGG CCC CGG-3' (FRAG. NO: 1672) (SEQ. ID N0:16857 5'-CGG GTC GGG GCC CCC C-3' (FRAG. NO: 1673) (SEQ. ID N0:1686) 5'- CGC GCC CGC G-3' (FRAG. NO: 1674) (SEQ. ID N0:1687) 5'-GGC GCC GTG CCG CGT CTT GGT GGC GGC GG-3' (FRAG 972) (SEQ. ID NO: 982) 5'-GTT CGC' GCC CGC GCG GGG CCC CTC CGG TCC-3' (IrRAG 973) (SEQ. ID NO: 983) I O 5'-GTT CGC GCC CGC GCG GGG CCC CTC CGG TCC-3' (IrRAG 974) (SEQ. ID NO:
984) 5'-CGG GTC GGG GCC CCC CGC GGC C-3' (FRAG 975 (SEQ. ID NO: 9837 5'-GCC TCG GGG CTG GGG CGC TGG TGG CCG GG-3' (FRAG 976) (SEQ. ID NO: 986) 5'-CCG CGC CTC CGC CTG CCG CTT CTG-3' (FRAG 977) (SEQ. ID NO: 987) 5'-GCT GGG CCC CGG GCG CCC CCT-3' (IrRAG 978) (SEQ. Q1 NO: 988) 1 S 5'-CCC CTC TTG CTC GGG TCC CCG TG-3' (FRAG 979) (SEQ. ID NO: 989) 5'-ACAGCGCGTCCTGTGTCTCCAGCAGCATGGCCGGGCCAGCTGGGCCCC-3' (FRAG 980) (SEQ. ID NO:
990) 5'-BCBGCGCGTCCTGTGTCTCCBGCBGCBTGGCCGGGCCBGCTGGGCCCC-3' (FRAG 981) (SEQ. 1D NO:
991) Human Adenosine A3 Rece~itor Anti-sense Oligonucleotide Frag 5'-ACA GAG CAG TGC TGT TGT TGG GCA TCT TGC CTT CCC AGG G BCB GBG CB TGC TGT
TGT TGG GCB TCT TGC CTT
ZO CCC BGG GCC CTT TTC TGG TGG GGT GGT GCT GTT GTT GGG CTT TCT TCT GTT CCC BCB
GBG CBG TGC TGT TGT TGG
GCB TCT TGC CTT CCC BGG GCC CTT TTC TGG TGG GGT GGT GCT GTT GTT GGG C TTT CTT
CTG TTC CC (FRAG.
N0:1675) (SEQ. ID N0:1688) 5'-GBG CB TGC-3' (FRAG. N0:1676) (SEQ. ID N0:1689) 5'-TTG TTG GGC-3' (FRAG. N0:16T~ (SEQ. ID N0:1690) 2S 5'-TGC CTT CCC BGG G-3' (FRAG. N0:1678) (SEQ. ID N0:1691) 5'-GTT GTT GGG CAT CTT GCC-3' (FRAG. N0:16?9) (SEQ ID N0:3) 5'-GTG GGC CTA GCT CTC GCC-3' (GRAG. N0:1680) (SEQ ID N0:57 5'-ACA GAG CA TGC TGT TGT TGG GCA TCT TGC CTT CCC AGG G-3' (FRAG 982) (SEQ. ID
NO: 992) 5'-BCB GBG CB TGC TGT TGT TGG GCB TCT TGC CTT CCC BGG G-3' (FRAG 983) (SEQ. ID
NO: 993) 3O 5'-CCC TTT TCT GGT GGG GTG-3' (FRAG 984) (SEQ. ID NO: 994) 5'-GTG CTG TTG TTG GGC-3' (FRAG 9857 (SEQ. ID NO: 9957 5'-TTT CTT CTG TTC CC-3' (FRAG 986) (SEQ. ID NO: 996) 5'-CCC TTT TCT GGT GGG GTG-3' (FRAG 987) (SEQ~ >D NO: 997) 5'-GTG CTG TTG TTG GGC-3' (FRAG 988) (SEQ. ID NO: 998) 3 S 5'-TTT CTT CTG TTC CC-3' (FRAG 989) (SEQ. ID NO: 999) Human IgE Recey or Q A_n_ti-sel>se Oligonucleotide Fra en s 5'-TTT CCC CTG GGT CTT CC CTC CTG CTC TTT TTT C ATT TGC TCT CCT ATT ACT TTC
TGT GTC CAT TTT TTC ATT
AAC CGA GCT GT BTT TGC TCT CCT BTT BCT TTC TGT GTC CBT TTT TTC BTT BBC CGB GCT
GT-3' (FRAG. N0:1681) (SEQ. ID N0:1692) 4O 5'-CCC CTG GG-3' (FRAG. N0:1682) (SEQ. >D N0:1693) 5'-GCTCTCCTBTT-3' (FRAG. N0:1683) (SEQ. >D N0:1694) 5'-CBTTBBCCGBGCTG-3' (FRAG. N0:1684) (SEQ. ID N0:16957 5'-TTT CCC CTG GGT CTT CC-3' (FRAG 990) (SEQ. ID NO: 1000) 5'-CTC CTG CTC TTT TTT C-3' (FRAG 991) (SEQ. ID NO: 1001) 4S ATTTGCTCTCCTATTACTTTCTGTGTCCATTTTTTCATTAACCGAGCTGT (FRAG 992) (SEQ. ID NO:
1002) BTTTGCTCTCCTBTTBCTITCTGTGTCCBT1T>TTCBTTBBCCGBGCTGT (FRAG 993) (SEQ. >D NO:
1003) Human Fc-~ Receptor GD23 Antigen (IgE Receptor) Antisense Oligo_nuci_entid~e Fra .ntc 5'-GCC TGT GTC TGT CCT CCT GCT TCG TTC CTC TCG TTC CTG CTT GGT GCC CTT GCC G
GTC CTG CTC CTC CGG GCT
S O GTG G GTC GTG GCC CTG GCT CCG GCT GGT GGG CTC CCC TGG CCT TCG CTG GCT GGC
GGC GTG C GGG TCT TGC
TCT GGG CCT GGC TGT GGC CGT GGT TGG GGG TCT TC GCT GCC TCC GTT TGG GTG GC TCT
CTG AAT ATT GAC CTT
CCT CCA TGG CGG TCC TGC TTG GAT TCT CCC GA TCT CTG BBT BTT GBC CTT CCT CCB TGG
CGG TCC TGC TTG GBT
TCT CCC GB-3' (FRAG 1685) (SEQ. ID N0:1696 ) 5'-GT CCT CCT-3' (FRAG 1686) (SEQ. ID NO: 1697) SS 5'-TGT GTC TGT CCT CC-3' (FRAG 1687) (SEQ. ID NO: 1698) 5'-GTG GCC CTG GC-3' (IrRAG 1688) (SEQ. >D NO: 1699) 5'-CGT GGT TGG GG-3' (FRAG 1689) (SEQ. ID NO: 1700) 5'-TCT CTG BBT BTT GBC C-3' (FRAG1690) (SEQ. ID N0:1701) 5'-GCC TGT GTC TGT CCT CCT-3' (FRAG 994) (SEQ. ID NO: 1004) 5'-GCT TCG TTC CTC TCG TTC-3' (FRAG 995 (SEQ. ID NO:1005~
5'-CTG CTT GGT GCC CTT GCC G-3' (FRAG 991 (SEQ. ID NO: 100 5'-GTC CTG CTC CTC CGG GCT GTG G-3' (FRAG 997) (SEQ. ID NO: lOD7) 5'-GTC GTG GCC CTG GCT CCG GCT GGT GGG CTC CCC TGG-3' (FRAG 998) (SEQ. ID NO:
1008) S 5'-CCT TCG CTG GCT GGC GGC GTG C-3' (FRAG 999) (SEQ. ID NO: 1009) 5'-GGG TCT TGC TCT GGG CCT GGC TGT-3' (FRAG 1000) (SEQ. ID NO: 1010) 5'-GGC CGT GGT TGG GGG TCT TC-3' (FRAG 1001) (SEQ. ID NO: 1011) 5'-GCT GCC.TCC GTT TGG GTG GC (FRAG 1002) (SEQ. iD NO: 1012) 5'-TCT CTG AAT ATT GAC CTT CCT CCA TGG CGG TCC TGC TTG GAT TCT CCC GA (FRAG
1003) (SEQ. ID NO: 1013) I O 5'-TCT CTG BBT BTT GBC CTT CCT CCB TGG CGG TCC TGC TTG GHT TCT CCC GB
(FRAG 1004) (SEQ. ID NO: 1014) H ~m n gE Receytor a b n i nti ence Oljgon~ICleotide Fra entc 5'- GCC TTT CCT GGT TCT CTT GTT GTT TTT GGG GTT TGG CTT ACA GTA GAG TAG GGG
ATT CCA TGG CAG GAG CCA
TCT TCT TCA TGG ACT CC TTC AAG GAG ACC TTA GGT TTC TGA GGG ACT GCT AAC ACG CCA
TCT GGA GC BCB GTB
GBG TBG GGG BTT CCB TGG CBG GBG CCB TCT TCT TCB TGG BCT CC TTC BBG GBG BCC TTB
GGT TTC TGB GGG BCT
I S GCT BBC BCG CCB TCT GGB GC GTT GTT TTT GGG GTT TGG CTT GCC TTT CCT GGT TCT
CTT BCB GTB GBG TBG GGG
BTT CCB TGG CBG GBG CCB TCT TCT TCB TGG BCT CC TTC BBG GBG BCC TTB GGT TTC TGB
GGG BCT GCT BBC BCG
CCB TCT GGH GC-3' (FRAG. NO: 1691) (SEQ. ID N0:1702) 5'- TGG BCT CC -3' (FRAG. NO: 1692) (SEQ. ID N0:1703) ZO 5'-CCB TCT GGB-3' (FRAG. NO: 1693) (SEQ. ID N0:1704) 5'-CT GCT BBC BCG-3' (FRAG. NO: 1694) (SEQ. ID N0:1705) 5'-GTT TTT GGG GTT TG-3' (FRAG. NO: 1695) (SEQ. ID N0:1706) 5'-GCC TTT CCT GGT TCT CTT GTT GTT TTT GGG GTT TGG CTT-3' (FRAG. NO:1005) (SEQ. ID N0:1015) 5'-ACAGTAGAGTAGGGGATTCCATGGCAGGAGCCATCTTCTTCATGGACTCC-3' (FRAG. NO:1006) (SEQ.
ID N0:1016) ZS 5'-TTC AAG GAG ACC TTA GGT TTC TGA GGG ACT GCT AAC ACG CCA TCT GGA GC-3' (FRAG. N0:1007) (SEQ. ID
N0:1017) 5'-BCB GTB GBG TBG GGG BTT CCB TGG CBG GBG CCB TCT TCT TCB TGG BCT CC TTC BBG
GBG BCC TTB GGT TTC TGB
GGG-3' (FRAG. NO:1008) (SEQ. ID NO:1018) 5'-BCT GCT BBC BCG CCB TCT GGB GC-3' (FRAG. N0:1009) (SEQ. ID N0:1019) 3O 5'-GTT GTT TTT GGG GTT TGG CTT-3' (FRAG. NO:1010) (SEQ. ID N0:1020) 5'-GCC TTT CCT GGT TCT CTT-3' (P'RAG. NO:1011) (SEQ. ID N0:1021) 5'-BCBGTBGBGTBGGGGBTTCCBTGGCBGGBGCCBTCTTCTTCBTGGBCTCC-3' (FRAG. N0:1012) (SEQ.
u) N0:1022) 5'-TTC BBG GBG BCC TTB GGT TTC TGB GGG BCT GCT BBC BCG CCB TCT GGB GC-3' (FRAG. N0:1013) (SEQ. ID
NO > 1023) 35 Humari IlsE Receptor (Fc Epsilon Rl Anti-cencP nlivnnnrlpntirlP FraQmpnte 5'-GCC TGT GTC TGT CCT CCT GCT TCG TTC CTC TCG TTC CTG CTT GGT GCC CTT GCC G
GTC CTG CTC CTC CGG GCT
GTG G GTC CTC GCC CTG GCT CCG GCT GGT GGG CTC CCC TGG CCT TCG CTG GCT GGC GGC
GTG C CCC BGB BCG BGB
CCC GGB CCG BCB GGC CGT GGT TGG GGG TCT TC GCT GCC TCC GTT TGG GTG GC GAT CTC
TGA ATA TTGA CCT TCC
ATG GCG GTC CTG CTT GGA GBT CTC TGB BTB TTGB CCT TCC BTG GCG GTC CTG CTT GGB-3' (FRAG: 1696] (SEQ. ID
4O NO:I707) 5'-TCG TTC CTC TCG-3' (FRAG: 1697) (SEQ. ID N0:1708) 5'-BGB BCG BGB C-3' (FRAG: 169$) (SEQ. ID N0:1709) 5'-TGB BTB TTGB-3' (FRAG: 1699) (SEQ. ID N0:1710) 5'-GCC TGT GTC TGT CCT CCT-3' (FRAG. N0:1014) (SEQ. ID N0:1024) 4S 5'-GCT TCG TTC CTC TCG TTC-3' (FRAG. NO:1015)(SEQ. ID N0:1025~
5'-CTG CTT GGT GCC CTT GCC G-3' (FRAG. N0:1016)(SEQ. ID NO:10?.6) 5'-GTC CTG CTC CTC CGG GCT GTG G-3' (FRAG. N0:1017)(SEQ. ID N0:1027) 5'-GTC CTC GCC CTG GCT CCG GCT GGT GGG CTC CCC TGG-3' (FRAG. NO:1018) (SEQ. ID
N0:1028) 5'-CCT TCG CTG GCT GGC GGC GTG C-3' (FRAG. N0:1019) (SEQ. ID N0:1029) SO 5'-CCC BGB BCG BGB CCC GGB CCG BCH-3' (irRAG. N0:1020) (SEQ. ID N0:1030) 5'-GGC CGT GGT TGG GGG TCT TC-3' (FRAG. N0:1021) (SEQ. ID N0:1031) 5'-GCT GCC TCC GTT TGG GTG GC-3' (FRAG. N0:1022) (SEQ. ID N0:1032) 5'-GBT CTC TGB BTB TTGB CCT TCC BTG GCG GTC CTG CTT GGB-3' (FRAG. N0:1023) (SEQ. >D N0:1033) Human Histidine Decarboxvlase nti- en a OjigonLrleotide Fr2 S S 5'-TCT CCC TTG GGC TCT GGC TCC TTC TC TCT CTC TCC CTC TCT CTC TGT CGC CTC
CGC CCT GGC TGC TGG GGT
GGT GGT GC TTT TGT TCT TCC TTG CTG CC GCC CCG CTG CTT GTC T TC CTC G CTC TGT
CCC TCT CTC TCT GTB CTC
CTC BGG CTC CBT CBT CTC CCT TGG GC-3' (FRAG. N0:1700) (SEQ. ID N0:1711) 5'-GGC TCT GGC (FRAG. N0:1701) (SEQ. ID NO: 1712) 5'-CCC TTG G (FRAG. N0:1702) (SEQ. ID NO: 1713) 5'- TT TGT TCT TCC (FRAG. N0:1703) (SEQ. ID NO: 1714) 5'- TCT CCC TTG GGC TCT GGC TCC TTC TC-3' (FRAG. N0:1024) (SEQ. ID NO: 1034) S 5'- TCT CTC TCC CTC TCT CTC TGT -3' (FRAG. N0:1025) (SEQ. ID N0:1035) 5'- CGC CTC CGC CCT GGC TGC TGG GGT GGT GGT GC-3' (FRAG. N0:1026) (SEQ. ID
N0:103~
5'- TTT TGT TCT TCC TTG CTG CC-3' (FRAG. N0:1027) (SEQ. ID N0:1037) 5'- GCC CCG CTG CTT GTC T TC CTC G-3' (FRAG. N0:1028) (SEQ. iD N0:1038) 5'-CTC TGT CCC TCT CTC TCT GTB CTC CTC BGG CTC CBT CBT CTC CCT TGG GC (FRAG.
N0:1029) (SEQ, m N0:1039) Iiu_m__an Beta Trvrnitace A_nh-sere OLgonucleoi idp g~,~,ntc 5'-C1T GCT CCT GGG GGC CTC CTG GTC CCT CCG GGT GTT CCC GGC GGG CCT GGC CTG GGG
CBG GGG CCG CGT BGG
CGC GGC TCG CCB GGB CGG GCB GCG CCB GCB GCH GCH GBT TCB GCB TCC TGG-3' (FRAG.
N0:1704) (SEQ. ID NO:

5'- GCT CCT GGG GGC CT-3' (FRAG. N0:1705) (SEQ. ID NO: 171 1 S 5'-CGT BGG CGC-3' (FRAG. N0:170~ (SEQ. ID NO: 1717) 5'-T GGC CTG GGG-3' (FRAG. N0:1707) (SEQ. ID NO: 1718) 5'-CTT GCT CCT GGG GGC CTC CTG-3' (FRAG. N0:1030) (SEQ. ID N0:1040) 5'-GTC CCT CCG GGT GTT CCC GGC-3' (FRAG. N0:1031) (SEQ. ID N0:1041) 5'-GGG CCT GGC CTG GGG CBG GGG CCG CGT BGG CGC GGC TCG CCB GGB CGG GCB GCG CCB
GCB GCB GCB GBT TCB
GCB TCC TGG-3' (FRAG. N0:1032) (SEQ. ID N0:1042) Hum~n_ Trvrptase-I A_n_ti-sense Oligonurlenti,~g Frntc 5'-CTT GCT CCT GGG GGC CTC CTG GTC CCT CTG GCT G TT CCC GGC CCT GGB CTG GGG
CBG GGG CCG CGT BGG CGC
GGC TCG CCB GGB CGG GCB GCG CCB GCB GCB GCB GGC TCB GCB TCC TGG CCB CGG BBT
TCC-3' (FRAG. NO: 1708) (SEQ. ID N0:1719) ZS 5'-CT CCT GGG GGC CTC CTG-3' (FRAG. N0:1709) (SEQ. ID N0:1720) 5'-B TCC TGG CCB CGG BBT TCC -3' (FRAG. N0:1710) (SEQ. ID N0:1721) 5'-GTC CCT C-3' (FRAG. N0:1711) (SEQ. ID N0:1722) 5'-CTT GCT CCT GGG GGC CTC CTG-3' (P'RAG. N0:1033) (SEQ. ID N0:1043) 5'-GTC CCT CTG GCT G TT CCC GGC-3' (FRAG. N0:1034) (SEQ. ID N0:1044) 3O 5'-CCT GGB CTG GGG CBG GGG CCG CGT BGG CGC GGC TCG CCB GGB CGG GCB GCG CCB
GCB GCB GCB GGC TCB GCB
TCC TGG CCB CGG BBT TCC -3' (FRAG. N0:1035) (SEQ. ID N0:1045) Hu_m__a_n Prostagla_n_din D Svn ha a Anti-c .n. ,~ ' nnn~lP
5'-GGT GTG CGG GGC CTG GTG CC CCT GGG CCT CGG GTG CTG CCT GT GCG CTG CCT TCT
TCT CCT GG GTC CTC GCC
GGG GCC CTT GCT GCC CTG GCT GT GCC CTG GGG GTC TGG GTT CGG CTG T CCC CBG CBG
GBC CBG TCC CBT CCB
3 S CBG CGT GTG BTG BGT BGC CBT TCT CCT GCB GCC GBG-3' (FRAG. N0:1712) (SEQ.
ID N0:1723) 5'-T TCT CCT GCB GCC GBG -3' (FRAG. N0:1713) (SEQ. ID N0:1724) 5'-CTT GCT GCC CTG GCT GT-3' (FRAG. N0:1714) (SEQ. ID N0:1725) 5'- TCT TCT CCT GG-3' (FRAG. N0:1715) (SEQ. ID N0:172~
5'-GGT GTG CGG GGC CTG GTG CC-3' (FRAG. N0:103~ (SEQ. ID N0:104~
4O 5'-CCT GGG CCT CGG GTG CTG CCT GT-3' (DRAG. N0:1037) (SEQ. ID N0:1047) 5'-GCG CTG CCT TCT TCT CCT GG-3' (FRAG. N0:1038) (SEQ. ID N0:1048) 5'-GTC CTC GCC GGG GCC CTT GCT GCC CTG GCT GT-3' (FRAG. N0:1039) (SEQ. ID
N0:1049) 5'-GCC CTG GGG GTC TGG GTT CGG CTG T-3' (FRAG. N0:1040) (SEQ. ID NO:1050) 5'-CCC CBG CBG GBC CBG TCC CBT CCB CBG CGT GTG BTG BGT BGC CHT TCT CCT GCB GCC
GBG -3' 4S (FRAG. N0:1041) (SEQ. ID NO:1051) H iman ; l~c oox;~genase-2 Anti-sense Oligonucleotide Frag en s 5'-GGG CGC GGG CGB GCB TCG C TTT GGG CTT TTC TCC TTT GGT T TGB GCG CCB GGB CCG
CGC BCH GCB GCB GGG
CGC GGG CGB GCH TCG CBG CGG CGG GCB GGG-3' (P'RAG. NO: 171 (SEQ. ID N0:1727) 5'-G GCB GGG -3' (FRAG. NO: 1717) (SEQ. ID NO: 1728) SO 5'-TCC TTT GGT T-3' (FRAG. N0:1718) (SEQ. ID N0:1729) 5'- GGG CGC GGG CGB GCB TCG C-3' (FRAG. N0:1042) (SEQ. n) N0:1052) 5'- TTT GGG CTT TTC TCC TTT GGT T-3' (FRAG. N0:1043) (SEQ. ID N0:1053) 5'-TGB GCG CCB GGB CCG CGC BCB GCH GCB GGG CGC GGG CGB GCB TCG CBG CGG CGG GCB
GGG -3' (FRAG. N0:1044) (SEQ. ID N0:1054) SS Human Eosinopihil Cationic Protein Ant.-cense Oligonucleotide Frag~nts 5'-CCT CCT TCC TGG TCT GTC TGC CBG BCB BBT TTG GGB BGT GBB CBG TTT TGG BBC CBT
GTT TCC CBG TCT CTG BGC
TGT GGC-3' (FRAG. NO: 1719) (SEQ. ID N0:1730) 5'-TTC TCC TTT GGT T-3' (P'RAG. N0:1720) (SEQ. ID NO: 1731) 5'-T TTC TCC TTT GGT T-3' (FRAG. N0:1721) (S'EQ. ID N0:1732) S 5'- GGG CGC GGG CGB GCB TCG C-3' (FRAG. N0:1042) (SEQ. ID N0:1052) 5'- TTT GGG CTT TTC TCC TTT GGT T-3' (FRAG. N0:1043) (SEQ. ID N0:1053) 5'-TCiB GCG CCB GGB CCG CGC BCB GCB GCB GGG CGC GGG CGB GCB TCG CBG CGG CGG
GCB GGG -3' (FRAG. N0:1044) (SEQ. ID N0:1054) Hu_m_an E.osinopi il Derived Neurotoxin Anti- a s . Oligonucleotide Fragp~ntC
1 O 5'-GCC CTG CTG CTC TTT CTG CT TCC CTT GGT GGG TTG GGC C GCT GGT TGT TCT
GGG GTT C TT(i CTG CCC CTT CT(i TCC C TGT TTG CTG GTG TCT GCG C 3'- CCC CBB CBG BBG BBG CBG BCB BBT TTG GGB
BGT GBB CHG TTT TGG HBC CBT
GTT TCC TGT-3' (FRAG. NO: 1722) (SEQ. ID NO: 1733) 5'-TTC CTG T-3' (DRAG. N0:1723) (SEQ. 1D NO: 1734) 1 S 5'-CTC TTT CTG CT-3' (FRAG. NO: 1724) (SEQ. ID N0:1735) 5'-CCC CTT CTG TCC C-3' (FRAG. N0:1725) (SEQ. n) NO: 173 5'- GCC CTG CTG CTC TTT CTG CT-3' (FRAG. N0:1047) (SEQ. ID N0:1057) 5'- TCC CTT GGT GGG TTG GGC C-3' (FRAG. N0:1048) (SEQ. ID NO:1058) 5'- GCT GGT TGT TCT GGG GTT C-3' (IrRAG. N0:1049) (SEQ. ID N0:1059) ZO 5'- TTG CTG CCC CTT CTG TCC C-3' (FRAG. NO:1050) (SEQ. ID N0:1060) 5'- TGT TTG CTG GTG TCT GCG C -3' (FRAG. N0:1051) (SEQ. ID N0:1061) 5'- CCC CBB CBG BBG BHG CBG BCB BBT TTG GGB BGT GBB CBG TTT TGG BBC CBT GTT
TCC TGT-3' (FRAG. N0:1052) (SEQ. n) N0:1062) Hum~n_ Eosinohhil Peroxidase Anti-selise Oligonucleotide Fragm~ntc 2S 5'-GCG CTC GGC CTG GTC CCG G GGG TCT CCT CTT GTT GTT GC TTG CGC CTC CTG CTG
GGG GT CC CTC TGT TCT TGT
TTT GGG GGC GGG CCC GGC CGT TGT CTT G GTT TGG GGG TTT CCG TTG GGG TTC TCC TGG
CCC GGG CCT TGC CC
GGC CGT GGT CCC GGC TTC GTTCCT GTC TCC GTC TCG GCT CTT CTG GGG CCT TGC GCT GTC
TTT GGT G 5'-GCB CCG
TCC BGT GBT GGT GCG GTB CTT GTC GCT GCB GCG CTC GGC CTG GTC CCG GBG BGC -3' (FRAG. NO: 172 (SEQ. n) NO: 1737) 3O 5'-TC GGC CTG GTC CCG G-3' (FRAG. NO: 1727) (SEQ. ID N0:1738) 5'-TGG GGG TTT CCG TTG-3' (P'RAG. NO: 1728) (SEQ. ID NO: 1739) 5'-TG GTC CCG GBG BGC -3.' (FRAG. NO: 1729) (SEQ. ID NO: 1740) 5'-GCG CTC GGC CTG GTC CCG G-3' (FRAG. N0:1053) (SEQ. ID N0:1063) 5'-GGG TCT CCT CTT GTT GTT GC-3' (FRAG. N0:1054) (SEQ. ID N0:1064) 3 S 5'- TTG CGC CTC CTG CTG GGG GT CC-3' (P'RAG. N0:1055) (5'EQ. ID N0:1065) 5'-CTC TGT TCT TGT TTT GGG GGC-3' (FRAG. N0:105~ (SEQ. ID N0:106~
5'-GGG CCC GGC CGT TGT CTT G-3' (FRAG. N0:1057) (SEQ. ID N0:1067) S'-GTT TGG GGG TTT CCG TTG-3' (FRAG. N0:1058) (S'EQ. ID N0:1068) 5'-GGG TTC TCC TGG CCC GGG CCT TGC CC-3' (FRAG. N0:1059)(SEQ. ID N0:1069) 4O 5'-GGC CGT GGT CCC GGC TTC GTT GC-3' (irRAG. N0:1060) (SEQ. ID N0:1070) 5'-CCT GTC TCC GTC TCG GCT CTT CTG-3' (FRAG. N0:1061) (SEQ. ID N0:1071) 5'-GGG CCT TGC GCT GTC TTT GGT G-3' (FRAG. N0:1062) (SEQ. ID N0:1072) 5'-GCH CCG TCC BGT GBT GGT GCG GTB CTT GTC GCT GCB GCG CTC GGC CTG GTC CCG GBG
BGC -3' (FRAG. N0:1063) (SEQ. ID N0:1073) 4S Human Intercellular Adhesion Molecule-1 (ICAM-1) Anti-sense Otigonucleotide Frag 5'-GCG CGG GCC GGG GGC TGC TGG G GGT TGG CCC GGG GTG CCC C GCC GCT GGG TGC CCT
CGT CCT CTG CGG TC
GTG TCT CCT GGC TCT GGT TCC CC GCT GCG CCC GTT GTC CTC TGG GGT GGC CTT C GCT
CCC GGG TCT GGT TCT TGT
GT TGG GGG TCC CTT TTT GGG CCT GTT GT GGC GTG GCT TGT GTG TTC GGT TTC TGC CCT
GTC CTC CGG CGT CCC
SO CGG BGC CTC CCC GGG GCB GGB TGB CTT TTG BGG GGG BCB CBG BTG TCT GGG CHT TGC
CBG GTC CTG GGB BCB GBG
CCC CGB GCB GGB CCB GGB GTG CGG GCB GCG CGG GCC GGG GGC TGC TGG GBG CCB TBG
CGB GGC TGB G-3' (FRAG. NO: 1730) (SEQ. >D NO: 1741) 5'-GGG GGC TGC TGG G-3' (FRAG. NO: 1731) (SEQ. ID N0:1742) SS 5'-T GTC CTC CGG CGT CCC-3' (FRAG. N0:1732) (SEQ. ID N0:1743) 5'-G CCB TBG CGB GGC TGB G-3' (FRAG. NO: 1733) (SEQ. ID NO: 1744) 5'-CTC TGG GGT GGC CTT C-3' (FRAG. N0:1734) (SEQ. ID N0:1745) 5'-GCG CGG GCC GGG GGC TGC TGG G-3' (FRAG. N0:1064) (SEQ. ID N0:1074) 5'-GGT TGG CCC GGG GTG CCC C-3' (P'RAG. N0:1065) (SEQ. m N0:1075) 5'-GCC GCT GGG TGC CCT CGT CCT CTG CGG TC-3' (DRAG. NO:IOfi6) (SEQ. ID N0:107~
5'-GTG TCT CCT GGC TCT GGT TCC CC-3' (FRAG. N0:1067) (SEQ. ID N0:1077) 5'-GCT GCG CCC GTT GTC CTC TGG GGT GGC CTT C-3' (FRAG. N0:1068) (SEQ. ID
N0:1078) S 5'-GCT CCC GGG TCT GGT TCT TGT GT-3' (FRAG. N0:1069) (SEQ. m NO:I079) 5'-TGG GGG TCC CTT TTT GGG CCT GTT GT-3' (FRAG. N0:1070) (SEQ. ID NO:1080) 5'-GGC GTG GCT TGT GTG TTC GGT TTC-3' (FRAG. N0:1071) (SEQ. ID N0:1081) 5'-TGC CCT.GTC CTC CGG CGT CCC-3' (FRAG. N0:1072) (SEQ. >D N0:1082) 5'- CGG BGC CTC CCC GGG GCB GGB TGB CTT TTG BGG GGG BCB CHG BTG TCT GGG CBT
TGC CBG GTC CTG GGB BCB
I O GBG CCC CGB GCB GGB CCB GGB GTG CGG GCB GCG CGG GCC GGG GGC TGC TGG GBG
CCB TBG CGB GGC TGB G-3' (FRAG. NO:10?3) (SEQ. >D N0:1083) Human Vascular Cell Ad_h ion Molecnlp myrAM_~,) Anti-sense OLgonu~lp~~:~~p 5'-CCT CTT TTC TGT TTT TCC C CTC TGC CTT TGT TTG GGT TCG CTT CCT TTC TGC TTC
TTC C CTG TGT CTC CTG TCT
I S CCG CTT TTT TCT TC GTC TTT GTT GTT TTC TCT TCC TTG CTG BGC BBG BTB TCT BGB
TTC TGG GGT GGT CTC GBT
TTT BBBB GCT TGH GBB GCT GCB BBC BTT HTC CBB BGT BTB TTT GBG GCT CCB BGG BTC
BCG BCC BTC TTC CCB GGC
BTT TTH BGT TGC TGT CGT-3' (FRAG. NO: 1735) (SEQ. ID NO: 174 5'-C TGT CGT-3' (FRAG. N0:173~ (SEQ. ID N0:1747) 5'-TGC TTC TTC C-3' (FRAG. N0:1737) (SEQ. ID N0:1748) ZO HSVCAMIASI: 5'-CCT CTT TTC TGT TTT TCC C-3' (FRAG. N0:1074) (SEQ. ID
N0:1084) HSVCAMIAS2: 5'-CTC TGC CTT TGT TTG GGT TCG-3' (FRAG. N0:1075) (SEQ. ID
NO:1085) HSVCAM1AS3: 5'-CTT CCT TTC TGC TTC TTC C-3' (FRAG. N0:1076) (SEQ. ID N0:1084) HSVCAM1AS4: 5'-CTG TGT CTC CTG TCT CCG CTT TTT TCT TC-3' (FRAG. N0:1077) (SEQ.
ID N0:1087) HSVCAM1AS5: 5'-GTC TTT GTT GTT TTC TCT TCC TTG-3' (FRAG. N0:1078) (SFQ. ID
N0:1088) ZS CTG BGC BBG BTB TCT BGB TTC TGG GGT GGT CTC GBT TTT BBHB GCT TGB GBB GCT
GCB BBC BTT BTC CBB BGT BTB
TTT GBG GCT CCB BGG BTC HCG BCC BTC TTC CCB GGC BTT TTB BGT TGC TGT CGT (FRAG.
N0:1079) (SEQ. ID N0:1~9) Human Endothelial Leukocyte Adhesion Molecule M-11 Anti-sense Oljgonuclentidp Fray 5'-BBG TGB GBG CTG BGB GBB BCT GTG BBG CBB TCB TGB CTT CBB GBG TTC TTT TCB CCC
GTT CTT GGC TTC TTC TGT

TGG GGC CGT CCT TGC CTG
CTG G GTT CTT GGC TTC TTC TGT CCG T TGG CTT CTC GTT GTC CC TGT GGG CTT CTC GTT
GTC CC CCC TTC GGG
GGC TGG TGG GGC CGT CCT TGC CTG CTG G (FRAG. NO: 1738) (SEQ. ID NO: 1749) 5'-CCT TGC CTG CTG G-3' (FRAG. NO: 1739) (SEQ. ID NO: 1750) 5'-GTT GTC CC-3' (FRAG. NO: 1740) (SEQ. ID N0:1751) 3 S 5'-GTT CTT GGC TTC TTC TGT C-3' (FRAG. N0:1080) (SEQ. iD N0:1090) 5'-GGC TGG TGG-3' (FRAG. N0:1083) (SEQ. ID N0:1093) 5'-CGT TGG CTT CTC GTT GTC CC-3' (FRAG. N0:1081) (SEQ. ID N0:1091) 5'-TGT GGG CTT CTC GTT GTC CC-3' (FRAG. N0:1082) (SEQ. ID N0:1092) 5'-CCC TTC GGG GGC TGG TGG-3' (P'RAG. N0:1083) (SEQ. ID N0:1093) 4O 5'-GGC CGT CCT TGC CTG CTG G-3' (FRAG. N0:1084) (SEQ. ID N0:1094) Human P ~electin Frag~n~
5'-TTT TCT CTT TCG CTT TCT TTT CGT CTC CTG TTC CTC CTT TT TTG CTG TTT TTT CTC
CTT CTT CTC TCC TTT
CTT TTC-3' (FRAG. NO: 1741) (SEQ. ID NO: 1752) 5'-TCC TTT CTT TTC-3' (FI3AG. NO: 1742) (SEQ. ID NO: 1753) 4S 5'-CTC CTT TT-3' (FRAG. N0:1743) (SEQ. ID N0:1754) 5'-TTT TCT CTT TCG CTT TCT TTT CGT CTC CTG TTC CTC CTT TT-3' (FRAG. NO:1085) (SEQ. ID N0:1095) 5'-TTG CTG TTT TTT CTC CTT CTT CTC TCC TTT CTT TTC-3' (FRAG. NO:1~ (SEQ. ID
N0:109~
Human Endothelial Mon~rte Activating Factor Anti-ggnse OLgonucleotide Fr a 5'-TTT TCT CTT TCG CTT TCT TTT CGT CTC CTG TTC CTC CTT TT TTG CTG TTT TTT CTC
CTT CTT CTC TCC TTT
SO CTT TTC-3' (FRAG. NO: 1744) (SEQ. ID NO: 1755) 5' -CC TTT CTT TTC (FRAG. NO: 1745) (SEQ. ID NO: 175 5'-CTG TTC CTC CTT TT-3' (FRAG. N0:1746) (SEQ. ID N0:1757) 5'-TTT TCT CTT TCG CTT TCT TTT CGT CTC CTG TTC CTC CTT TT-3' (FRAG. N0:1087) (SEQ. ID N0:1097) 5'-TTG CTG TTT TTT CTC CTT CTT CTC TCC TTT CTT TTC-3' (FRAG. N0:1~8) (SEQ. n) N0:1098) 5'-CTC TGT CTT GTT CTG GTC CTT CGT GGG GCT CTG TGT CGC GTG G GTG CGG CCG TGG
CC GGC GGB CCB GGB GTT
GGB GCB GGB GCB GGB CGG GCB GGC GGC TCB TGT TTG GBT CGG CBG GBG GCB CTC (FRAG.
NO: 1747) (SEQ. ID NO:
1758) S 5'-G GBG GCB CTC-3' (FRAG. NO: 1748) (SEQ. ID NO: 1759) 5'-GT GGG GCT CTG-3' (FRAG. N0:1749) (SEQ. ID N0:1760) HUMIL3AAS1: 5'-CTC TGT CTT GTT CTG GTC CTT CGT GGG GCT CTG-3' (FRAG. N0:1089) (SEQ. ID N0:1099) HUMII3AAS2: 5'-TGT CGC GTG G GTG CGG CCG TGG CC-3' (FRAG. N0:1090) (SEQ. ID
NO:1100) GGC GGB CCB GCiB GTT GGB GCB GGB GCB GGB CGG GCB GGC GGC TCB TGT TTG GBT CGG
CBG GBG GCB CTC (FRAG.
1 O N0:1091) (SEQ. ID NO:1101) Hu_m__a_n_ IL3 Rece~itor A_n_ti-sen_.ce Oligonucleotide Fray 5'-TCT GGG GTG TCC TGG CCT TCG TGG TTC CTC T'fC CTT CGT TTG CCG TCC GCG GGG
GCC CCC GGG CCT GGC TGC
GCT CCT GCC CCG CCT CTT TCC CGG GCT CTT GCG CTG GGG GGT GCT CC CGT GTG TTT GCG
CCC TC CTC CTG GTC
GCG CTT GTC GTT TTG GGG CCG GCT TTG CCC GCC TCC CGG CGC CTG GCC CGG CC TTC CTG
GGC TGC GTG CGC GTT

GTT TGC CGT CCG CGG GGG CCC
CCG GGC CT GGC TGC GCT CCT GCC CCG CCT CTT TCC CGG GCT CTT GCG CTG GGG GGT GCT
CCC GTG TGT TTG CGC
CCT CCT CCT GGT CGC GCT TGT CGT TTT GG GCC CGG CTT TGC CCG CCT CCC GGC GCC TGG
CCC GGC CTT CCT GGG
CTG CGT GCG CGT TCT GTT CTT CTT CCT GGC GCA GGA GAC AGG GCA GGG CGA TCA GGA
GCA GCG TGA GCC AAA
GGA GGA CCA TCG GGA ACG CAG CTC CGG AAC GCA GGA CAG AGG TGC C GC BGG BGB CBG
GGC BGG GCG BTC BGG
ZO BGC BGC GTG BGC CBB BGG BGG BCC BTC GGG BBC GCB GCT CCG GBB CGC BGG BCB GBG
GTG CC-3' (FRAG. NO: 1750) (SEQ. ID NO: 1761) GBG GTG CC-3' (FRAG. NO: 1751) (SEQ. ID NO: 1762) 5'- GCC CCG C-3' (FRAG. N0:1752) (SEQ. ID N0:1763) 5'-TCTGGGGTGTCCTG (FRAG. N0:1092) (SEQ. ID N0:1102) ZS 5'-GCCTTCGTGGTTCC (F'RAG. N0:1093) (SEQ. ID N0:1103) 5'-TCTTCCTTCGTTTGC (FRAG. N0:1094) (SEQ. ID N0:1104) 5'-CGTCCGCGGGGGCCCCCGGGCCT (PTtAG. N0:1095) (SEQ. ID NO:IlOS~
5'-GGC TGC GCT CCT GCC CCG C (FRAG. N0:1096) (SEQ. ID N0:1106) S'-CTCTTTCCCGGGCTCTT (FRAG. N0:1097) (SEQ. ID N0:1107) 3O 5'-GCGCTGGGGGGTGCTCC (FRAG. N0:1098) (SEQ. ID NO:1108) 5'-CGTGTGTTTGCGCCCTCCTCCTGGTCGC (FRAG. N0:1099) (SEQ. ID N0:1109) S'-GCTTGTCGTTTTGG (FRAG. NO:1100) (SEQ. ID NO:1110) 5'-GGCCGGCTTTGCCCGCCTCCC (FRAG. NO:1101) (SEQ. ID NO:1111) 5'-GGCGCCTGGCCCGGCC (FRAG. N0:1102) (SEQ. ID N0:1112) 3 S 5'-TTCCTGGGCTGCGTGCGC (FRAG. N0:1103) (SEQ. ID N0:1113) 5'-GTTCTGTTCTTCTTCCTGGC (FRAG. N0:1104) (SEQ. ID N0:1114) 5'-GCB GGB GBC BGG GCB GGG CGB TCB GGB GCB GCG TGB GCC BBB GGB GGB CCB TCG GGB
BCG CBG CTC CGG BBC
GCB GGB 5'-CBG BGG TGC C (FRAG. NO:I105) (SEQ. n) NO:1115) Human Ih-4 Anti-~er~;,se Oligonucl_potidP Frag~ntc 4O 5'-CTC TGG TTG GCT TCC TTC GCC GGC BCB TGC TBG CBG GBB GBB CBG BGG GGG BBG
CBG TTG GGB GGT GBG BCC
CBT TBB TBG GTG TCG B-3' (FRAG. NO: 1753) (SEQ. ID NO: 1764) 5'-GCC GGC BCB-3' (FRAG. NO: 1754) (SEQ. ID NO: 1765) 5'-T TCC TTC-3' (FRAG. N0:1755) (SEQ. ID N0:17(~
5'-CTC TGG TTG GCT TCC TTC-3' (FRAG. NO:lI06) (SEQ. ID N0:1116) 4S 5'-GCCGGCBCBTGCTBGCBGGBBGBBCBGBGGGGGBBGCBGTTGGGBGGTGBGBCCCBTTBBTBGGTGTCGB-3' (FRAG. N0:1107) (SEQ. ID N0:1117) Human IL.~L Receytor Anti-tense Oligoneclentidp Fragment 5'-TCT GCC CTG TCC GCC GGC TCT TCG GTG GCT CGG CCC CGC TCC TTG TCT TGC CGC GGG
TTG GTT CCT GGG CCT
GGT TCT TGC GGG CGT TTC GGT CTG CTG GCT GGT CTG GGC CCG CGG TGC GGC GGG TGG
CTT GCT GTT CTG CCT GGG
SO CTC TCC CCT CTC CTC CTT TTC TCC CTT CCT CTG TCT TGC CTC CTT CCT CTG GGT CCT
CTT GGC CTG GGC GCT CTT
CCC CTC GGG CGG CTG CGG GCG CTC GTG CTG CCT GGT CCG CTC CCT GGG GGT GCT CCT
TCC CTT TCC CCG CTC GTG
GGG TTT GCG GGG CTG GGC TGC CCT GGG GGG TCT GGG CCT TTT GGG GTC GGC TGG CTG
CTG CTT CGG GCC GCC
TGG GCT TCC CTG TGC CCC TTT CCT CTG CTG GGT CCC CCT CCC GTT CCA AGC TGC ACC
GCA CAG ACC GGC GCT ACA
GGA CAG AGC CAG GCA AGC ACC CAT GGG GAT CCA GGC CCA GCT GTT CCB BGC TGC BCC
GCB CBG BCC GGC GCT
SS BCB GGH CBG BGC CBG GCB BGC BCC CBT GGG GBT CCB GGC CCB GCT G -3' (FRAG.
NO: 1756) (SEQ >D NO: 1767) 5'-TCTGCGC-3' (FRAG. NO: 1757) (SFQ ID NO: 1768) 5'-CCT GCT CCT GGG G (FRAG. N0:1758) (SEQ. >D N0:1769) 5'-TCTGCGCGCCCCTGCTCC (FRAG. N0:1108) (SEQ. ID N0:1118) 5'-CGCCCGGCTTCTCT (FRAG. N0:1109) (SEQ. ID N0:1119) 5'-CGTGTGGGCTTCGG (FRAG. NO:1110) (SEQ. ID N0:1120) 5'-CCCCGCGCCTCCGTTGTTCTC (P'RAG. NO:Illl) (SEQ. !D N0:1121) 5'-TGCTCGCTGGGCTTO (P7tAG. N0:1112) (SEQ. ID N0:1122) S 5'-GGTTTCCTGGGGCCCTGGGTTTC (FRAG. N0:1113) (SEQ. ID N0:1123) 5'-TCTGCCGGGTCGTTTTC (FRAG. N0:1114) (SEQ. iD N0:1124) 5'-GGGTGCTGGCTGCG (FRAG. NO:1115) (SEQ. ID N0:1125) 5'-CTTGGTGCTGGGGCTCC (FRAG. NO:111~ (SEQ. ID N0:112~
5'-GGCGGCTGCGGGCTGGGTTGGG (FRAG. N0:1117) (SEQ. n) N0:1127) I O 5'-C1TGGCTGGTTCCTGGCCTCGGG (FRAG. N0:1118) (SEQ. ID N0:1128) 5'-CCTCCTCCTCCTCCTCGCTCCCTTTITCTTCCTCT (FRAG. N0:1119) (SEQ. ID N0:1129) 5'-TCCCTGCTGCTCTC (P'RAG. NO:I120) (SEQ. ID N0:1130) 5'-TGCCCTCCCTTCCCTCCTGG (FRAG. N0:1121) (SEQ. ID N0:1131) 5'-GGTGCCTCCTTGGGCCCTGC (FRAG. N0:1122) (SEQ. ID N0:1132) I S 5'-GGCTGCTCCTTGCCCC (FRAG. N0:1123) (SEQ. ID N0:1133) 5'-CTCTGGGTCGGGCTGGC (P'RAG. N0:1124) (SEQ. ID N0:1134) 5'-GGGGCGTCTCTGTGC (FRAG. N0:1125) (SEQ. ID N0:1135) 5'-CTGGCCTGGGTGCC (FRAG. N0:1126) (SEQ. ID N0:113~
5'-GCCTCTCCTGGGGGGGTGGCTCCCTGTCC (FRAG. N0:1127) (SEQ. ID N0:1137) ZO 5'-CCTTTTCCCCCGGCTCC (FRAG. N0:1128) (SEQ. ID N0:1138) 5'-GTGGGGGCTTTGGC (FRAG. N0:1129) (SEQ. ID N0:1139) 5'-GGG GGT CTG TGG CCT GCT CCT GGG G (FRAG. N0:1130) (SEQ. m N0:1140) 5'-AGGGGTCTGGGGCCCTC (FRAG. N0:1131) (SEQ. ID N0:1141) 5'-TTTTGGGGGTCTGGCTTG (FRAG. N0:1132) (SEQ. ID NO:I142) 2S 5'-GCCTGGCTGCCTTCC (FRAG. N0:1133) (SEQ. ID N0:1143) 5'-GGGGCCTGCCGTGGGGC (FRAG. N0:1134) (SEQ. ID N0:1144) 5'-TGTCCTCTGTTGCTCCCCTT (FRAG. N0:1135) (SEQ. ID N0:1145) 5'-TGCCTGCTGTCTGG (FRAG. N0:1136) (SEQ. ID N0:1146) 5'-GGTTCCCGCCTTCCCT (FRAG. N0:1137) (SEQ. ID N0:1147) 3O 5'-GTT CCC AGA GCT TGC CAC CTG CAG CAG GAC CAG GCA GCT CAC AGG GAA CAG GAG
CCC AGA GCA AAG CCA CCC
CAT TGG GAG ATG CCA AGG CAC CAG GCT G (FRAG. N0:1138) (SEQ. ID N0:1148) 5'-GTT CCC BGB GCT TGC CBC CTG CBG CBG GBC CBG GCB GCT CBC BGG GBB CBG GBG CCC
BGB GCB BBG CCB CCC
CBT TGG GBG BTG CCB BGG CBC CBG GCT G-3' (FRAG. N0:1139) (SEQ. ID N0:1149) Human IL5* Anti-sense Oligonucleotide Frag~gp~
3 S 5'-TCCCTGTTTC CCCCCTTTCG TTCTGCGTTT GCCTTTGGCG TTTTTTGTTT GTTTTCTCTC
TCCGTCTTTC TTCTCCCCT
GTGGGBBTTT CTGTGGGGBT GGCBTBCBCG TBGGCBGCTC CBBGBGCTBG CBBBCTCBBB TGCBGBBGCB
TCCTCBTGGC
TCTGBBBCGG TGGGAATTTC TGTGGGGBTG GCATACACGT AGGCAGCTCC AAGAGCTAGC AAACTCAAAT
GCAGAAGCATC CTCATGGCTC TGAAACG-3' (P'RAG. NO: 1759) (SEQ. ID NO: 1770) 5'-GCC CCG GG-3' (FRAG. NO: 1760) (SEQ. ID NO: 1771) 4O 5'-G GGT TTC T-3' (FRAG. NO: 1761) (SEQ. ID NO: 1772) 5'-GTG GGG BTG GC-3' (FRAG. NO: 1762) (SEQ. ID N0:1773_) S'-CCB BGB GCT BGC-3' (PltAG. NO: 1763) (SEQ. ID NO: 1774) 5'-TCC CTG TTT CCC CCC TTT-3' (FRAG. N0:1140) (SEQ. ID NO:1150) 5'-CGT TCT GCG TTT GCC TTT GGC-3' (FRAG. N0:1141)(SEQ. ID NO:1151) 4S 5'-GTT TTT TGT TTG TTT TCT-3' (FRAG. N0:1142)(SEQ. n) N0:1152) 5'-CTC TCC GTC TTT CTT CTC C-3' (FRAG. N0:1143) (SEQ. ID N0:1i53) 5'-CCT CCT GCC TGT GTC CCT GCT CCC C-3' (FRAG. N0:1144) (SEQ. ID N0:1154) 5'-GAG GGT TTC TGG CTT CCT CTC T-3' (FRAG. N0:1145) (SEQ. ID N0:1155) S'-TGT CTC TCT GTC CTT TTG TT-3' (FRAG. N0:1146) (SEQ. ID N0:1156) SO 5'-TGT TGT GCG GCC TGG TGC TGC CCT GCC CCG GG-3' (FRAG. N0:1147) (SEQ. ID
N0:1157) 5'-GTG GGA ATT TCT GTG GGG BTG GCA TAC ACG TAG GCA GCT CCA AGA GCT AGC AAA CTC
AAA TGC AGA AGC
ATC CTC ATG GCT CTG AAA CG-3' (FRAG. NO: 1764) (SEQ. ID NO: 1775) 5'-GTG GGB BTT TCT GTG GGG BTG GCB TBC BCG TBG GCB GCT CCB BGB GCT BGC BBB CTC
BBB TGC BGB BGC BTC
CTC BTG GCT CTG BBB CG-3' (FRAG. N0:1148) (SEQ. m NO:1158) SS ~Iuman Ih-5 Receytor An isense Oligonucleotide Fragtnentc 5'-CTCAGTGGCC CCCAAAAGGA TGAGTAATAC ATGCGCCACG ATGATCATAT CCTTTTTACT
ATGAGGCCOT
GTCTGTCGTG TCTTTCCTTT GCTCTTGGTG TGTCTTTGCT GTGCCCTGCC TCTCTGCCCG TGTCTGTCGT
GTCTTTCCTT
TGCTCTTGGT GTGTCTTTGC TGTGCCCTGC CTCTCTGCC CGTGTCTGTC GTGTCTTTCC TTTGCTCTTG
GTGTGTCTTT
GCTGTGCCCT GCCTCTCTGC-3' (FRAG. NO: 1765) (SEQ. ID NO: 1776) 6O 5'-CCG TGT C-3' (FRAG. NO: 1766) (SEQ. ID NO: 1777) 5'-GCCCTGCC-3' (FRAG. NO: 1767) (SEQ. ID NO: 1778) 5'-CCG TGT CTG TCG TGT CT-3' (DRAG. N0:1149) (SEQ. ID N0:1159) 5'-TTCCTTTGCTCTTG-3' (FRAG. N0:1150) (SEQ. ID N0:1160) 5'-GTGTGTCTTTGCTGT-3' (FRAG. N0:1151) (SEQ.1D N0:1161) S 5'-GCCCTGCCTCTCTGC-3' (FRAG. N0:1152) (SEQ. ID N0:1162) 5'-CT CBGTGGCCCC CBBBBGGBTG BGTBBTBCBT GCGCCBCGBT GBTCBTBTCC TTTTTBCTBT GBGG
(FRAG. NO: 1768) (SEQ. ID NO: 1779) human IL-G Rece for Fr:
5'-GGGGGTGGCT TCCTGCCGCG'!'CT~CTGGGCC GTCCCGTCCC TCGGCCCCGC GCCGCGCTCG
GCTCCTCTCC CTCTGGCCCG
I O GCTCGGGGCG GGGCGGGGCG GTGGGCGGGC GGCGCTGCCC TGCGCGCGGC GCTGGCCCCT
GCTGGCCGTC GGCTGCGCGC
TGCTGGCTGC CCTGCTGGCC GCGCCG(iGGC CTGTCCGCCT CTGCGGGCGC TGTCTCCTGG CTTGTCTTCC

CTGGGGTGGG GCTGGGCGGC CGGCCCGGTG CTGGGGCTCC TCGGGGGG(iG GGGCTCTTCC GGGCTGTCTC
CCTCCGGGGC
GGGGGTTTCT GGCCGTGGGG GTCTTGCCTG GCCTCCGGGC TCCTGCTTGT CTTGCCTTCC TTCTCTGGTC
GGTTGTGGCT
CGGGGCTCCG TGGGTCCCTG GCGCCCGTTT GTGTTTTGTC TTTTCCCCTG GCGTCCCTGT GCCCCTCTCC
TCTCCTTCCT
I S CTGCTTCTCG CTCTCCTTTG TGGGGCCCTC CCTGCTGCTC TTGGTTTTGG GCTI'1T1~ITC
TCTTCCTCCT TTTTCGTGCG
TGGGCCTCCG CACGCCTCTT GCCACCTCCT GCGCAGGGCA GCGCCTTGG GGCCAGCGCC GCTCCCGGCG
CGGCCAGCAG
GGCAGCCAGC AGCGCGCAGC CGACGGCCAG CATGCTTCCT CCTCGGCTAC CACTCCATGG TCCCGCAGAG
GCGGACAGGC
GCBCGCCTC TTGCCBCCTC CTGCGCBGGG CBGCGCCTTG GGGCCBGCGC CGCTCCCGGC GCGGCCBGCB
GGGCBGCCBG
CBGCGCGCBG CCGBCGGCCB GCBTGCTTCC TCCTCGGCTB CCBCTCCBTG GTCCCGCBGB GGCGGBCBGG C-3' ZO (FRAG. NO: 1769) (SEQ. ID NO: 1780) 5'-CCCGGCGC-3' (FRAG. N0:1184) (SEQ. ID N0:1194) 5'-GGCCBGCBGG-3' (FRAG. NO:1186) (SEQ. ID N0:1196) 5'-GCBGCCBGCBGCG-3' (FRAG. NO: 1770) (SEQ. ID NO: 1781) 5'-C GCBGCCGBCGGCC -3' (FRAG. NO: 1771) (SEQ. ID NO: 1782) 2S 5'-GGGGGTGGCTTCCTGCC3'- (FRAG. N0:1153) (SEQ. ID N0:1163) 5'-GCGTCTCTGGGCCGTCCC-3' (FRAG. N0:1154) (SEQ. ID N0:1164) 5'-GTCCCTCGGCCCCGCGCCGCGCTCGGCTCCTCTCCC-3' (FRAG. N0:1155) (SEQ. ID N0:1165) 5'-TCTGGCCCGGCTC-3' (FRAG. N0:1156) (SEQ. ID N0:1166) 5'-GGGGCGGGGCGGGGCGGTGGGCGGGC-3' (FRAG. N0:1157) (SEQ. ID N0:1167) 3O 5'-GGCGCTGCCCTGCGC-3' (FRAG. N0:1158) (SEQ. ID N0:1168) 5'-GCGGCGCTGGCCCC-3' (FRAG. N0:1159) (SEQ. ID N0:1169) 5'-TGCTGGCCGTCGGCTGCGCGCTGCTGGCTGCCCT-3' (FRAG. N0:1160) (SEQ. ID N0:1170) 5'-GCTGGCCGCGCCGGG-3' (FRAG. N0:1161) (SEQ. ID N0:1171) 5'-GCCTGTCCGCCTCTGCGGG-3' (FRAG. N0:1162) (SEQ. ID N0:1172) 3S 5'-CGCTGTCTCCTGGC-3' (FRAG. N0:1163) (SEQ. ID N0:1173) 5'-TTGTCTTCCGGCTCT-3' (FRAG. N0:1164) (SEQ. ID N0:1174) 5'-TCTGCTGGGGTGGG-3' (FRAG. N0:1165) (SEQ. ID N0:1175) 5'-GCTGGGCGGCCGGCCCGGT-3' (FRAG. N0:1166) (SEQ. ID N0:1176) 5'-GCTGGGGCTCCTCGGGGGG-3' (FRAG. N0:1167) (SEQ. ID N0:1177) 4O 5'-GGGGGCTCTTCCGG-3' (FRAG. N0:1168) (SEQ. LD N0:1178) 5'-GCTGTCTCCCTCCGGG-3' (FRAG. N0:1169) (SEQ. ID N0:1179) 5'-GCGGGGGTTTCTGGCC-3' (FRAG. N0:1170) (SEQ. ID N0:1180) 5'-GTGGGGGTCTTGCC-3' (FRAG. N0:1171) (SEQ. ID N0:1181) 5'-TGGCCTCCGGGCTCC-3' (FRAG. N0:1172) (SEQ. ID N0:1182) 4S 5'-TGCTTGTCTTGCCTTCCTTC-3' (FRAG. N0:1173) (SEQ. iD N0:1183) 5'-TCTGGTCGGTTGTGGCTCG-3' (FRAG. N0:1174) (SEQ. 1D N0:1184) 5'-GGGCTCCGTGGGTCCCTGGC-3' (FRAG. N0:1175) (SEQ. ID NO:1185) 5'-GCCCGTTTGTGTTTTGTC-3' (IrRAG. N0:1176) (SEQ. ID N0:1186) 5'-TTTTCCCCTGGCGT-3' (FRAG. N0:117~ (SEQ. ID N0:1187) SO 5'-CCCTGTGCCCCTCTCCTCTCCTTCCTCTGC1TCTC-3' (FRAG. N0:1178) (SEQ. ID N0:1188) 5'-GCTCTCCTTTGTGGG-3' (F'RAG. N0:1179) (SEQ. ID N0:1189) S'-GCCCTCCCTGCTGCT-3' (FRAG. N0:1180) (SEQ. ID N0:1190) 5'-CTTGGTTTTGGGCT-3' (FRAG. N0:1181) (SEQ. ID N0:1191) 5'-TITt~ITCTCTTCCTCCTTTTTC-3' (FItAG. N0:1182) (SEQ. ID N0:1192) S S 5'-GTGCGTGGGCCTCC-3' (FRAG. N0:1183) (SEQ. ID N0:1193) GCACGCCTCTTGCCACCTCCTGCGCAGGGCAGCGCCTTGGGGCCAGCGCCGCTCCCGGCGCGGCCAGCAGGGCAGCCAG
CAGCG
CGCAGCCGACGGCCAGCATGCTTCCTCCTCGGCTACCACTCCATGGTCCCGCAGAGGCGGACAGGC-3' 5(FRAG. NO:1185) (SEQ. ID N0:119~
GCBCGCCTCTTGCCBCCTCCTGCGCBGGGCBGCGCCTTGGGGCCBGCGCCGCTCCCGGCGCGGCCBGCBGGGCBGCCBG
CBGCGC
GCBGCCGBCGGCCBGCBTGCTTCCTCCTCGGCTBCCBCTCCBTGGTCCCGCBGBGGCGGBCBGGC-3' SO

(FRAG. N0:1187) (SEQ. ID N0:1197) Human IL-6 Anti-sense Oligonur_1_Pntide Fr~4g~nl.C
5'-GGGGGTGGCT TCCTGCCGCG TCT'CTGGGCC GTCCCGTCCC TCGGCCCCGC GCCGCGCTCG
GCTCCTCTCC CTCTGGCCCG
GCTCGGGGCG GGGCGGGGCG GTGGGCGGGC GGCGCTGCCC TGCGCGCGGC GCTGGCCCCT CCTGGCCGTC
GGCTGCGCGC
S TGCTGGCTGC CCTGCTGGCC GCGCCGGGGC CTGTCCGCCT CTGCGGGCGC TGTCTCCTGG CTTGTCTTCC
GGCTCTTCTG
CTGGGGTGGG GCTGGGCGGC CGGCCCGGTG CTGGGGCTCC TCGGGGGGGG GGGCTCTTCC GGGCTGTCTC
CCTCCGGGGC
GGGGGTTTCT GGCCGTGGGG GTCTTGCCTG GCCTCCGGGC TCCTGCTTGT CTTGCCTTCC TTCTCTGGTC
GGTTGTGGCT
CGGGGCTCCG TGGGTCCCTG GCGCCCGTTT GTGTTTTGTC TTTTCCCCTG GCGTCCCTGT GCCCCTCTCC
TCTCCTTCCT
CTGCTTCTCG CTCTCCTTTG TGGGGCCCTC CCTGCTGCTC TTGGTTTl'GG GCTTTTTI~I'C
TCTTCCTCCT TTTTCGTGCG
I O TGGGCCTCC GCACGCCTCT TGCCACCTCC TGCGCAGGGC AGCGCCTTGG GGCCAGCGCC
GCTCCCGGCG CGGCCAGCAG
GGCAGCCAGC AGCGCGCAGC CGACGGCCAG CATGCTTCCT CCTCGGCTAC CACTCCATGG TCCCGCAGAG
GCGGACAGGC
GCBCGCCTC TTGCCBCCTC CTGCGCBGGG CBGCGCCTTG GGGCCBGCGC CGCTCCCGGC GCGGCCBGCB
GGGCBGCCBG
CBGCGCGCBG CCGBCGGCCB GCBTGCTTCC TCCTCGGCTB CCBCTCCBTG GTCCCGCBGB GGCGGBCBGG C-3' (FRAG.
N0:1772) (SEQ. ID N0:1783) I S 5'-GGGGCBGG-3' (FRAG. N0:1773) (SEQ. 1D N0:1784) 5'-GBBGGCBG CBGGC-3' (FRAG. N0:1774) (SEQ. ID N0:1785) 5'-CCBGGBGCBG CCCC-3' (FRAG. N0:1775) (SEQ. ID N0:178~
5'-BGGG BGBHGGCBBC-3' (FRAG. N0:177~ (SEQ. ID N0:1787) 5'-GCT TCT CTT TCG TTC CCG GTG GGC TCG-3' (FRAG. N0:1188) (SEQ. ID N0:1198) 2O 5'-GTG GCT GTC TGT GTG GGG CGG CT-3' (FRAG. N0:1189) (SEQ. ID N0:1199) 5'-GTG CCT CTT TGC TGC TTT C-3' (FRAG. N0:1190) (SEQ. ID N0:12t10) 5'-GAT TCT TTG CCT TTT TCT GC-3' (FRAG. N0:1191) (SEQ. ID N0:1201) 5'-C'hCCTGGGGG TBCTGGGGCB GGGBBGGCBG CBGGCBBCBC CBGGBGCBGC CCCBGGGBGB
BGGCHBCTGG BCCGBBGGCG
CTTGTGGBGB BGGBGTTCBT BGCTGGGCTC CTGGBGGGGB GBTBGBGC-3' (FRAG. N0:1777) (SEQ.
ID N0:1788) 2S Human Monocyte-derived Neutrophil Chemotactic Factor Anti-Se~;e Ohgonucle~ntide Frag~, .gntt 5'-GGGGTGGBBB GGTTTGGBGT BTGTCTTTBT GCBCTGBCHT CTBBGTTCTT TBGCBCTCCT
TGGCBBBBCT GCBCCTTCBC
BCBGBGCTGC BGBBBTCBGG BBGGCTGCCB BGBGBGCCBC GGCCBGCTTG GBBGTCBTGT TTBCBCBCBG
TGBGBTGGTT
CCTTCCGGGC TTGTGTGCTC TGCTGTCTCT TGGTTCCTTC CGGTGGTTTC TTCCTGGCTC TTGTCCTTTC
TCTTGG CCCT
30 TGGC-3' (FRAG. NO:I778) (SEQ. ID NO: 1789) 5'-GGBGT BTG-3' (FRAG. N0:1779) (SEQ. ID NO: 1790) 5'-GCHCTGBCBT CT-3' (P'RAG. N0:1780) (SEQ. ID N0:1791) 5'-CCG GTG G-3' (FRAG. N0:1781) (SEQ. ID NO: 1792) 5'-GG CCC TTG GC-3' (P'RAG. N0:1782) (SEQ. ID NO: 1793) 3 S 5'-GCT TGT GTG CTC TGC TGT CTC T-3' (FRAG. N0:1192) (SEQ. ID N0:1202) 5'-TGG TTC CTT CCG GTG GTT TCT TCC TGG CTC TTG TCC T-3' (FRAG. N0:1193) (SEQ.
ID N0:1203) 5'-TTC TCT TGG CCC TTG GC-3' (FRAG. N0:1194) (SEQ. ID N0:1204) 5'-GGGGTGGBBB GGTTTGGBGT BTGTCTTTBT GCBCTGBCBT CTBBGTTCTT TBGCBCTCCT
TGGCBBBBCT GCBCCTTCBC
BCBGBGC-3' (FRAG. N0:1783) (SEQ. ID NO: 1794) 5'-GGGCTCCCGC CGCGBGBGGT TBTGGGCTCC CBGGBCCBCC CGCBCCGCGC GGBCGTTTBC
BTTCGCCBCG CBGTGCGCGG
CCGBCBTGBC GBBGTTGGGC GCBBTCBGGG TGGCGCCGCB GBBGTGGCCT CCGCGCBGCT GCBGGGBCBC
CBTGBBGGGC
CBCGCGTGGG GCCGCGCTCG CCGGCCCCCC BCBBTCTCCG BGGCCBGCGC GGTGCCCCCC BGCBGCBBGG
CCGGCBGGBC
BCBGGCGBGG BGBCBCGCGB GTCGGCGGCC GBGGt3TCBTG GTGGGGCTGG GGCTCCGGGG TCTCTGCCCC
TCCGTGCTGG

CGGGTGCiGCT
CCCGCCGCGC GCCGGCCTGC CGGCCCCTCG TGGGTCCTGC TGGCCGGGTC CGGGTCCCGG GGGTGGGGCG
CGBGTCGGCG
GCCGHGGGTC-3' (FRAG. N0:1784) (SEQ. D) NO: 1795) 5'-GG TGG GGC-3' (FRAG. N0:1785) (SEQ. ID NO: 179 5'-G GGG CCG -3' (FRAG. N0:178~ (SEQ. ID N0:1797) SO 5'- GGC CGG GTC CGG G-3' (FRAG. N0:1787) (SEQ. ID NO: 1798) 5'-TGG TGG GGC TGG GGC TCC GGG GTC TCT GCC CCT CCG TGC-3' (FRAG. N0:1195) (SEQ. ID N0:1205) 5'-CGC GTG GGG CCG CGC TCG CCG GCC CCC C-3' (FRAG. N0:119~ {SEQ. ID N0:120~
5'-CCT GCC GGG TGG GCT CCC GCC GCG-3' (FRAG. N0:1197) (SEQ. ID N0:1207) 5'-CGC CGG CCT GCC GGC CCC TC-3' (FRAG. N0:1198) (SEQ. ID N0:1208) SS 5'-GTG GGT CCT GCT GGC CGG GTC CGG GTC CCG GGG GTG GGG-3' (FRAG. N0:1199) (SEQ. ID N0:12119) 5'-CGC GBG TCG GCG GCC GBG GGT C-3' (FRAG. N0:1100) (SEQ. ID N0:1210) 5'-GGGCTCCCGC CGCGBGBGGT TBTGGGCTCC CBGGBCCBCC CGCBCCGCGC GGBCGTTTBC
BTTCGCCBCG CBGTGCGCGG

CCGBCBTGBC GBBGTTGGGC GCHBTCBGGG TGGCGCCGCB GBBGTGGCCT CCGCGCBGCT GCBGGGBCBC
CBTGBBGGGC
CBCGCGTGGG GCCGCGCTCG CCGGCCCCCC BCBBTCTCCG BGGCCBGCGC GGTGCCCCCC BGCBGCBBGG
CCGGCBGGBC
BCBGGCGBGG BGBCBCGCGB GTCGGCGGCC GBGGGTCBTG GTGGGGCTGG GGCTCCGGGG TCTCTGCCCC
TCCGTGC-3' (FRAG. N0:1788) (SEQ. ID NO: 1799) S
5'-CGGGBGTGGG GGTCCTGGBC GGCBCTGHBG GCBTCCBGGG CTCCCTTCCB GTCCTTCTTG
TCCGCTGCCB GCBCCCCTTC
BTTCCBGBGG CTGBTGGCCT CCBCCBGGGB CBTGBTTBGG TBGBBBCTBG GBGGCCGGCC TCCBCCBGGG
BCBTGGTCCT
TCTTGTCCGC TGCCTCTCTG GGGTTTTCGG TCTGGGTGGG CTTTCCTCCT GGGGCTGCTG CTGGGCTCTT

CTGGCCTGGT GCTCTCTCGT GCCCTTTCCC TTGGGTGTCT TGTTT1TGTG GCCTCCBCCB GGGBCBTG-3' (FRAG. N0:1789) I O (SEQ. ID NO: 1800) 5'-CGGGBGTGGG GG-3 ' (FRAG.N0:1790) (SEQ. ID NO: 1801) 5'-GCCBGCBCCCC-3' (FItAG.N0:1791) (SEQ. ID NO: 1802) 5'-C CBC CBG-3' (FRAG.N0:1792) (SEQ. ID NO: 1803) 5'-GGC CTC CHC CBG GGB CBT G-3' (FRAG. N0:1201) (SEQ. ID N0:1211) I S 5'-GTC CTT CTT GTC CGC TGC C -3' (FRAG. N0:1202) (SEQ. ID N0:121Z) 5'-TCT CTG GGG TTT TCG GTC TGG GTG G-3 (FRAG. N0:1203) (SEQ. ID N0:1213) 5'-GCT TTC CTC CTG GGG CTG CTG CTG-3' (FRAG. N0:12114) (SEQ. ID NO:I214) 5'-GGC TCT TCT TTT TGT TTC TGG CCT GGT G-3' (FRAG. NO:1205) (SEQ. ID NO:I21~
5'-CTC TCT CGT GCC CTT TCC-3' (FRAG. N0:120~ (SEQ. ID N0:121~
2O 5'-CTT GGG TGT CTT GTT TTT GT-3' (FRAG. N0:1207) (SEQ. ID N0:1217) 5'-GGC CTC CBC CBG GGB CBT G-3' (FRAG. N0:1208) (SEQ. ID N0:1218) 5'-CGGGBGTGGG GGTCCTGGBC GGCBCTGBBG GCBTCCHGGG CTCCCTTCCB GTCCTTCTTG
TCCGCTGCCB GCBCCCCTTC
HTTCCBGBGG CTGBTGGCCT CCBCCBGGGB CBTGBTTBGG TBGHBBCTBG GBGGCC-3' (FRAG.
N0:1793) (SEQ. ID NO:
1804) 2S Human Cathenisin O Anti-sense Oligon leo »le Frag~nts 5'-CCCTCCBCBT CTGCTCTGBC CTGCTGGBCT CTGGBTCTGB BGBTBCGCCB TGTBGGGGCG
GGBGTGGGGC CTGCTCTCCC
GGCCTCCGBT GBTCTCCCCT GCCTCBGCCC CBGTGGGTBG GBGBBBGGCC BGCBGBBGCH GGBGTGGCTG
CBTCTTTCCT
GGTGGGGCCT GCTCTCCCGG CCTCCGTGTG TTGCTGGGTG TTTTCCCGTC TCTGGTCTGC CTTCGGGGGT
CGT-3' (FRAG.
N0:1794) (SEQ. ID NO: 180 5'-GBBGBTHCGCC-3' (IrRAG. N0:1795~ (SEQ. ID NO: 180 S'-CBGCCCCBG-3' (FRAG. N0:179~ (SEQ. ID NO: 1807) 5'-TCC CGT CTC TGG-3' (FRAG. N0:1797) (SEQ. iD NO: 18~) 5'-GTG GGG CCT GCT CTC CCG GCC TCC G-3' (P'RAG. N0:1209) (SEQ. ID N0:1219) 5'-TGT GTT GCT GG GTG TTT TCC CGT CTC TGG-3' (FRAG. N0:1210) (SEQ. ID N0:1220) 3 S 5'-TCT GCC TTC GGG GGT CGT-3' (FRAG. N0:1211) (SEQ. ID N0:1221) 5'-CCCTCCBCBT CTGCTCTGBC CTGCTGGBCT CTGGBTCTGB BGBTBCGCCB TGTBGGGGCG
GGBGTGGGGC CTGCTCTCCC
GGCCTCCGBT GBTCTCCCCT GCCTCBGCCC CBGTGGGTBG GBGBBBGGCC BGCBGBBGCB GGBGTGGCTG-3' (FRAG.
N0:1798) (SEQ. ID NO: 1809) Humm__a_n_ Defensin 1 Anti-sense Oligonucleotide Fray en s 4O 5'-CCGGGGCTGC BGCBBCCTCB TCBGCTCTTG CCTGGBGTGG CTCBGCCTGG GCCTGCBGGG
CCBCCBGGBG BBTGGCBGCB
BGGBTGGCGB GGGTCCTCBT GGCTGGGGTC BCBGBTCCTC TBGCTBGGCB GGGTGHCCBG BGBGGGC GGG
TCC TCB TGG
CTG GGG GCC TGG GCC TGC BGG GCC GCT CTT GCC TGG BGT GGC TC GCC CBG SGT CTT CCC
TGG T-3' (FRAG.N0:1799) (SEQ. ID NO: 1810) 5'-CCGGGGC-3' (P'RAG.N0:1800) (SEQ. ID NO: 1811) 4S 5'-GG GCCTGCBGGG CC-3' (FRAG.N0:1801) (SEQ. ID NO: 1812) 5'-GGCBGCB BGG-3' (FRAG.N0:1802) (SEQ. ID NO: 1813) 5'-GGG TCC TCB TGG CTG GGG-3' (FRAG. N0:1212) (SEQ. ID N0:1222) 5'-GCC TGG GCC TGC BGG GCC-3' (FRAG. N0:1213) (SEQ. n) N0:1223) 5'-GCT CTT GCC TGG BGT GGC TC-3' (FRAG. N0:1214) (SEQ. ID N0:1224) SO 5'-GCC CBG BGT CTT CCC TGG T-3' (FRAG. N0:1215~ (SEQ. ID N0:122~
5'-CCGGGGCTGC BGCBBCCTCB TCBGCTCZTG CCTGGBGTGG CTCBGCCTGG GCCTGCBGGG
CCBCCBGGBG BBTGGCBGCB
BGGBTGGCGB GGGTCCTCBT GGCTGGGGTC BCBGBTCCTC TBGCTBGGCH GGGTGBCCBG BGBGGGC-3' (FRAG.N0:1803) (SEQ. ID NO: 1814) 5'-CGCTGCBBTC TGCTCCGGGG CTGCBGCBBC CTCBTCBGCTC TTGCCTGGBGTG GCTCBGCCTGG
GCCTGCBGGG
CCBCCBGGBGB BTGGCBGCBBG GBTGGCGBGGG TCCTCBTGGC TGGGGTCBCCT GGBGGBGGGB
GBGCBGGGGG
TCCTCBTGGC TGGGGTCCCT CTCTCCCGTC CT-3' (FRAG. N0:1804) (SEQ. ID N0:1815) 5'-GGCBGCBBGG-3' (FRAG. N0:1805) (SEQ. ID N0:181~
S 5'-GG CTG GGG-3' (FRAG. N0:180~ (SEQ. ID NO:181~
5'-GGGGTCHCC-3' (FRAG. NO:180~ (SEQ. 1D N0:1818) 5'-GGG TCC TCB TGG CTG GGG TC-3' (FRAG. N0:1216) (SEQ. ID N0:1226) 5'-CCT CTC TCC CGT CCT-3' (FRAG. N0:121'n (SEQ. ID N0:11,2n 5'-CGCTGCHBTC TGCTCCGGGG CTGCBGCBBC CTCBTCBGCTC TTGCCTGGBGTG GCTCBGCCTGG
GCCTGCBGGG
I O CCBCCBGGBGB BTGGCBGCBBG GBTGGCGBGGG TCCTCBTGGC TGGGGTCBCCT GGBGGBGGGB
GBGCBGG-3' (FRAG.
N0:18~) (SEQ. ID N0:1819) Human Macrophage Inflammatory Protein-1-alpha/RANTES
Receytor Anti-sense Oligonucleotide Fragments 5'-GTCZ1TGTTT CTGGGCTCGT GCCCCBTCCC GGCTTCTCTC TGGTTCCGTC CTCTGTGGTG
TTTGGCCCTG CTTCCTTTTG
IS CCTGTTGAGG GGGCAGCAGT TGGGCCCCAA AGGCCCTCTC GTTCACCTTC TGGCACGGAGTT
GCATCCCCATA
GTCAAACTCT GTGGTCGTGT CATAGTCCTC TGTGGTGTTT GGAGTTTCCA TCCCGGCTTC TCTCTGGTTC
CAAGGGAGB
GGGGGCBGCB GTTGGGCCCC BBBGGCCCTC TCGTTCBCCT TCTGGCBCGG BGTTGCBTCC CCBTBGTCBB
BCTCTGTGGT
CGTGTCBTBG TCCTCTGTGG TGTTTGGBGT TTCCBTCCCG GCTTCTCTCT GGTTCCBBGG GB-3' (FRAG.
N0:1809) (SEQ.
1D N0:1820) 20 S'-GGGCC CC-3' (FRAG. N0:1810) (SEQ. ID N0:1821) 5'-GGGGGCBGC-3' (FRAG. N0:1811) (SEQ. ID N0:1822) 5'-CCCGGCTTC-3' (P'RAG. N0:1812) (SEQ. ID N0:1823) 5'-GTC TTT GTT TCT GGG CTC GTG CC-3' (DRAG. N0:1218) (SEQ. ID N0:1228) 5'-CCB TCC CGG CTT CTC TCT GGT TCC-3' (FitAG. N0:1219) (SEQ. ID N0:1229) 2.S 5'-GTC CTCTGT GGT GTT TGG-3' (FRAG. N0:1220) (SEQ. iD N0:12311) 5'-CCC TGC TTC CTT TTG CCT GTT-3' (FRAG. N0:1221) (SEQ. m N0:1231) ' GAGGGGGCAGCAGTTGGGCCCCAAAGGCCCTCTCGTTCACCTTCTGGCACGGAGTTGCATCCCCATAGTCAAACTCTGT
GGT
CGT-3' 3O (FRAG. N0:1222) (SEQ. ID N0:1232) 5'-GTCATAGTCCTCTGTGGTGTTTGGAGTTTCCATCCCGGCTTCTCTCTGGTTCCAAGGGA-3 ' (FRAG.
N0:1223) (SEQ. ID
N0:1233) 5'-GBGGGGGCBG CBGTTGGGCC CCBBBGGCCC TCTCGTTCBC CTTCTGGCBC GGBGTTGCBT
CCCCBTBGTC BBBCTCTGTG
GTCGTG-3' (FRAG. N0:1224) (SEQ. ID N0:1134) 3 S 5'-TCHTBGTCCTCTGTGGTGTTTGGBGTTPCCBTCCCGGCTTCTCTCTGGTTCCBBGGGB-3' (FRAG.
N0:1225) (SEQ. iD N0:1235) 5'-GGGCBCGGGG CBGTGGGCGG GCBBTGTBGG CBBBGCBGCB GGGTGTGGTG TCCGBGGBBT
BTGGGGBGGC BGBTGCBGGS
GCGCBGBGGG CBGTBGCBBT GBGGBTGBCB GCGBGGCGTG CCGCGGBGBC CTTCBTGGTB CCTGTGGBGB
GGCTGTCGGB
GGGGGTGTGG TGTCCGCTTG GCGGTTCTTT CGGGTGTTTC TTCTCTGGGT TGGCCTGCTG CTCGTCGTGGT
CGCTCCGCTC
4O CCGGGTTCGT CTCGCTCTGT CGCCCCTTCC TTCCTTGTCG TGTTCCTCCC TTCCTTGCCT CT-3' (FRAG. NO: 1813) (SEQ.
ID NO: 1824) 5'-GGGTTGGC-3' (PItAG. NO: 1814) (SEQ. ID NO: 1825) 5'-CGGGG CBG-3' (FRAG. NO: 1815) (SEQ. ID NO: 1826) 5'-CCCGGGTTCG-3' (FRAG. NO: 1816) (SEQ. ID NO: 182T, 4S 5'-GGGTGTGGTG-3' (FRAG. NO: 181 (SEQ. ID NO: 1828) 5'-GGGCBCGGGG CBGTGGGCGG GCBHTGTBGG CBBBGCBGCB GGGTGTGGTG TCCGBGGBBT
BTGGGGBGGC BGBTGCBGGB
GCGC-3' (FRAG. N0:1226) (SEQ. ID N0:1236) 5'-BGBGGGCBGTBGCBBTGBGGBTGBCBGCGBGGCGTGCCGCGGBGBCCTTCBTGGTBCCTGTGGBGBGGCTGTCGGBGG-3' (FRAG. N0:122~ (SEQ. ID N0:123'n SO 5'-GGGTGTGGTGTCCGC7TGGCGGTTCTTTCGGGTGTTTCTTCTCTGGGTTGGCCTGCTGCTCGTCGTGGTC-3' (FRAG.
N0:1228) (SEQ. ID N0:1238) 5'-GCTCCGCTCCCGGGTTCGTCTCGCTCTGTCGCCCCTTCCTTCCTTGTCGTGTTCCTCCCTTCCTTGCCTCT-3' (FRAG.
N0:1229) S S (SEQ. ID N0:1239) 5'~GGGTGTGGTGTCCG-3' (FRAG. N0:123(1) (SEQ. ID N0:1240) 5'-CTTGGCGGTTCTTTCGGGTG-3' (FRAG. N0:1231) (SEQ. ID N0:1241) 5'-TTTCTTCTCTGGGTTGGC-3' (FRAG. N0:1232) (SEQ. ID N0:1242) 5'-CTGCTGCTCGTCGTGGTC-3' (FRAG. N0:1233) (SEQ. ID N0:1243) S'-GCTCCGCTCCCGGGTTC-3' (FRAG. N0:1234) (SEQ. >D N0:1244) 5'-GTCTCGCTCTGTCGCCC-3' (FRAG. N0:1235) (SEQ. ID N0:11.45) 5'-CTTCCTTCCTTGTC-3' (FRAG. N0:1236) (SEQ. ID N0:1246) S'-GTGTTCCTCCCTTCCTTGCCTCT-3' (FRAG. N0:123~ (SEQ. ID N0:124~
S 5'-GGGCBCGGGG CBGTGGGCGG GCBBTGTBGG CBBBGCBGCB GGGTGTGGTG TCCGBGGBBT
BTGGGGBGGC BGBTGCBGGB
GCGCBGBGGG CBGTBGCBBT GBGGBTGBCB GCGBGGCGTG CCGCGGBGBC CTTCBTGGTB CCTGTGGBGB
GGCTGTCGGB
GG-3' (FRAG. N0:1818) (SEQ. ID N0:1829) Human Muscarinic Acet~rl~holine Receytor HMl* anti-sense Oligonur_1_r_~tide Fragp~~ntc S'-GCTGCCCGGC GGGGTGTGCG CTfGGCGCTC CCGTGCTCGG T1~CTC1~GTCT CCCGGTCCCC
CiTGCCTGGC GTCTCGGGCC
I O TTCGTCCTCI' TCCTCT'I'C'1T CCTTCCGCTC CGTGGGGGCT GCTTGCiTGCiG GGCCTGTGCCT
CGGGGTCCCG GGGCTTCTGG
CCCTTGCCGT TCATGGTGGC TAGGTGGGGC GTTCBTGGTG GCTBGGTGGG GC-3' (FRAG. N0:1819) (SEQ. ID NO: 1830) 5'-GGTGGGGC-3' (FRAG. N0:1820) (SEQ. ID NO: 1831) 5'-GCCCGGCGGGG-3' (FRAG. N0:1821) (SEQ. ID NO: 1832) S'-CGG GGC TTC TGG CCC-3' (FRAG. N0:1822) (SEQ. >D NO: 1833) I S 5'-GTT CBT GGT GGC THG GTG GGG C-3' (FRAG. N0:1238) (SEQ. ID N0:1248) 5'-GCT GCC CGG CGG GGT GTG CGC TTG GC-3' (FRAG. N0:1239) (SEQ. ID NO:1?A9) 5'-GCT CCC GTG CTC GGT TCT CTG TCT CCC GGT-3' (FRAG. N0:1240) (SEQ. ID
N0:1250) 5'-CCC CCT TTG CCT GGC GTC TCG G-3' (FRAG. N0:1241) (SEQ. ID N0:1251) S'-GCC TTC GTC CTC TTC CTC TTC TTC CTT CC-3' (FRAG. N0:1242) (SEQ. ID N0:1252) ZO S'-GCT CCG TGG GGG CTG CTT GGT GGG GGC CTG TGC CTC GGG GTC C-3' (FRAG.
N0:1243) (SEQ. ID N0:1253) S'-CGG GGC TTC TGG CCC TTG CC-3' (FRAG. N0:1244) (SEQ. ID N0:1254) 5'-GTT CAT GGT GGC TAG GTG GGG C-3' (FRAG. NO: 1245) (SEQ. ID N0:1255) Human Muscarinic Acehrlcholi_n_e Receytor HM3* Anti-sense Oligonucleotide Frag~g ~C
5'-GGG GTG GGT BGG CCG TGT CTG GGGGTT GGC CBT GTT GGT TGC CTCT TGG TGG TGC GCC
GGG CGCG TCT TGG CTT
ZS TCT TCT CCT TCG GGC CCT CGG GCC GGT GCT TGT GGGCT CCT CCC GGG CGG CCT CCC
CGG GCG GGG GCT TCT
TGGCG CTG GCG GGG GGG CCT CCTGCT CTG TGG CTG GGC GTT CCT TGG TGT TCT GGG
TGGTGG CGG GCG TGG TGG
CCT CTG TGGGGG CCC GCG GCT GCB GGG GTTG CCT GTC TGC TTC GTCCTT TGC GCT CCC GGG
CCG CCGGG GTG GGT
AGG CCG TGT CTG GGGGTT GGC CAT GTT GGT TGC CGGG CCC GCG GCT GCA GGG G-3' (FRAG. N0:1823) (SEQ. ID
N0:1934) 3O 5'-CCC GGG CGG-3' (FRAG. N0:1824) (SEQ. >D N0:1835) 5'-G GCG GGG GGG CC-3' (FRAG. N0:1825~ (SEQ. ID N0:1836) 5'-CCC GGG CCG CC-3' (FRAG. NO: 1826) (SEQ. ID NO: 183 5'-GG CCG TGT-3' (FRAG. N0:182~ (SEQ. ID N0:1838) 5'-GGG GTG GGT BGG CCG TGT CTG GGG-3' (FRAG. N0:1246) (SEQ. ID N0:1256) 3 S S'-GTT GGC CBT GTT GGT TGC C-3' (FRAG. N0:124n (SEQ. ID N0:1257) 5'-TCT TGG TGG TGC GCC GGG C-3' (FRAG. N0:1248) (SEQ. ID N0:12S8) 5'-GCG TCT TGG CTT TCT TCT CCT TCG GGC CCT CGG GCC GGT GCT TGT GG-3' (FRAG.
N0:1249) (SEQ. ID N0:1259) 5'-GCT CCT CCC GGG CGG CCT CCC CGG GCG GGG GCT TCT TG-3' (FRAG. N0:1250) (SEQ.
ID N0:1260) S'-GCG CTG GCG GGG GGG CCT CCT CC-3' (FRAG. N0:12S1) (SEQ. ID N0:1261) 4O S'-GCT CTG TGG CTG GGC GTT CCT TGG TGT TCT GGG TGG C-3' (FRAG. N0:1252) (SEQ. ID N0:1262) 5'-TGG CGG GCG TGG TGG CCT CTG TGG TGG-3' (FRAG. N0:1253) (SEQ. ID N0:1263) 5'-GGG CCC GCG GCT GCB GGG G-3' (FRAG. N0:1254) (SEQ. ID N0:1264) 5'-TTG CCT GTC TGC TTC GTC-3' (FRAG. N0:1255) (SEQ. ID N0:1265~
5'-CTT TGC GCT CCC GGG CCG CC-3' (FRAG. N0:1256) (SEQ. ID N0:121~
4S 5'-GGG GTG GGT AGG CCG TGT CTG GGG-3' (FRAG. N0:125~ (SEQ. ID N0:1267) 5'-GTT GGC CAT GTT GGT TGC C-3' (FRAG. N0:1258) (SEQ. ID N0:1268) 5'-GGG CCC GCG GCT GCA GGG G-3' (FRAG. N0:1259) (SEQ. ID N0:1269) Human Fibronectin* Antisense Oligonucleotide Fragments 5'-CGG TTT CCT TTG CGG TC TTG GCC CGG GCT CCG GGT G CCC GCC CGC CCG CCG GCC
GCC GC CCC GCC GGG CTG
SO TCC CCG CCC CGC CCC GGC CCG GGG CGC GGG GG CGG CCC TCC CGC CCC TCT GG GCC
GGC GCG GGC GTC GG CCG
CTC GCG CCT GGG GTT CCC TCT CCT CCC CCT GTG C GCC TGC CTC TTG CTC TTCTGC GTC
CGC TGC CTT CTC CC CTC
TCC TCG GCC GTT GCC TGT GC TGT CCG TCC TGT CGC CCT TCC GTG GTG C TGT TGT CTC
TTC TGC CCT C GGT GTG
CTG GTG CTG GTG GTG GTG CCT CTG CCC GTG CTC GCCCTG CCT GGG CTG GCC TCT TCG GGT
GTG GCT TTG GGG CTC
TCT TGG TTG CCC TTT CTT CTC GTG GTG CCT CTC CTC CCT GGC TTG GTC GT TGT CTG GGG
TGG TGC TCC TCT CCC
S S TTT CCC TGC TGG CCG TTT GT
CCT GTT TTC TGT CTT CCT CT TTC CTC CTG TTT CTC CGT TTG GCT TGC TGC TTG CGG GGC
TGT CTC C CTT GCC CCT
GTG GGC TTT CCC TGG TCC GGT CTT CTC CTT GGG GGT C GCC CTT CTT GGT GGG CTGGCT
CGT CTG TCT TTT TCC TTC

C TGG GGG TGG CCG TTG TGG GCG GTG TGG TCC GCC T TGC CTC TGC TGG TCT TTC-3' (FRAG. N0:1828) (SLQ. m NO:
1839) 5'-GGCCCGGGC-3' (FRAG. N0:1829) (SEQ. iD NO: 1840) 5'-GCCGGCGCGGGCG-3' (FRAG. N0:1830) (SEQ. ID N0:1841) S 5'-GCCTGGGCTGGCC-3' (FRAG. N0:1831) (SEQ. ID NO: 1842) 5'-GGGGG TGGCCG-3' (FRAG. N0:1832) (SEQ. ID NO: 1843) 5'-GG GGG TGG CCG TTG TGG GCG G-3' (P'RAG. N0:1833) (SEQ. ID NO: 1844) 5'-CGG TTT CCT TTG CGG TC-3' (FRAG. N0:1260)(SEQ. ID N0:1270) 5'-TTG GCC CGG GCT CCG GGT G-3' (FRAG. N0:1261)(SEQ. ID N0:1271) I O 5'-CCC GCC CGC CCG CCG GCC GCC GC-3' (FRAG. N0:1262)(SEQ. ID N0:1272) 5'-CCC GCC GGG CTG TCC CCG CCC CGC CCC-3' (FRAG. N0:1263)(SEQ. ID N0:1273) 5'-GGC CCG GGG CGC GGG GG-3' (FRAG. N0:1264)(SEQ.1D N0:1214) 5'-CGG CCC TCC CGC CCC TCT GG-3' (FRAG. N0:126~(SEQ, m NO:1275~
5'-GCC GGC GCG GGC GTC GG-3' (FRAG. N0:126~(SEQ. ID N0:127~
I S 5'-CCG CTC GCG CCT GGG GTT CCC TCT CCT CCC CCT GTG C-3' (FRAG.
N0:1267)(SEQ. m N0:1277) 5'-GCC TGC CTC TTG CTC TTC-3' (FRAG. N0:1268)(SEQ. m N0:1278) 5'-TGC GTC CGC TGC CTT CTC CC-3' (FRAG. N0:1269)(SEQ. ID N0:1279) 5'CTC TCC TCG GCC GTT GCC TGT GC-3' (FRAG. N0:1270)(SEQ. m N0:1280) 5'-TGT CCG TCC TGT CGC CCT TCC GTG GTG C-3' (FRAG. N0:1271)(SEQ. iD N0:1281) ZO 5'-TGT TGT CTC TTC TGC CCT C-3' (FRAG. N0:1272)(SEQ. ID N0:1282) 5'-GGT GTG CTG GTG CTG GTG GTG GTG-3' (FRAG. N0:1273)(SEQ. ID N0:1283) 5'-CCT CTG CCC GTG CTC GCC-3' (FRAG. N0:1274)(SEQ. ID N0:1284) 5'-CTG CCT GGG CTG GCC TCT TCG GGT-3' (FRAG. N0:1275)(SEQ. ID N0:1285) 5'-GTG GCT TTG GGG CTC TCT TGG TTG CCC TTT-3' {FRAG. N0:127~(SEQ. ID N0:1286) ZS 5'-CTT CTC GTG GTG CCT CTC CTC CCT GGC TTG GTC GT-3' (FRAG. N0:1277)(SEQ.
ID N0:1287) 5'- TGT CTG GGG TGG TGC TCC TCT CCC-3' (FRAG. N0:1278)(SEQ. ID N0:1288) 5'-TTT CCC TGC TGG CCG TTT GT-3' (FRAG. N0:1279)(SEQ. m N0:1189) 5'-CCT GTT TTC TGT CTT CCT CT-3' (FRAG. N0:1280)(SEQ. ID N0:1290) 5'-TTC CTC CTG TTT CTC CGT-3' (FRAG. N0:1281)(SEQ. ID N0:1291) 3O 5'-TTG GCT TGC TGC TTG CGG GGC TGT CTC C-3' (FRAG. N0:1282)(SEQ. ID
N0:1292) 5'-CTT GCC CCT GTG GGC TTT CCC-3' (FRAG. N0:1283)(SEQ. ID N0:1293) 5'-TGG TCC GGT CTT CTC CTT GGG GGT C-3' (FRAG. N0:1284)(SEQ. iD N0:1294) 5'-GCC CTT CTT GGT GGG CTG-3' (FRAG. N0:1285~(SEQ. ID N0:129~
5'-GCT CGT CTG TCT TTT TCC TTC C-3' (FRAG. N0:1286)(SEQ. ID N0:1296) 3 S 5'-TGG GGG TGG CCG TTG TGG GCG GTG TGG TCC GCC T-3' (FRAG. N0:1287)(SEQ.
ID N0:1297) 5'-TGC CTC TGC TGG TCT TTC-3' (FRAG. N0:1288)(SEQ. ID N0:1298) Huma_n_ InterleLkin_8* Fragments Antisense O~~onecipntide Fray 5'-GBTGTITGTT BCCBBBGCBT CBBGBBTHGC TTTGCTBTCT BBGGBTCBCH TTTBGBCBTB
GGBBBBCGCT GTBGGTCHGBB
BGBTGTGCTT BCCTPCBCBC BGBGCTGCBG BBBTCBGGBBGG CTGCCBBGBGBG CCBCGGCCBGC
TTGGBGTCBT
4O GZT1'BCBCBC BGTGBGGTGC TCCGGTGGCT TTZ'TGCTTGT GTGCTCTGCT GTCTCTG TTC
CTTCCGGTGG TTTCTTCCTG
GCTCTTGTCC TTTCTCTTGG CCCTTGGCCC-3' (P'RAG. N0:1834) (SEQ. ID N0:184~
5'-G CTC CGG-3' (FRAG. N0:1835) (SEQ. ID N0:184~
5'-CBBGBBTBGC-3' (FRAG. N0:183~ (SEQ. ID N0:1847) 5'-CBCBC BGTGBGGTGC-3' (FRAG. N0:1837) (SEQ. ID N0:1848) 4S 5'-HCCBBBGCBT CBHGBHTBGC-3' (FRAG. N0:1838) (SEQ. ID N0:1849) S'-GCCBBGBGHG CCBCGGCCBGC-3' (FRAG. N0:1839) (SEQ. ID N0:1850) 5'-GTG CTC CGG TGG CTT TTT-3' (DRAG. N0:1289)(SEQ. ID N0:1299) S'-GCT TGT GTG CTC TGC TGT CTC TG-3' (FRAG. N0:1290)(SEQ. ID N0:1300) 5'-'TTC CTT CCG GTG GTT TCT TCC TGG CTC TTG TCC T-3' (FRAG. N0:1291)(SEQ. iD
N0:1301) SO 5'-TTC TCT TGG CCC TTG GCC C-3' (FRAG. N0:1292)(SEQ. ID N0:1302) 5'-GBTGITfGTT BCCBBBGCBT CBBGBBTBGC TTTGCTBTCT BBGGBTCBCB TTTBGBCBTH
GGBBBBCGCT GTBGGTCBGBB
BGBTGTGCTT BCCTfCBCBC BGBGCTGCBG BBBTCBGGBBGG CTGCCBBGBGBG CCBCGGCCBGC
TTGGBGTCBT
GTI'I'BCBCBC BGTGBGGTGC TCCGGTGGCT TTITGCTTGT-3' (FRAG. N0:1840) (SEQ. ID
NO:1851) Human IL_8 Rece or Alyha Antisense Oligonucleotide Fragment SS S'-ACAGGGGCTG TAATCTTCATC TGCAGGTGGC ATGCCAGTGA AATITAGATC ATCAAAATCC
CACATCTGTG
GATCTGTAAT ATITGACATG TCCTCTTCAG TTTCAGCAAT GGTCfGATCT AACTGAAGCA CCGGCCAGGB
CBGGGGCTGT
BBTCTTCBTC TGCBGGTGGC BTGCCBGTGB BBTTTBGBTC BTCBBBBTCC CBCHTCTGTG GBTCTGTBBT
H'iTTGBCBTG

TGTTGTTGCG
GCGCTCGGTT GGTGTGGCCC CTGTGGTGCT TCGTITCCCC CTCTTTCTCT TTGTTCGGGG GTTCTTGTGG
CGGGCTGCTT
GO GTCTCG1TCC-3' SS

(PTtAG. N0:1841) (SEQ. ID N0:1852) 5'-CBGGGGC-3' (ItRAG. N0:1842) (SEQ. ID N0:1853) 5'-GCBGGTGGC-3' (FRAG. N0:1843) (SEQ.1D N0:1854) 5'-GCGGCGCTC-3' (P'RAG. N0:1844) (SEQ. ID N0:1855) S 5'-TGGCTCGGTGCTTCTGCCCC (FRAG. N0:1293)(SEQ. ID N0:1303) 5'-TGTTGTTGCGGCGCTC (FRAG. N0:1194)(SEQ. ID N0:1304) 5'-GGTTGGTGTGGCCCCTG (FRAG. N0:1295)(SEQ. ID N0:1305) 5'-TGGTGCTTCGTTTCC (FRAG. N0:1296)(SEQ. ID N0:130I~
5'-CCCTCTtTCTCTTTGTTC (P'RAG. N0:129~(SEQ. ID N0:130'n I O 5'-GGGGGTTCTTGTGGC (FRAG. N0:1298)(SEQ. ID N0:1308) 5'-GGGCTGCTTGTCTCGTTCC (FRAG. N0:1299)(SEQ, iD N0:1309) 5'-ACAGGGGCTG TAATCTTCATC TGCAGGTGGC ATGCCAGTGA AATTTAGATC ATCAAAATCC
CACATCTGTG
GATCTGTAAT ATTTGACATG TCCTCTTCAG TTTCAGCAAT GGTTZ'GATCT AACfGAAGCA CCGGCCAGG-3' (FRAG. N0:1845) (SEQ. ID N0:1856) I S 5'-B CBGGGGCTGT BBTCTTCBTC TGCBGGTGGC BTGCCBGTGB BBTTTHGBTC BTCBBBBTCC
CBCBTCTGTG GBTCTGTBBT
BTTTGBCBTG TCCTCTTCBG TTTCBGCBB TGGTTTGBTC TBBCTGBBGC BCCGGCCBGG-3' (FRAG.
N0:1846) (SEQ. ID
N0:185'n 5'-CTTGBGCBGG BBGCTCTGGG GCBGGGBGCT GGCBGGGCCC BGGGGGGTGG CTTCCTGCBC
TGTCCBGBGT GCBCTGTGCC
ZO BCBGCBGCBG CTGCBGGGCC BTCBGCTTCB TGGGGCTCTG GGTGGCBGGT CCBGCCBTGG
GTCTGGGTGG GGCTGGGCTG
CBGGCTCCGG GCGGTCCBGCCBTGGGTCTG GGGGCTGGG CTGCBGGCTC CGGGCGGGCG GGTGCGGGCT
GCGTGCTGGG
GGCTGCCCCG CAGGCCCTGC GGTCCBGCCB TGGGTCTGGG GGCTGGGCTG CBGGCfCCGG GCGGGCGGGT
GCGGGCTGCG
TGCTGGGGGC TGCCCCGCAG GCCCTGC-3' (FRAG. N0:184'n (SEQ. ID NO: 1858) 5'-GBGCBGG BBG-3' (FRAG. N0:1848) (SEQ. ID NO: 1859) 2S 5'-GCCBCBGCBGCHGC-3' (FRAG. N0:1849) (SEQ. ID NO: 1860) 5'-GGG TGC GGG C-3' (FRAG. N0:1850) (SEQ. ID NO: 1861) 5'-GGT CCB GCC BTG GGT CTG GG-3' (P'RAG. N0:1300)(SEQ. ID N0:1310) 5'-GGC TGG GCT GCB GGC TCC GG-3' (FRAG. N0:1301)(SEQ. ID N0:1311) 5'-GCG GGC GGG TGC GGG CTG CGT GCT GGG-3' (FRAG. N0:1302)(SEQ. ID N0:1312) 3O 5'-GGC TGC CCC GCA GGC CCT GC-3' (DRAG. N0:13113)(SEQ. ID N0:1313) 5'-CTTGBGCBGG BBGCTCTGGG GCBGGGBGCT GGCBGGGCCC BGGGGGGTGG CTTCCTGCBC
TGTCCBGBGT GCBCTGTGCC
BCBGCBGCBG CTGCBGGGCC BTCBGCTTCB TGGGGCTCTG GGTGGCBGGT CCBGCCBTGG GTCTGGGTGG
GGCTGGGCTG
CBGGCTCCGG GC-3' (FRAG. N0:1851) (SEQ. >D NO: 1862) Human Tumor Necrosis Factor a Antisense Olig9inucleotide Fragments 3 S 5'-GCBCCGCCTG GBGCCCTGGG GCCCCCCTGT CTTCTTGGGG BGCGCCTCCT CGGCCBGCTC
CBCGTCCCGG BTCBTGCTTT
CBGTGCTCBT GGTGTCCTTT CCBGGGGBGB GBGGGGCTGG TCCTCTGCTG TCCTTGCTGG TGCTCBTGGT
GTCCTTTCCG
CCCTGGGGCC CCCCTGTCTT CTTGGGGCCT CTTCCCTCTG GGGGCCGTCT CTCTCCCTCT CTTGCGTCTC
TCTCTTTCTC
TCTCTCTCTT CCCCTTTCCC GCTCTTTCTG TCTCGGTGTC TGGTTTTCTC TCTCCGCTGG CTGCCTGTCT
GGCCTGCGCT
CTTGGCCTGT GCTGTTCCTC CTCCGGTTCC TGTCCTCTCT GTCTGTCGCC CCCTCTGGGG TCTCCCTCTG
GGTGGTGGTC

GCTGGCGCTG GTCCTCTGCTGTC
CTTGCTGGTG CTCBTGGTGT CCTTTCCGCC CTGGGGCCCC CCTGTCTTCT TGGGGCCTCT TCCCTCTGGG
GGCCGTCTC
TCTCCCTCTC TTGCGTCTCT CTCTTTCTCT CTCTCTCTTC CCCTTTCCCG CTCTTTCTGT CTCGGTGTCT
GGTTTTCTCT
CTCCGCTGGC TGCCTGTCTG GCCTGCGCTC TTGGCCTGTG CTGTTCCTCC TCCGGTTCCT GTCCTCTCTG
TCTGTCGCCC
CCTCTGGGGT CTCCCTCTGG CGTGGTGGTC TTGTTGCTTG GGCTGGGCTC CGTGTCTCCB GTGCTCBTGG
TGTCCGCTGB
4S GGGBGCGTCT GCTGGC-3' (FRAG. N0:1852) (SEQ. ID N0:1863) 5'-GGGGCCCCCC-3' (FRAG. N0:1853) (SEQ. m N0:1864) 5'- GGG GGC CG TCT-3' (FRAG. N0:1854) (SEQ. ID N0:1865) S'-CCBGGGGBGB GBGGGGCTGG-3' (FRAG. N0:1855) (SEQ. ID N0:1866) ' SO
GCBCCGCCTGGBGCCCTGGGGCCCCCCTGTCTTCTTGGGGBGCGCCTCCTCGGCCBGCTCCBCGTCCCGGBTCBTGCTT
1'CBGTGC
TCBTGGTGTCCTTTCCBGGGGBGBGBGGG-3' (DRAG. N0:1304) (SEQ. ID N0:1314) 5'-GCT GGT CCT CTG CTG TCC TTG CTG GTG CTC BTG GTG TCC TTT CC GCC CTG GGG CCC
CCC TGT CTT CTT GGG G
CCT CTT CCC TCT GGG GGC CG TCT CTC TCC CTC TCT TGC GTC TCT C TCT TTC TCT CTC
TCT CTT CCC C TTT CCC GCT
CTT TCT GTC TC GGT GTC TGG TTT TCT CTC TCC GCT GGC TGC CTG TCT GGC CTG CGC TCT
T GGC CTG TGC TGT TCC
S S TCC TCC GGT TCC TGT CCT CTC TGT CTG TC GCC CCC TCT GGG GTC TCC CTC TGG C
GTG GTG GTC TTG TTG CTT GGG
CTG GGC TCC GTG TCT C CHG TGC TCB TGG TGT CC-3' (FRAG. N0:1305) (SEQ. ID
N0:1315) 5'-GCT GBG GGB GCG TCT GCT GGC GCT GGT CCT CTG CTG TCC TTG CTG GTG CTC BTG GTG
TCC TTT CC GCC CTG GGG
CCC CCC TGT CTT CTT GGG G CCT CTT CCC TCT GGG GGC CG TCT CTC TCC CTC TCT TGC
GTC TCT C TCT TTC TCT CTC
TCT CTT CCC C TTT CCC GCT CTT TCT GTC TC GGT GTC TGG TTT TCT CTC TCC GCT GGC
TGC CTG TCT GGC CTG CGC

TCT T GGC CTG TGC TGT TCC TCC TCC GGT TCC TGT CCT CTC TGT CTG TC GCC CCC TCT
GG(i GTC TCC CTC TGG C
GTG GTG GTC TTG TTG CTT GGCi CTG GGC TCC GTG TCT C CBG TGC TCB TGG TGT CC GCT
GBG GGB GCG TCT GCT GGC-3.
(FRAG. N0:1306) (SEQ. ID N0:1316) S 5'-GCT GGT CCT CTG CTG TCC TTG CTG-3' (FRAG. N0:1655) (SEQ. ID N0:1665) 5'-GTG CTC BTG GTG TCC TTT CC-3' (FRAG. N0:1656)(SEQ. ID N0:16fi6) 5'-GCC CTG GGG CCC CCC TGT CTT CTT GGG G-3' (FRAG. N0:165'n{SEQ. ID N0:1667) 5'-CCT CTT CCC TCT GGG GGC CG-3' (DRAG. N0:1658)(SEQ. ID N0:1668) 5'-TCT CTC TCC CTC TCT TGC GTC TCT C-3' (FRAG. N0:1659)(SEQ. ID N0:1669) 1 O 5'-TCT TTC TCT CTC TCT CTT CCC C-3' (FRAG. N0:1660)(SEQ. ID N0:1670) 5'-TTT CCC GCT CTT TCT GTC TC-3' (FRAG. N0:1661)(SEQ. m N0:1671) 5'-GGT GTC TGG TTT TCT CTC TCC-3' (FRAG. N0:1662)(SEQ. a) NO:I672) 3'-GCT GGC TGC CTG TCT GGC CTG CGC TCT T-3' (FRAG. N0:1663)(SEQ. m N0:1673) , 5'-GGC CTG TGC TGT TCC TCC-3' (FRAG. N0:1664)(S~Q. m N0:1673) I S 5'-TCC GGT TCC TGT CCT CTC TGT CTG TC-3' (FRAG. N0:166~(SEQ. ID N0:1675~
5'-GCC CCC TCT GGG GTC TCC CTC TGG C-3' (FRAG. N0:1666)(SEQ. ID N0:1676) S'-GTG GTG GTC TTG TTG CTT-3' (FRAG. N0:1667)(SEQ. ID N0:1677) 5'-GGG CTG GGC TCC GTG TCT C-3' (FRAG. N0:1668)(SEQ. ID N0:1678) 5'-CBG TGC TCB TGG TGT CC-3' (FRAG. N0:1669)(S'EQ. ID N0:1679) ZO 5'-GCT GBG GGB GCG TCT GCT GGC-3' (FRAG. N0:1670)(SEQ. ID N0:1680) Htirr_san I ~u_k_ot_riene C4 S3rnthase Antise_n_se OligoQucleotide Fragments 5'-CTCGGTBGBC GCGCTCGBBC TCGGGTGGGC CGGTGGTGBG CGGCGGCGBCB CGCGGHBGGC
CCTGCGCGCC
GBGBTCBCCTG CBGGGBGBBG TBGGCTTGCB GCHGGBCTCC CBGGBGGGTG BCBGCBGCCB GTBGBGCTBC
CTCGTCCTTC
BTGGTBCCGT CGGTGTGGTG GCBCGGGCTG TGTGTGBBGG CGBGCTGGGC CCCGTCTGCT GCTCCTCGTG
CCGCCTCGTC

CGTGGCTCCG GCTCTTCTTT
CCCGGCTCCGT CGGCCCGGGG GCCTTGGTCT CCCTCGTCCT TCBTGGTBCC G-3' (FRAG. N0:1856) (SEQ ID NO: 1867) 5'-GCB GCBGGBC-3' (FRAG. N0:1857) (SEQ ID NO: 1868) 5'-CCCGGCTCCG-3' (FRAG. N0:1858) (SEQ ID NO: 1869) 5'-CGGCCCGGGG GCC-3' (FRAG. N0:1859) (SEQ ID NO: 1870) 30 5'-CB CGCGG-3' (FRAG. N0:1860) (SEQ ID NO: 1871) 5'-GCC CCG TCT GCT GCT CCT CGT GCC G-3' (FRAG. N0:1307)(SEQ. iD N0:1317) 5'-CCT CGT CCT TCA TGG TAC CGT CGG TGT GGT GGC-3' (FRAG. N0:1308)(SEQ. ID
N0:1318) 5'-CTC GGG TGG GCC GGT GGT G-3' (FRAG. N0:1309)(SEQ. ID N0:1319) 5'-GGG CGC GCG CGC TCG CGT-3' (FRAG. N0:1310)(SEQ. ID N0:1320) 3 S 5'-GGC TCC GGC TCT TCT TTC CCG GCT CCG TCG GCC CGG GGG CCT TGG TCT C-3' (FRAG. N0:1311) (SRQ. ID N0:1321) 5'-CCT CGT CCT TCB TGG TBC CG-3' (FRAG. N0:1312)(SEQ. ID N0:1322) 5'-CTCGGTBGBC GCGCTCGBBC TCGGGTGGGC CGGTGGTGBG CGGCGGCGBCB CGCGGBBGGC
CCTGCGCGCC
GBGBTCBCCTG CBGGGBGBBG TBGGCTTGCH GCBGGBCTCC CBGGBGGGTG BCBGCBGCCB GTBGBGCTBC
CTCGTCCTTC
BTGGTBCCGT CGGTGTGGTG GCBCGGGCTG TGTGTGBBGG CGBGCTGG-3' (FRAG. N0:1861) (SEQ
ID NO: 1872) 40 Human Endothelia-1 Antisense OligonucleotidP Frag~ntc 5'-BCCGGCGGBG CCGCCBGGGT GGBCTGGGBG TGGGTTfCT'C CCCGCCGTTC TCBCCCBCCG
CGCTGBGCTC BGCGCCTBBG
BCTGCTGTTT CTGGBGCTCC TTGGCBBGCC BCBBBCBGCB GBGBGBBBBT CBTGBGCBBB TBBTCCBTTC
TGBBBBBBBG
GGBTCBBBBB CCTCCCGTTC CCCGTTCGCC TGGCGCGCGC TGCGGGTTCC TCGTGGGTTT CTCCCCGCCG
TTCTCCGGTC
TGTTGCCTTT GTGGGCTTCT TGTCTTTTTG GCTGTTCTTT TCCTGCTTGG CGTCTTTTCC TTTClTI'GTG
CTCGGTTGTG

GTTCCTCGTG GGTI-PPGTCCC
CGCCGTTCTC CGGTCTGTTG CCTTTGTGGG CTTCTTGTCT TTTTGGCTGT TCTTTTCCTG CTTGGCGTCT
TTTCCTTTCT
TTGTGCTCGG TTGTGGGTCC GCTGGTCCTT TGCCCTGTGT GTTTCTGCTG-3' (FRAG. N0:1862) (SEQ. ID N0:1873) 5'-CCGGCGGBG CCGCCBGGGT GGBC-3' (FRAG. N0:1863) (SEQ. iD N0:1874) 5'-CCGCCBGGG-3' (FRAG. N0:1864) (SEQ. ID N0:1875) SO 5'-GGCGCGCGC-3' (FRAG. N0:1865) (SEQ. ID N0:1876) 5'-GTGGGTCCGC-3' (FRAG. N0:1866) (SEQ. ID N0:1877) 5'-CCCGTTCGCCTGGCGC-3' (FRAG. N0:1313)(SEQ. ID N0:1323) 5'-GCGCTGCGGGTTCCTC-3' {FRAG. N0:1314)(SEQ. iD N0:1324) 5'-GTGGGTTTCTCCCCGCCGTTCTC-3' (FRAG. N0:1315)(SEQ. ID N0:132~
SS 5'-CGGTCTGTTGCCTTTGTGGG -3' (FRAG. N0:1316)(SEQ. ID N0:1326) 5'-CTTCTTGTCTTTITGGCT-3' (FRAG. N0:1317)(SEQ. ID N0:1327) 5'-GTTCTTTTCCTGCTTGGC-3' (FRAG. N0:1318)(SEQ. ID N0:1328) 5'-GTCTI'1TCCTTTCTT-3' (FRAG. N0:1319)(SEQ. m N0:1329) 5'-TGTGCTCGGTTGTGGGTC-3' (FRAG. N0:1320)(SEQ. ID N0:1330) 60 5'-CGCTGGTCCTTTGCC-3' (FRAG. N0:1321)(SEQ. iD N0:1331) WO 99/138$6 PCT/US98/19419 5'-CTGTGTGTTTCTGCTG-3' (P'RAG. N0:1322)(SEQ. ID N0:1332) 5'-CCCGTTCGCCTGGCGC-3' (FRAG. N0:13Z3)(SEQ. ID N0:1333) 5'-GCGCTGCGGGTTCCTC-3' (FRAG. N0:1324)(SEQ. ID N0:1334) 5'-GTGGGTTTCTCCCCGCCGTTCTC-3' (FRAG. N0:1325(SEQ. m N0:1335) S 5'-CGGTCTGTTGCCTTTGTGGG-3' (FRAG. N0:132~(SEQ. ID N0:133~
5'-CTTCTTGTCTTTTTGGCT-3' (FRAG. N0:1327)(SEQ. ID N0:1337) 5'-GTTCTTTTCCTGCTTGGC-3' (FRAG. N0:1328)(SEQ. ID N0:1338) 5'-GTCTTTTCCTTTCTT-3' (FRAG. N0:1329)(SEQ. ID N0:1339) 5'-TGTGCTCGGTTGTGGGTC-3' (P'RAG. N0:1330)(SEQ. ID N0:1340) 1 ~ 5'-CGCTGGTCCTTTGCC-3' (FRAG. N0:1331)(SEQ. ID N0:1341) 5'-CTGTGTGTTTCTGCTG-3' (FRAG. N0:1332)(SEQ. iD N0:1342) FndotheLn ReSetltor FT-B ~n_tise~e Oligonllcleotide FraQment~
5'-GCCCTGTCGG GCGGGAAGCC TCTC7CCTCT CCCCAGATC CGCGACAGGC CGCAGGCAAG AACCAGCGCA
ACCAGGGCGC
GTCCGCACAG ACTTGGAGGC GGCTGCATGC TGCTACCTGC TCCAGAAGCG TCCGGTGGCC GCCGCGCC
CTGTCGGGCG
IS GGBBGCCTCT CTCCTCTCCC CBGBTCCGCG BCBGGCCGCB GGCBBGBBCC BGCGCBBCCB
GGGCGCGTCC GCBCBGBCTT
GGBGGCGGCT GCBTGCTGCT BCCTGCTCGGGCG GGBBGCCTCCG GTGGCCGCCG CGCGTCCGGT
GGCCGCCGCG
CCTCTCTCCT CTCCCCGTGG CCCTGTCGGG CGGGTCCTGC CGTCCTGTCT CCTTTTCTTT TGCTGTCTTG
TCTTCCCGTC
TCTGCTTT-3' (FRAG. NO: 1867) (SEQ. ID NO: 1878) Zfl 5'-CGGGCG GGBBGCC-3' (FRAG. NO: 1868) (SEQ. ID NO: 1879) 5'-CGGGCGGG-3' (FRAG. NO: 1869) (SEQ. ID NO: 1880) 5'-CCGCBCBGBC-3' (FRAG. NO: 1870) (SEQ. iD NO: 1881) 5'-GCGTCCGGTGGCCGCCGC-3' (FRAG. N0:1333)(SEQ. ID N0:1343) 5'-GCCTCTCTCCTCTCCCC-3' (FRAG. N0:1334)(SEQ. ID N0:1344) ZS 5'-GTGGCCCTGTCGGGCGGG-3' (FRAG. N0:1335)(SEQ. ID N0:1345) 5'-TCCTGCCGTCCTGTCTCCTTT-3' (FRAG. N0:1336)(SEQ. ID N0:1346) 5'-TCTTTTGCTGTCTTGT-3' (FRAG. N0:1337)(SEQ. ID N0:1347) 5'-CTTCCCGTCTCTGCTTT-3' (FRAG. N0:1338)(SEQ. 1D N0:1348) 5'-GCCCTGTCGG GCGGGAAGCC TCTCTCCTCT CCCCAGATC CGCGACAGGC CGCAGGCAAG AACCAGCGCA
ACCAGGGCGC
3O GTCCGCACAG ACTTGGAGGC GGCTGCATGC TGCTACCTGC TCCAGAAGCG TCCGGTGGCC GCCGC-3' pFRAG. NO: 1871) (SEQ. ID NO: 1882) 5'-GCCCTGTCGG GCGGGBBGCC TCTCTCCTCT CCCCBGBTCC GCGHCBGGCC GCBGGCBBGB BCCBGCGCB
BCCBGGGCGC
GTCCGCBCBG BCTTGGBGGC GGCTGCBTGC TGCTBCCTGC TCCBGBBGCG TCCGGTGGCC GCCGC-3' (FRAG. NO: 1872) (SEQ. ID NO: 1883) 5'-GTC1'GTCCTC CCCGTCTCCT CCCACTGCTT CTCCCGGGGG CTTCCCCGGC TTCGGGTGGC
CGGTGTCCCG GGCTCCGGCG
CGGCGGCGGC TTCGGCTGCG GGTGGGTGGC GCGGGCTGCC GGGTCCGCGC GGCGCCTGGG CCCTTGTGCT
GCTZ'ITfGCT
TGTTCCGTTC TGGCTGCTCC GGTCTGTGTT GTGGTTGTTT TGTTTCTTCT TGGGTGTGGG CCTTGCGGTT
TTGGCTGTGG
GCCCTTTGGG GCCTTGGCTT CTGGCTCGTC TGTCCTCCCC GTCTCCTCCC ACTGCTTCT CCCGGGGGCT
TCCCCGGCTT

GGGCTGCCGG GTCCGCGCGG
CGCCTGGGCC CTTGTGCTGC TTZ'ITGCTTG TTCCGTTCTG GCTGCTCCGG TCTGTGTTGT GGTTGTTTTG
TTTCTTCTTG
GGTGTGGGCC TTGCGGTTTT GGCTGTGGGC CCTTTGGGGC CTTGGCTTCT GGCTCCAT CCACATGATT
GCTTAGATTT
GTGCTCiTATC TCTCAGGATT ATCACTGATT ACACATCCAA CCAGTGCCAG CCAAAAGGAT GCCCTGAGGC
AAAGGGTTTC
CATCTTGAGG CAAATTTGAG GACBTCCBC BTGHTTGCTT BGBTTTGTGC TGTBTCTCTC BGGBTTBTCB
CTGBTTBCBC

3' (FRAG. N0:1873) (SEQ. ID NO: 1884) 5'-GBGGCBBBGGG-3' (FRAG. N0:1874) (SEQ. ID NO: 1885) 5'-GCCBGCCBB BBGGB-3' (FRAG. N0:1875) (SEQ. ID NO: 1886) 5'-CGCCTGGGCC C-3' (FRAG. N0:1876) (SEQ. ID NO: 1887) S~ 5'-GTCTGTCCTCCCCGTCTCCTCCC-3' (FRAG. N0:1339)(SEQ. ID N0:1349) 5'-ACTGCTTCTCCCGGGG-3' (FRAG. N0:1340)(SEQ. ID N0:1350) 5'-GCTTCCCCGGCTTC-3' (FRAG. N0:1341)(SEQ. ID N0:1351) 5'-GGGTGGCCGGTGTCCCGGGCTCCGGCGCGGCGGC-3' (FRAG. N0:1342)(SEQ. ID N0:1352) S'-GGCTTCGGCTGC-3' (FRAG. N0:1343)(SEQ. ID N0:1353) SS 5'-GGGTGGGTGGCGCGG-3' (FRAG. N0:1344)(SEQ. ID N0:1354) 5'-GCTGCCGGGTCCGCGCGGCGCCTGGGCC-3' (FRAG. N0:1345)(SEQ. ID N0:1355) 5'-CTTGTGCTGCTTTT-3' (FRAG. N0:1346(SEQ. 1D N0:1356) 5'-TGCTTGTTCCGTTC-3' (FRAG. N0:1347)(SEQ. ID N0:1357) 5'-TGGCTGCTCCGGTCTGTGTTGTGGTTGTTTTG-3' (FRAG. N0:1348)(SEQ. ID N0:1358) 5'-TTTCTTCTTGGGTGTGGG-3' (FRAG. N0:1349)(SEQ. ID N0:1359) 5'-CCTTGCGGTTTTGG-3' (FRAG. N0:1350)(SEQ. m N0:13611) 5'-CTGTGGGCCCTTTG-3' (FRAG. N0:1351)(SEQ. ID N0:1361) S'-GGGCCTTGGCTTCTGGCTC-3' (FRAG. N0:1352)(SEQ. ID N0:1362) 5'-CATCCACATG ATTGCTTAGA TTTGTGCTGT ATCTCTCAGG ATTATCACTG ATTACACATC
CAACCAGTGC CAGCCAAAAG
GATGCCCTGA GGCAAAGGGT TTCCATCTTG AGGCAAATTT GAGGA-3' (FRAG. N0:1353)(SEQ. ID
N0:1363) S'-CBTCCBCBTG BTTGCTTBGB TTTGTGCTGT BTCTCTCBGG BTTBTCBCTG BTTBCBCBTC
CBBCCBGTGC CBGCCBBBBG
GBTGCCCTGB GGCBBBGGGT TTCCBTCTTG BGGCBBBTTT GHGGB-3' (FRAG. N0:1354)(SEQ. ID
N0:1364) Snb~ ante P A_n_tise~e Oligonecleotide An icense O~oT nLClgQy.de ~a I O 5'-CTGCTGBGGC TTGGGTCTCC GGGCGBTZ'CT CTGCBGBBGB TGC1'CBHBGG GCTCCGGCBG
TTCCTCCTTG BTCTGGTCGCT
GTCGTBCCBG TCGGBCCBGT BHTTCHGBTC BTCBTTGGCT CCTBTITCZT CTGCBBBCBG CTGBGTGGBG
BCBBGHBBBB
BGBCTGCCBB GGCCBCGBGG BTTTTCBTGT TGGBTITTGC GBCGGBCBGT CCCGCGGGGT GCTGAGTTTC
TCTGGTTCCT
CCGBGCGCBC GTGGTCGCTC CGCGTTTCTC TGGTTCCTCC GGTCCCGCGG GGTGCTGTCT GGTCGCTGTC
GTGGCTTGGG
TCTCCGGGCG GTTTCCTTCC TTTTCCGC-3' (FRAG. N0:1877) (SEQ ID NO: 1888) 1 S 5'-C1'CC GGGCGB-3' (FRAG. N0:1878) (SEQ ID NO: 1889) S'-GGCCBCGBGG-3' (FRAG. N0:1879) (SEQ iD NO: 1890) 5'-GGGTCTCCGGGCG-3' (FRAG. N0:1880) (SEQ ID NO: 1891) 5'-GGG TCTCCGGGCG G-3' (FRAG. N0:1881) (SEQ ID N0:1892) 5'-CGTGGTCGCTCCGC-3' (FRAG. N0:1355)(SEQ. ID N0:1365~
S'-GTTTCTCTGGTTCCTCCG-3' (FRAG. N0:13S~(SEQ. ID N0:136~
S'-GTCCCGCGGGGTGCTG-3' (FRAG. N0:135'n(SEQ. ID N0:1367) S'-TCTGGTCGCTGTCGT-3' (FRAG. N0:1358)(SEQ. ID N0:1368) 5'-GGCTTGGGTCTCCGGGCG-3' (FRAG. N0:1359)(SEQ. ID N0:1369) 5'-GTTTCCTTCCTTTTCCGC-3' (FRAG. N0:1360)(SEQ. ID N0:13?0) ZS 5'-CTGCTGBGGC TTGGGTCTCC GGGCGBTTCT CTGCBGBBGB TGCTCBBBGG GCTCCGGCBG
TTCCTCCTTG HTCTGGTCGCT
GTCGTBCCBG TCGGBCCBGT BBTTCBGBTC BTCBTTGGCT CCTBTTTCTT CTGCBBBCBG CTGBGTGGBG
BCBBGBBBBB
BGBCTGCCHB GGCCBCGBGG BTTTTCBTGT TGGBTTTTGC GBCGGHCHGT CCCGCGGGGT GCTGAGTTTC
TCTGGTTCCT
CCGBGCGCB-3' (FRAG. N0:1882) (SEQ ID NO: 1893) SLbsta_n_ce P Recepitor Antisence Oligon>3cleotide Fragments 3O 5'-GGGCTBBGBT GBTCCBCBTC BCTHCCBCGT TGCCCBCCBC BGBGGTCBCC BCBBTGBCCG
TGTBGGCBGC TGCCCHHBGG
BCBBTTTGCC BGGCTGGTTG CBCGHBCTGB TTGGGTTCCG BGGTGTTBGT GGSGBTGTTT GGGGBGBGGT
CTGBGTCCBC
CGGGBGGBCG TTBTCCBTTT CGBBGCTBGG CGGTBBBGCC CTBCTBTCTG TBCBCBBCCC CCCTCTGCHG
CBGBGTCCTG
TCGTGGCGCC TGGGGCTCBG GGTCCGGGC TAAGATGATC CACATCACTA CCACGTTGCC CACCACAGAG
GTCACCACAA
TGACCGTGTA GGCAGCTGCC CAAAGGACAA TTTGCCAGGC TGGTTGCACG AACTGATTGG GTTCCGAGGT
GTTAGTGGAG

AAAGCCCTAC TATCTGTACA
CAACCCCCCT CTGCAGCAGA GTCCTGTCGT GGCGCCTGGG GCTCAGGGTC CGTCCTGTCG TGGCGCCTGG
GGCTCTTCTT
TTGTGGGCTC TTTGGTGGCT GTGGCTGTGG TCTCTGTGGT TGCTGCCCTG GGTCTGGGGG TGTGGCCTTG
GGGCCGTCCT
CTGGCTCCTC CTCGTGGGCC CCC-3' (FRAG. N0:1883) (SEQ. ID N0:1894) S'-GGGBGGBCG-3' (FRAG. N0:1884) (SEQ. ID N0:1895) S'-GGGTC CG-3' (FRAG. N0:1885) (SEQ. ID N0:189~
5-'GGGCC CCC-3' (FRAG. N0:1886) (SEQ. ID N0:189'n S'-GTCCTGTCGTGGCGCCTGGGGCTC-3' (FRAG. N0:1361)(SEQ. iD N0:1371) 5'-TTCTTTTGTGGGCT-3' (FRAG. N0:1362)(SEQ. ID N0:1372) 5'-CTTTGGTGGCTGTGGCTG-3' (FRAG. N0:1363)(SEQ. ID N0:1373) 4S S'-TGGTCTCTGTGGTTG-3' (FRAG. N0:1364)(SEQ. ID N0:1374) 5'-CTGCCCTGGGTCTGG-3' (FRAG. N0:1365)(SEQ. ID N0:1375) S'-GGGTGTGGCCTTGGGGCCGTCCTCTGGCTCCTCCTCGTGGGCCCCC (FRAG. N0:1366)(SEQ. ID
N0:1376) S'-GGGCTAAGAT GATCCACATC ACTACCACGTTGCCCACCAC AGAGGTCACC ACAATGACCG TGTAGGCAGC
TGCCCAAAGG
ACAATTTGCC AGGCTGGTTG CACGAACTGA TTGGGTTCCG AGGTGTTAGT GGAGATGTTT GGGGAGAGGT
CTGAGTCCAC
S O CGGGAGGACG TTATCCATTTC GAAGCTAGGC GGTAAAGCCC TACTATCTGTA CACAACCCCC
CTCTGCAGCA GAGTCCTGTC
GTGGCGCCTG GGGCTCAGGGTCC-3' (FRAG. N0:1367)(SEQ. ID N0:13Tn 5'-GGGCTBBGHT GBTCCBCHTC HCTBCCBCGT TGCCCBCCBC BGBGGTCBCC BCBBTGBCCG
TGTBGGCBGC TGCCCBBBGG
BCHBTTTGCC BGGCTGGTTG CBCGBBCTGB TTGGGTTCCG BGGTGTTBGT GGBGBTGTTT GGGGBGBGGTC
TGBGTCCBCC
GGGBGGBCGT TBTCCBTTTC GBBGCTBGGC GGTHBBGCCC TBCTBTCTGTB CBCBBCCCCC CTCTGCBGCB
GBGTCCTGTC
SS GTGGCGCCTG GGGCTCBGGG TCC-3' (FRAG. N0:1368) (SEQ. ID N0:1378) Ch~rmase Antisense O 'gonllcleotides Antisense OligonLCleotide Fray 5'-GGBGCTGBTB CTGCHGATTT CBGBGGGBBG BBCCCTGBTB CTCBCCHGCT TCBGCTCTGG
BGCBCBBGBG BBBGBGCBGC
BGGGGGHGBG GBHGBBGCBG CBTCTTCCCB GBGBGGCTGC CTGBGCBBBT GCTGGTTTTC CTTTCCBGTC
TTGGGTTTTB

TBBCTCCCBG BBGGCBBGBG BGGGGCBBGG CGTTTTCTTC TCTCGCTGGT TTTCCTTTCC TGGCAGTGGG
TGGGGGTGGG
GGTGGGGTGG CTTCCTTGTT CCTGGGGGTG TCCTCTTGCT CTGGGCTTTT CTCCCCTTTT CCTTCCTGTC
TGTTTTCCTG
GGGCTCTCCT CTGTCTCTGT GTCCTTGCCC TGGCCCTCTT CCCTCTCCTG TCTCCTGTCC CTGTGTTCCG
CCCGTCTTCC
CTCTCCTGAC CTCCTIZTCC TCCGCTGGGT GGGGCCCTGC CTGTTCTCTG CTCCCTGGCT TGGGGTTTCT
TCTGTGTGTC
S TTCTTCCTCT GTTGGCTGGC TTTCTCCTTC TTTTGTCTTC CTGGGTGCCC CTTCTTCCTT TCTTGGGTCC
TTGGTGCTTG
GGCTGGG-3' (DRAG. N0:1887) (SEQ. ID N0:1898) S'-GGBGCBCBBG-3' (FRAG. N0:1888) (SEQ. ID N0:1899) 5'-GHBGCBGC-3' (FRAG. N0:1889) (SEQ. ID N0:1900) 5'-GGGGCBBGG CG-3' (FRAG. N0:1890) (SEQ. ID N0:1901) 1 O 5'-CGTTTTCTTCZ'CTC-3' (P'RAG. N0:1369)(SEQ. ID N0:1379) S'-GCTGGTTTTCCTTTCC-3' (FRAG. N0:1370)(SEQ. ID N0:1380) S'-TGGCAGTGGGTGGGGGTGGGGGTGGGGTGGC-3' (FRAG. N0:1371)(SEQ. )D N0:1381) S'-TTCCTTGTTCCTGGGGGTGTCCT-3' (FRAG. N0:1372)(SEQ. ID N0:136Z) 5'-C7TGCTCTGGGCTTiTCI'-3' (FRAG. N0:1373xSEQ. ID N0:1383) 1 S 5'-CCCCTTITCCTTCC-3' (FRAG. N0:1374)(SEQ. ID N0:1384) S'-TGTCTGTTTTCCTGOGG-3' (FRAG. N0:1375)(SEQ. ID N0:1385) 5'-CTCTCCTCTGTCTCTGTGT-3' (FRAG. N0:1376)(SEQ. ID N0:1386) 5'-CCTTGCCCTGGCCC-3' (FRAG. N0:1377)(SEQ. ID N0:1387) 5'-TCTTCCCTCTCCTGTCTCCTGT-3' (FRAG. N0:1378xSEQ. ID N0:1388) 20 5'-CCCTGTGTTCCGCCC-3' (FRAG. N0:1379)(SEQ. ID N0:1389) S'-GTCTTCCCTCTCCTG-3' (FRAG. N0:1380xSEQ. ID N0:1390) S'-ACCTCCTTTTCCTCCG-3' (FRAG. N0:1381)(SEQ. ID N0:1391) 5'-CTGGGTGGGGCCCTG-3' (FRAG. N0:1382)(SEQ. ID N0:1392) 5'-CCTGTTCTCTGCTCCC-3' (FRAG. N0:1383)(SEQ. ID N0:1393) ZS S'-TGGCTTGGGGT'ITC7TCTG-3' (FRAG. NO:1384)(SEQ. ID N0:1394) 5'-TGTGTCTTCTTCCTCTGTT-3' (FRAG. N0:1385)(SEQ. ID N0:1395) 5'-GGCTGGCTTTCTCCTTC-3' (FRAG. N0:1386)(SEQ. ID N0:1396) 5'-TTTTGTCTTCCTGGG-3' (FRAG. N0:1387)(SEQ. ID N0:1397) 5'-TGCCCCTTCTTCCTTTCTTGGG-3' (FRAG. N0:1388)(SEQ. ID N0:1398) S'-TCCTTGGTGCTTGGGCTGGG-3' (FRAG. N0:1389)(SEQ. ID N0:1399) S'-GGBGCTGBTB CTGCBGATTT CBGBGGGBBG BBCCCTGBTB CTCBCCBGCT TCBGCTCTGG
BGCBCBBGBG HBBGBGCBGC
BGGGGGBGBG GBBGBBGCBG CBTCTTCCCB GBGBGGCTGC CTGBGCBBBT GCTGGTTTTC CTTTCCBGTC
TTGGGTTTTB
TBBCTCCCBG BBGGCBBGHG BGGGGCBBGG-3' (ERAG. N0:1891) (SEQ. ID N0:1902) Fndot_h_elial Nitric Oxide ~3~nth_ase t~ntisense Oligonuceotide Frag~en~C
3 S 5'-GCGTCTTGGG GTGCBGGGCC CBTCCTGCTG CGCCTGGGCG CTGCTG1'GCG TCCGTCTGCT
GGGGGGCCGG GGTGGCTGGG
CCCTGCTTGC CGCACGACCC CGGGCCGACC CGAGGCTCGG GGGGCTGTGT TCTGGCGCTG GTGGGCTTGG
GCCCCTCTGG
GGGCTGGGTT TCCTGCTGCG CCTGGGCGCT GGCGTCTTGG GGTGCGGGGC CGGGGGGCCG GGGGGCCGCT
GTTCGTGGGC
CTGGGGGTGC CTGTGGCTGC CGGTTGCCCC GGTTGGTGGC GCCGTCCTGC TGCCGGTCGT TGGCTGGGTC
CCCCCGCCCG
TTTCCTGGGG TCCGCGTGGG GTGCTCCGGT TCCTCGTGCC GCTGCTGCCT TGTCTTTCCG GCCGTGGCGG
CGTGGTGGTC

TCTTCCTGGT GGCTCTGGGC
CCGGCCGGTC TCGGGCGTCT CGTGTTCGCT CTTGTGCTGT TCCGGCCGCT CCTTCCTCTT CCGCCGCCGC
CGCTCCCCGC
CCGCTCGTCG CCCTGGCCCG GCCTCCTCCT GGCCGCTGTC TCGGGCGGCG GCCTTGGCGC TCCGTTTGGG
GCTGCCTCTG
GCGCTTCCGG CCCTCGGCCT GGGCGCTCTC TTCCGCCTGT GCTGGTGGCC CTCGTGGGCC CCTCCTGGCC
TCCGGTGTCC
TGTGGTCCCC CGGCTGGTGG CCGGGCCGGT TGGGCGGGCG TGGGCGCCGG CGGGTCCTCC GGGCTGCCCT
TCTCCGCCGG

TGCCGGGGTC TCCGGGCTTG
CCCCGCGCTG CTGGGCGTTC TGCGGTCTTG GGGTTGTCTG TGGCCCCGCT CGTGTCGCCC TCCGTCGCCC
GTCGCCGGCC
TCGTCCCCTC CTGGGTGCGC GGCGGGCTGG TCCTGGCGTT TTGCTCCTTC CTGGGCGTCT TGGGGTGCBG
GGCCCBTCCT
GCTGCGCCTG GGCGCTGCTG TGCGTCCGTC TGCTGGGGGG CCGGGGTGGC TGGGCCCTGC TTGCCGCACG
ACCCCGGGCC
GACCCGAGGC TCGGGGGGCT GTGTt'CTGGC GCI'GGI~aGGC TTGGGCCCCT CTGGGGGCTG
GGTTTCCTGC TGCGCCTGGG
SO CGCTGGCGTC TTGGGGTGCG GGGCCGGGGG GCCGGGGGGC CGCTGTTCGT GGGCCTGGGG
GTGCCTGTGG CTGCCGGTTG
CCCCGGTTGG TGGCGCCGTC CTGCTGCCGG TCGTTGGCTG GGTCCCCCCG CCCGTTTCCT GGGGTCCGCG
TGGGGTGCTC
CGGTTCCTCG TGCCGCTGCT GCCTTGTCTT TCCGGCCGTG GCGGCGTGGT GGTCCGCCCC CCCTGGCCTT
CTGCTCGGGG
TCTGGCTGGT TGCCGGTGCC CTTGGCGGCG GTCTTCTTCC TGGTGGCTCT GGGCCCGGCC GGTCTCGGGC
GTCTCGTGTT
CGCTCTTGTG CTGTTCCGGC CGCTCCTTCC TCTTCCGCCG CCGCCGCTCC CCGCCCGCTC GTCGCCCTGG
CCCGGCCTCC
S S TCCTGGCCGC TGTCTCGGGC GGCGGCCTTG GCGCTCCGTT TGGGGCTGCC TCTGGCGCTT
CCGGCCCTCG GCCTGGGCGC
TCTCTTCCGC CTGTGCTGGT GGCCCTCGTG GGCCCCTCCT GGCCTCCGGT GTCCTGTGGT CCCCCGGCTG
GTGGCCGGGC
CGGTTGGGCG GGCGTGGGCG CCGGCGGGTC CTCCGGGCTG CCCTTCTCCG CCGGGGGTCC CGCGCTCCTG
CTGTTCCCTG
GGCTCTTCTG CCTCTCTCCT GGGTGGGTGC TGGGTGCCGG GGTCTCCGGG CTTGCCCCGC GCTGCTGGGC
GTTCTGCGGT
CTTGGGGTTG TCTGTGCiCCC CGCTCGTGTC GCCCTCCGTC GCCCGTCGCC GGCCTCGTCC CCTCCTGGGT
GCGCGGCGGG
6O CTGGTCCTGG CGTTTTGCTC CTTCCTGG-3' (DRAG. N0:1892) (SEQ. ID NO: 1903) S'-GCGGGGCCG-3' (FRAG. N0:1893) (SEQ. m NO: 1904) S'-CGGGGGGC-3' (FRAG. N0:1894) (SEQ. ID NO: 1905) 5'-GCGCGGCGGGC-3' (FRAG. N0:1895~ (SEQ. ID NO:1906) 5"-CTGTGCGTCCGTCTGCTGG (FRAG. N0:1390)(SEQ. ID N0:1400) GGGGCCGGGGTGGCTGGGCCCTGCTTGCCGC (FRAG. N0:1391xSEQ. ID N0:1401) ACGACCCCGGGCCGACCCGAG (FRAG. N0:1392xSEQ. >D N0:1402) S GCTCGGGGGGCTGTGTTCTGGCGCTGGTGGG (FRAG. N0:1393XSEQ. ID N0:1403) CTTGGGCCCCTCTGGGGGCTGGGTT (FRAG. N0:1394xSEQ. ID N0:1404) TCCTGCTGCGCCTGGGCGCTG (FRAG. N0:1395)(SEQ. ID N0:1405) GCGTCTTGGGGTGC (FRAG. N0:1396)(SEQ. ID N0:1406) GGGGCCGGGGGGCCGGGGG (FRAG. N0:1397)(SEQ. ID N0:1407) 1 O GCCGCTGTTCGTGGGCCTGGG (FRAG. N0:1398)(SEQ. ID N0:1408) GGTGCCTGTGGCTGCC (FRAG. N0:1399)(SEQ. ID N0:1409) GGTTGCCCCGGTTGGTGGC (FRAG. N0:1400xSEQ. ID N0:1410) GCCGTCCTGCTCiCCGGT (FRAG. N0:1401)(SEQ. ID N0:141i) CGTTGGCTGGGTCCCCCCGC (FRAG. N0:1402XSEQ. ID N0:1412) 1 S CCGTTTCCTGGGGTCC (FRAG. N0:1403)(SEQ. ID N0:1413) GCGTGGGGTGCTCC (FRAG. N0:1404XSEQ. ID N0:1414) GGTTCCTCGTGCCG (FRAG. N0:1405)(SEQ. ID N0:1415) CTGCTGCCTTGTCTTTCC (FRAG. N0:1406)(SEQ. ID N0:1416) GGCCGTGGCGGCGTGGTGGTCC (FRAG. N0:1407)(SEQ. ID N0:1417) ZO GCCCCCCCTGGCCTTCTGCTC (FRAG. N0:1408)(SEQ. ID N0:1418) GGGGTCTGGCTGGT (FRAG. N0:1409xSEQ. ID N0:1419) TGCCGGTGCCCTTGGCGGC (FRAG. N0:1410)(SEQ. ID N0:1420) GGTCTTCZTCCTGGTG (FRAG. N0:1411)(SEQ. ID N0:1421) GCTCTGGGCCCGGCCGGTCTCGG (FRAG. N0:1412)(SEQ. ID N0:1422) ZS GCGTCTCGTGTTCG (FRAG. N0:1413)(SEQ. ID N0:1423) CTCTTGTGCTGTTCCGGCCG (FRAG. N0:1414)(SEQ. ID N0:1424) CTCCTTCCTCTTCCGCCGCC (FRAG. N0:1415)(SEQ. ID N0:1425) GCCGCTCCCCGCCC (FRAG. N0:141b)(SEQ. ID N0:1426) GCTCGTCGCCCTGGCCC (FRAG. N0:1417)(SEQ. ID N0:1427) 3O GGCCTCCTCCTGGCCGC (FRAG. N0:1418)(SEQ. ID N0:1428) TGTCTCGGGCGGCGGCCTTGGC (FRAG. N0:1419XSEQ. ID N0:1429) GCTCCGTTTGGGGCTG (FRAG. N0:1420)(SEQ. ID N0:1430) CCTCTGGCGCTTCC (FRAG. N0:1421)(SEQ. ID N0:1431) GGCCCTCGGCCTGGGCGCTC (FRAG. N0:1422)(SEQ. ID N0:1432) 3 S TCTTCCGCCTGTGC (FRAG. N0:1423)(SEQ. ID N0:1433) TGGTGGCCCTCGTGG (FRAG. N0:1424)(SEQ. ID N0:1434) GCCCCTCCTGGCCTCCGGTGTCC (FRAG. N0:1425)(SEQ. ID N0:1435) TGTGGTCCCCCGGCTGGT (FRAG. N0:1426)(SEQ. ID N0:1436) GGCCGGGCCGGTTGGGCGGGC (FRAG. N0:1427)(SEQ. ID N0:1437) 4O GTGGGCGCCGGCGGGTCCTCC (FRAG. N0:1428)(SEQ. )D N0:1438) GGGCTGCCCTTCTCC (FRAG. N0:1429)(SEQ. ID N0:1439) GCCGGGGGTCCCGC (FRAG. NO: L430)(SEQ. ID N0:1440) GCTCCTGCTGTTCCCTGGGCTCTTCTGCC (FRAG. N0:1431)(SEQ. ID N0:1441) TCTCTCCTGGGTGGGTGCTGGGTGCCG (FRAG. N0:1432xSEQ. ID N0:1442) 4S GGGTCTCCGGGCTTG (FRAG. N0:1433)(SEQ. ID N0:1443) CCCCGCGCTGCTGGGCGTTCTGC (FRAG. N0:1434)(SEQ. ID N0:1444) GGTCTTGGGGTTGTC (FRAG. N0:1435)(SEQ. ID N0:1445) TGTGGCCCCGCTCG (FRAG. N0:1436)(SEQ. ID N0:1446) TGTCGCCCTCCGTCGCC (FRAG. N0:1437XSEQ. ID N0:1447) SO CGTCGCCGGCCTCGTCC (FRAG. N0:1438)(SEQ. ID N0:1448) CCTCCTGGGTGCGC (FRAG. N0:1439)(SEQ. ID N0:1449) GGCGGGCTGGTCCT (FRAG. N0:1440)(SEQ. ID N0:1450) GGCGTTTTGCTCCTTCCTGG (FltAG. N0:1441)(SEQ. ID N0:1451) 5'-GCGTCTTGGGGTGCBGGGCCCBTCCTGCTGCGCCTGGGCGCTG-3' (FRAG. N0:1896) (SEQ. ID NO:
1907) SS
5'-CTGCCCCBGT TTTTGBTCCT CBCBTGCCGT GGGGBGGBCB BTGGCTGCCT CCCCGGGGTT
1~1'GCTGCTT GCTGCTTCTT
TCCCGTCTCC CTTCTTTCCC GTCTCCTTTT TGCCTCTTTG GGTTCCTGTT GTTTCTGGCC TGCTTGGTGG
CGGCTTGTGC
GTTTCCTCTC TCTTCTCTTG GGTCTCCGCT TCTCGTCCTG CCTTTTCCTG TCTCTGTCGC GCCGTTCCTC
CTCCGGCGTC
CTCCTGCCCT GTGCTGTTTG CCTCGGGTGG TGCGGGTCCC GGTGCTCCCC CGGCGGGCCG GCTGGTTGCC
TGGGCCTGTC
C)O TGGTGGGGTG TGGGGCCGCT GGGTTGGGGG TGTGGTGGGC TCTTCTGTGG CCTGTGGGGC
TGTTGGTGTC TCTGTGGGCG
TGTGCTGGGT CTTGGGGCTT CCTCCCTTGT GCTGGGTGCG GCCTCCCCGC CCCCCTTCTG GGCCGGTGGC
CTGGCTCCTT
GTGGGCGCTT CTGGCTCT'fG CCCTGTCCTT CTTCGCCTCG TGGCTGCTGG GCTGC-3' (IPRAG.
N0:1897) (SEQ. ID NO: 1908) 5'-CCCCGGGG-3' (FRAG. N0:189$) (SEQ. ID NO: 1909) 5'-GGGGCCGCTGGG-3' (FRAG. N0:1899) (SEQ. ID N0:1910) 5'-GGGGGTGTGG-3' (P'RAG. N0:1900) (SEQ. )D NO: 1911) 5'-CTGCCTCCCCGGGGT-3' (FRAG. N0:1442)(SEQ. m N0:1452) 5'-TTCTGCTGCTTGCTG-3' (FRAG. NO:lA43)(SEQ. ID N0:1453) 5'-CTTCTTTCCCGTCTCC-3' (FRAG. N0:1444)(SEQ. ID N0:1454) 5'-CTTCTTTCCCGTCTCC-3' (FRAG. N0:1445)(SEQ. ID N0:1455) 5'-TTTTTGCCTCTTTG-3' (FRAG. N0:144~(SEQ. ID N0:1456) 5'-GGTTCCTGTTGTTTCT-3' (FRAG. N0:1447)(SEQ. ID N0:1457) I O 5'-GGCCTGCTTGGTGGCG-3' (FRAG. N0:1418)(SEQ. ID N0:1458) 5'-GCTTGTGCGTTTCC-3' (FRAG. N0:1449)(SEQ.1D N0:1459) 5'-TCTCTCTTCTCTTGGGTCTCCGCTTCTCGTCCTGCC-3' (FRAG. N0:1450)(SFQ. m N0:1460) 5'-TTTTCCTGTCTCTGTCGC-3' (FRAG. N0:1451)(SEQ. ID N0:1461) 5'-GCCGTTCCTCCTCC-3' (FRAG. N0:1452)(SEQ. )D N0:1462) I S 5'-GGCGTCCTCCTGCCC-3' (FRAG. N0:1453)(SEQ. ID N0:1463) 5'-TGTGCTGTTTGCCTCGG-3' (FRAG. N0:1454HSEQ. ID N0:1464) 5'-GTGGTGCGGGTCCC-3' (FRAG. N0:1455)(SEQ. >D N0:1465) 5'-GGTGCTCCCCCGGC-3' (FRAG. N0:1456)(SEQ. 1D N0:1466) 5'-GGGCCGGCTGGTTGCCTGGGC-3' (FRAG. N0:1457)(SEQ. ID N0:1467) 2O 5'-CTGTCTGGTGGGGTGTGGGGCC-3' (FRAG. N0:1458)(SEQ. ID N0:1468) 5'-GCTGGGTTGGGGGTGTGGTG-3' (FRAG. N0:1459)(SEQ. ID N0:1469) 5'-GGCTCTTCTGTGGCC-3' (FRAG. N0:1460)(SEQ. ID N0:1470) 5'-TGTGGGGCTGTTGGTG-3' (FRAG. N0:1461)(SEQ. ID N0:1471) 5'-TCTCTGTGGGCGTGTG-3' (FRAG. N0a462)(SEQ. ID N0:1472) 2S 5'-CTGGGTCTTGGGGCTTC-3' (FRAG. N0:1463xSEQ. ID N0:1473) 5'-CTCCCTTGTGCTGGG-3' (FRAG. N0:1464)(SEQ. ID N0:1474) 5'-TGCGGCCTCCCCGC-3' (FRAG. N0:1465)(SEQ. ID N0:1475) 5'-CCCCCTTCTGGGCC-3' (FRAG. N0:1466)(SEQ. ID N0:1476) 5'-GGTGGCCTGGCTCCTTGTGG-3' (FRAG. N0:1467)(SEQ. ID N0:1477) 3O 5'-GCGCTTCTGGCTCTTG-3' (FRAG. N0:1468xSEQ. ID N0:1478) 5'-CCCTGTCCTTCTTCGCCTCGT-3' (FRAG. N0:1469)(SEQ. ID N0:1479) 5'-GGCTGCTGGGCTGC-3' (FRAG. N0:1470xSEQ. ID N0:1480) 5'-CTGCCCCBGTTTTTGBTCCTCBCBTGCCGTGGGGBGGBCBBTGG-3' (FRAG. N0:1901) (SEQ. ID
NO: 1912) NF-1 A Antisense OligonLCleotide Fray 3 S 5'-CGGCCCTTCT CACTCiGAGGC ACCGGGCAGT CCTCCATGGG AGGGTTGGGC TTGGCCGGGG
CTGCCCGGTG CCTCCTCTfG
GCTGGTCCCT CGTTGTCCTT GGGCCCCGC TCCCGCTGCT CGGCCTCCGT GTTCTTTGGC CTCTTGCTCC
GCCTGCTGTC
TTGTCCCGTC CCCTCCTCGC TTGCGTTTCC CTCTTCCTTG TCTTCCAGGC CTTCCTCCGC TTCCGCTGCT
GGGGCCCGCG
CCGGGGGGGC GCTCGGCTCC GCGGCTTCCT CCCCGGCTGG GGGGTCCTGG TCTCCGGGGC CTGCGGCTCG
CGGGCTCGGG
GCTGCGTGCG CCGCGCGCGG CGTCCGCGGT GGGTGGCGCT GTCCCGCCGT GGTGTGTCTC CGTTCTCGTC
CTGCGCCGTC

GGGGCTTCGG GCTCGGGGCT
GTTCGTCCCC CCTGCCGCTC TGTGGCCTCC GGGGCTCCTC GTTTTCGCTG CTTCGGGTGT CCTTCTCGGC
GTGTGGCCCC
GGGTCCCGGC CCTGCTGGGC TGGGCGGGGT CGCTGCCCTG GGCTTCTGGC CCGTCTGGTT GTCTGTCGGT
GCTTGTCTCG
GGTTTCTGGC CTCTGTGCTG GGCGCTTCTC TGCCTCCTGC TCCGCCCTCC TGGTGGCTCG GCTGGGGGTG
CCCGTGCGGG
GGTGGGTGTG GGGTGTTTTC GGGGTCCTCC CCTTCCC-3' (FRAG. N0:1902) (SEQ. ID N0:1913) 4S 5'-GGGCGGGGTCGC-3' (FRAG. N0:1903) (SEQ. la N0:1914) 5'-GCGCCGTCC-3' (P'RAG. N0:1904) (SEQ. ID N0:1915) 5'-GGGCGTGGTGG-3' (P'RAG. N0:190~ (SEQ. ID N0:191~
5'-GT'fGGGCTTGGCCGGGG-3' (FRAG. N0:1471XSEQ. ID N0:1481) 5'-C1'GCCCGGTGCCTCC-3' (FRAG. N0:1472HSEQ. >D N0:1482) SO 5'-TCTTGGCTGGTCCCTCGT-3' (FRAG. N0:1473)(SEQ. ID N0:1483) 5'-TGTCCTTGGGCCCC-3' (FRAG. N0:1474)(SEQ. ID N0:1484) 5'-GCTCCCGCTGCTCGGCCTCCGT-3' (FRAG. N0:1475xSEQ. ID N0:1485) 5'-GTTCTTTGGCCTCTTGCTCC-3' (FRAG. N0:1476HSEQ. >D N0:1486) 5'-GCCTGCTGTCTTGTCC-3' (FRAG. N0:1477)(SEQ. ID N0:1487) SS 5'-CGTCCCCTCCTCGCTTGCGTTTC-3' (FRAG. N0:1478)(SEQ. ID N0:1488) 5'-CCTCTTCCTTGTCTTCCA-3' (FRAG. N0:1479)(SEQ. >D N0:1489) 5'-GGCCTTCCTCCGCTTCCGCTGC-3' (FRAG. N0:1480)(SEQ. ID N0:1490) 5'-TGGGGCCCGCGCCGG-3' (FRAG. N0:1481)(SEQ. ID N0:1491) 5'-GGGGGCGCTCGGCTCCGCGGCTTCCTCCCCGG-3' (FRAG. N0:1482)(SEQ. ID N0:1492) EO 5'-CTGGGGGGTCCTGG-3' (FRAG. N0:1483)(SEQ. ID N0:1493) S'-TCTCCGGGGCCTGCGGCTCGC-3' (FRAG. NO:1484)(SEQ. ID N0:1494) 5'-GGGCTCGGGGCTGCGTGCGCC-3' (FRAG. N0:1485xSEQ. ID N0:1495) WO 99/1388b PCTNS98/19419 5'-GCGCGCGGCGTCCGCGGTG-3' (FRAG. N0:1486)(SEQ. ID N0:1496) 5'-GGTGGCGCTGTCCCGCC-3' (FRAG. N0:1487)(SEQ. ID N0:1497) 5'-GTGGTGTGTCTCCGTTCTCGTCCTGCGCCGTC-3' (FRAG. N0:1488)(SEQ. ID N0:1498) S'-CTGGTCTGCCCGTGG-3' (FRAG. N0:1489)(SEQ. >D N0:1499) S 5'-GGTCCTGGGCGTGGTGG-3' (FRAG. N0:1490)(SEQ. ID NO:1500) 5'-GGGGCGTCTGGTGC-3' (FRAG. N0:1491)(SEQ. ID NO:1501) 5'-CTCGTCTGCCCCGTG-3' (FRAG. N0:1492)(SEQ. ID N0:1502) 5'-GGGCTTCGGGCTCGG-3' (FRAG. N0:1493)(SEQ. ID N0:1503) 5'-GGCTGTTCGTCCCCCCTGCCGCTCTGTGGCCTCC-3' (FRAG. N0:1494)(SEQ. ID N0:1504) 1 U S'-GGGGCTCCTCG1TI"fC-3' (FRAG. NO:1495xSEQ. ID NO:I505) 5'-GCTGCTTCGGGTGTCCTfCTC-3' (FRAG. N0:1496HSEQ. 1D N0:1506) 5'-GGCGTGTGGCCCCGG-3' (FRAG. N0:1497xSEQ. >D N0:1507) 5'-GTCCCGGCCCTGCTGGGCTGGGCGGGGTC-3' (FRAG. N0:1498xSEQ. ID NO:1508) 5'-GCTGCCCTGGGCTTCTGGCCCGTCT-3' (FRAG. N0:1499XSEQ. ID N0:1509) I S 5'-GGTTGTCTGTCGGT-3' (FRAG. NO:1500)(SEQ. ID NO:1510) 5'-GCTTGTCTCGGGTTTCTGG-3' (FRAG. NO:1501)(SEQ. ID NO:1511) 5'-CCTCTGTGCTGGGC-3' (FRAG. N0:1502)(SEQ. ID N0:1512) 5'-GCTTCTCTGCCTCCTGCTCC-3' (FRAG. N0:1503)(SEQ. ID N0:1513) 5'-GCCCTCCTGGTGGCTC-3' (FRAG. N0:1504)(SEQ. ID N0:1514) ZO 5'-GGCTGGGGGTGCCCGTGCG-3' (FRAG. NO:1505)(SEQ. ID NO:1515) 5'-GGGGTGGGTGTGGGGTGTT-3' (FRAG. N0:1506)(SEQ. ID N0:1516) 5'-TTCGGGGTCCTCCCCTTCCC-3' (FRAG. N0:1507)(SEQ. ID N0:1517) 5'-CGGCCCTTCTCACTGGAGGCACCGGGCAGTCCTCCATGGGAGG-3' (FRAG. N0:190~ (SEQ. ID
N0:191'n Human Maior Basic Protein Anti-sense Oligonucleotide Fra ents ZS 5'-GTT TCA TCT TGG CTT TAT CCTCT CCC CTT GTT CCT CCC CTCT CCT GCT CTG GRG
TCT CCT C TTC CCT CCC TCC
CCT GCC GTG TTG TCT GTG GGT GTC GTT TCG CTC TTG TTG CCC TGG GCC CTT CCC TGC
TGG GGG GGA GTT TCA TCT
TGG GTT TCB TCT TGG CTT TBT CCTCT CCC CTT GTT CCT CCC CTCT CCT GCT CTG GRG TCT
CCT C TTC CCT CCC TCC
CCT GCC GTG TTG TCT GTG GGT GTC GTT TCG CTC TTG TTG CCC TGG GCC CTT CCC TGC
TGG GGG GGB GTT TCB TCT
TGG-3' (FRAG. ID:1907) (SEQ. ID N0:1918) 3~ 5'-GGG GGA GTT-3' (FRAG. ID:1908) (SEQ. ID N0:1919) 5'-G CCC TGG GCC C-3' (FRAG. ID:1909) (SEQ. ID N0:1920) 5'-GTT TCA TCT TGG CTT TAT CC-3' (F'RAG. N0:1508) (SEQ. ID N0:1518) 5'-TCT CCC CTT GTT CCT CCC C-3' (FRAG. N0:1509)(SEQ. ID N0:1519) 5'-TCT CCT GCT CTG GRG TCT CCT C-3' (FRAG. N0:1510)(SEQ. ID N0:1520) 3S 5'-TTC CCT CCC TCC CCT GCC-3' (FRAG. NO:I511)(SEQ. ID N0:1521) 5'-GTG TTG TCT GTG GGT GTC C-3' (FRAG. N0:1512)(SEQ. ID N0:1522) 5'-GTT TCG CTC TTG TTG CCC-3' (FRAG. N0:1513)(SEQ. ID N0:1523) 5'-TGG GCC CTT CCC TGC TGG-3' (FRAG. NO: t514)(SEQ. ID N0:1524) 5'-GGG GGA GTT TCA TCT TGG-3' (FRAG. NO:I515)(SEQ. ID N0:1525) 4O 5'-GTT TCA TCT TGG CTT TAT CCTCT CCC CTT GTT CCT CCC CTCT CCT GCT CTG GRG
TCT CCT C TTC CCT CCC TCC
CCT GCC GTG TTG TCT GTG GGT GTC GTT TCG CTC TTG TTG CCC TGG GCC CTT CCC TGC
TGG GGG GGA GTT TCA TCT
TGG-3' (FRAG. ID:1910) (SEQ. ID N0:1921) 5'-GTT TCB TCT TGG CTT TBT CCTCT CCC CTT GTT CCT CCC CTCT CCT GCT CTG GRG TCT
CCT C TTC CCT CCC TCC
CCT GCC GTG TTG TCT GTG GGT GTC GTT TCG CTC TTG TTG CCC TGG GCC CTT CCC TGC
TGG GGG GGB GTT TCB TCT
4S TGG-3' {FRAG. n):1911) (SE.Q. )D N0:1922) 5'-GGG GGB GTT TCB TCT TGG CTT T-3' (FRAG. N0:1516xSEQ. ID N0:1526) 5'-GGG GGB GTT TCB TCT TGG CTT-3' (FRAG. N0:1517)(SEQ. ID N0:1527) 5'-GGG GGB GTT TCB TCT TGG CT-3' (FRAG. N0:1518)(SEQ. ID N0:1528) SO 5'-GGG GGB GTT TCB TCT TGG C-3' (FRAG. N0:1519)(SEQ. ID N0:1529) 5'-GGG GGB GTT TCB TCT TGG-3' (FRAG. N0:1520xSEQ. ID N0:1530) 5'-GGG GGB GTT TCB TCT TG-3' (FRAG. N0:1521)(SEQ. ID N0:1531) 5'-GGG GGB GTT TCB TCT T-3' (FRAG. N0:1522)(SEQ. iD N0:1532) 5'-GGG GGB GTT TCB TCT-3' (FRAG. N0:1523HSEQ. ID N0:1533) SS 5'-GGG GGB GTT TCB TC-3' (FRAG. N0:1524HSEQ. ID N0:1534) 5'-GGG GGB GTT TCB T-3' (FRAG. N0:1525)(SEQ. ID N0:1535) 5'-GGG GGB GTT TCB-3' (FRAG. N0:1526HSEQ. iD N0:1536) 5'-GG GGB GTT TCB TCT TGG CTT T-3' (FRAG. N0:1527)(SEQ. ID NO:1337) 5'-GG GGB GTT TCB TCT TGG CTT-3' (FRAG. N0:1528)(SEQ. ID N0:1538) 5'-GG GGB GTT TCB TCT TGG CT-3' (FRAG. N0:1529)(SEQ. ID N0:1539) 5'-GG GGB GTT TCB TCT' TGG C-3' (FRAG. N0:1530xSEQ. ID N0:1540) 5'-GG GGB GTT TCB TCT TGG-3' (FRAG. N0:1531xSEQ. ID N0:1541) 5'-GG GGB GTT TCB TCT TG-3' (FRAG. N0:1532)(SEQ. ID N0:1542) 5'-GG GGB GTT TCB TCT T-3' (FRAG. N0:1533)(SEQ. ID N0:1543) S 5'-GG GGB GTT TCB TCT-3' (FRAG. N0:1534)(SEQ. ID N0:1544) 5'-GG GGB GTT TCB TC-3' (FRAG. N0:1535)(SEQ. ID N0:1545) 5'-GG GGB GTT TCB T-3' (FRAG. N0:1536)(SEQ. ID N0:1546) 5'-G GGB GTT TCB TCT TGG CTT T-3' (FRAG. NO:l537XSEQ. ID N0:1547) 5'-G GGB GTT TCB TCT TGG CTT-3' (PRAG. N0:1538)(SEQ. ID N0:1548) 1 U 5'-G GGB GTT TCB TCT TGG CT-3' (FRAG. N0:1539HSEQ. ID N0:1549) 5'-G GGB GTT TCB TCT TGG C-3' (FRAG. N0:1540)(SEQ. ID N0:1530) 5'-G GGB GTT TCB TCT TGG-3' (FRAG. N0:1541HSEQ. ID N0:1551) 5'-G GGB GTT TCB TCT TG-3' (FRAG. N0:1542)(SEQ. ID N0:1552) 5'-G GGB GTT TCB TCT T-3' (FRAG. N0:1543xSEQ. ID N0:1553) I S 5'-G GGB GTT TCB TCT-3' (FRAG. N0:1544)(SEQ. ID N0:1554) 5'-G GGB GTT TCB TC-3' (FRAG. N0:1545xSEQ. ID N0:1555) 5'-GGB GTT TCB TCT TGG CTT T-3' (FRAG. N0:1546)(SEQ. ID NO:I556) 5'-GGB GTT TCB TCT TGG CTT-3' (FRAG. N0:1547)(SEQ. ID N0:1557) 5'-GGB GTT TCB TCT TGG CT-3' (FRAG. N0:1548XSEQ. ID N0:1558) ZO 5'-GGB GTT TCB TCT TGG C-3' (FRAG. N0:1549)(SEQ. ID N0:1559) 5'-GGB GTT TCB TCT TGG-3' (FRAG. N0:1530)(SEQ. ID N0:1560) 5'-GGB GTT TCB TCT TG-3' (FRAG. N0:1551xSEQ. ID N0:1561) 5'-GGB GTT TCB TCT T-3' (FRAG. N0:1552)(SEQ. ID N0:1562) 5'-GGB GTT TCB TCT-3' (FRAG. N0:1553)(SEQ. ID N0:1563) ZS 5'-GB GTT TCB TCT TGG CTT T-3' (FRAG. N0:1554)(SEQ. ID N0:1564) 5'-GB GTT TCB TCT TGG CTT-3' (FRAG. N0:1555)(SEQ. ID N0:1565) 5'-GB GTT TCB TCT TGG CT-3' (FRAG. N0:1556)(SEQ. ID N0:1566) 5'-GB GTT TCB TCT TGG C-3' (FRAG. N0:1557)(SEQ. ID N0:1567) 5'-GB GTT TCB TCT TGG-3' (FRAG. NO:I558)(SEQ. ID N0:1568) 3fl 5'-GB GTT TCB TCT TG-3' (FRAG. N0:1559XSEQ. ID N0:1569) 5'-GB GTT TCB TCT T-3' (FRAG. N0:1560HSEQ. ID N0:1570) 5'-B GTT TCB TCT TGG CTT T-3' (FRAG. N0:1561)(SEQ. ID N0a571) 5'-B GTT TCB TCT TGG CTT-3' (FRAG. N0:1562xSEQ. ID N0:1572) 5'-B GTT TCB TCT TGG CTT-3' (FRAG. N0:1563)(SEQ. ID N0:1573) 3S 5'-B GTT TCB TCT TGG CT-3' (FRAG. N0:1564)(SEQ. ID N0:1574) 5'-B GTT TCB TCT TGG C-3' (FRAG. N0:1565)(SEQ. ID N0:1575) 5'-B GTT TCB TCT TGG-3' (FRAG. N0:1565)(SEQ. ID N0:1576) 5'-B GTT TCB TCT TG-3' (fiRAG. N0:1567xSEQ. ID N0:1577) 5'-GTT TCB TCT TGG CTT T-3' (FRAG. N0:1568xSEQ. ID N0:1578) 4O 5'-GTT TCB TCT TGG CTT-3' (FRAG. N0:1569)(SEQ. ID N0:1579) 5'-GTT TCB TCT TGG CT-3' (FRAG. N0:1570XSEQ. ID N0:1580) 5'-GTT TCB TCT TGG C-3' (FRAG. N0:1571)(SEQ. ID N0:1581) 5'-GTT TCB TCT TGG-3' (FRAG. N0:1572)(SEQ. ID N0:1582) 5'-TT TCB TCT TGG CTT T-3' (FRAG. N0:1573)(SEQ. ID N0:1583) 4S 5'-TT TCB TCT TGG CTT-3' (FRAG. N0:1574XSEQ. ID N0:1584) 5'-TT TCB TCT TGG CT-3' (FRAG. N0:1575)(SEQ. ID NO:1585) 5'-TT TCB TCT TGG C-3' (FRAG. N0:15?6xSEQ. ID N0:1586) 5'-T TCB TCT TGG CTT T-3' (FRAG. N0:1577)(SEQ. ID N0:1587) 5'-T TCB TCT TGG CTT-3' (FRAG. N0:1578xSEQ. ID N0:1588) SU 5'-T TCB TCT TGG CT-3' (FRAG. N0:1579xSEQ. ID N0:1589) 5'-TCB TCT TGG CTT T-3' (FRAG. N0:1580)(SEQ. ID N0:1590) 5'-TCB TCT TGG CTT-3' (FRAG. N0:1581xSEQ. ID N0:1591) 5'-GGG GGB GTT TCB TCT TGG CTT T-3' (FRAG. N0:1582)(SEQ. ID N0:1592) 5'-GG GGB GTT TCB TCT TGG CTT T-3' (FRAG. N0:1583)(SEQ. ID N0:1593) SS 5'-G GGB GTT TCB TCT TGG CTT T-3' (FRAG. N0:1584XSEQ. ID N0:1594) 5'-GGB GTT TCB TCT TGG CTT T-3' (FRAG. N0:1585)(SEQ. ID N0:1595) 5'-GB GTT TCB TCT TGG CTT T-3' (FRAG. N0:1586)(SEQ. ID N0:1596) 5'-B GTT TCB TCT TGG CTT T-3' (FRAG. N0:1587)(SEQ. ID N0:1597) 5'-GTT TCB TCT TGG CTT T-3' (FRAG. N0:1588xSEQ. ID N0:1598) 6U 5'-TT TCB TCT TGG CTT T-3' (FRAG. N0:1589xSEQ. ID N0:1599) 5'-T TCB TCT TGG CTT T-3' (FRAG. N0:1590)(SEQ. iD N0:1600) 5'-TCB TCT TGG CTT T-3' (FRAG. N0:1591)(SEQ. ID N0:1601) 5'-CB TCT TGG CTT T-3' (FRAG. N0:1592)(SEQ. ID N0:1602) 5'-GGG GGB GTT TCB TCT TGG CTT-3' (FRAG. N0:1593)(SEQ. ID N0:1603) 5'-GG GGB GTT TCB TCT TGG CTT-3' (FRAG. N0:1594)(SEQ. m N0:1604) 5'-G GGB GTT TCB TCT TGG CTT-3' (FRAG. N0:159~(SEQ. ID N0:1605) 5'-GGB GTT TCB TCT TGG CTT-3' (FRAG. N0:1596)(SEQ. >D N0:1606) S'-GB GTT TCB TCT TGG CTT-3' (FRAG. N0:1597)(SEQ. ID N0:1607) S 5'-B GTT TCB TCT TGG CTT-3' (FRAG. N0:1598)(SEQ. ID N0:1608) 5'-GTT TCB TCT TGG CTT-3' (FRAG. N0:1599)(SEQ. ID N0:1609) 5'-TT TCB TCT TGG CTT-3' (FRAG. N0:1600)(SEQ. ID N0:1610) 5'-T TCB TCT TGG CTT-3' (PRAG. N0:1601)(SEQ. ID N0:1611) 5'-TCB TCT TGG CTT-3' (FRAG. N0:1602HSEQ. ID N0:1612) 1 O 5'-GGG GGB GTT TCB TCT TGG CT-3' (FRAG. N0:1603)(SEQ. ID N0:1613) 5'-GG GGB GTT TCB TCT TGG CT-3' (FRAG. N0:1604XSEQ. ID N0:1614) 5'-G GGB GTT TCB TCT TGG CT-3' (FRAG. N0:1605xSEQ. )D N0:1615) 5'-GGB GTT TCB TCT TGG CT-3' (FRAG. N0:1606)(SEQ. 1D N0:1616) 5'-GB GTT TCB TCT TGG CT-3' (FRAG. N0:1607)(SEQ. ID N0:1617) I S 5'-B GTT TCB TCT TGG CT-3' (FRAG. N0:1608)(SEQ. >D N0:1618) 5'-GTT TCB TCT TGG CT-3' (FRAG. N0:1609)(SEQ. ID N0:1619) 5'-TT TCB TCT TGG CT-3' (FRAG. N0:1610)(SEQ. >D N0:1620) 5'-T TCB TCT TGG CT-3' (FRAG. N0:1611)(SEQ. ID N0:1621) 5'-GGG GGB GTT TCB TCT TGG C-3' (FRAG. N0:1612)(SEQ. ID N0:1622) ZO 5'-GG GGB GTT TCB TCT TGG C-3' (FRAG. N0:1613)(SEQ. ID N0a623) 5'-G GGB GTT TCB TCT TGG C-3' (FRAG. N0:1614)(SEQ. ID N0:1624) 5'-GGB GTT TCB TCT TGG C-3' (FR.AG. N0:1615XSEQ. ID N0:1625) 5'-GB GTT TCB TCT TGG C-3' (FRAG. N0:1616)(SEQ. ID N0:1626) 5'-B GTT TCB TCT TGG C-3' (FRAG. N0:1617)(SEQ. ID N0:1627) ZS 5'-GTT TCB TCT TGG C-3' (FRAG. N0:1618)(SEQ. ID N0:1628) 5'-TT TCB TCT TGG C-3' (FRAG. N0:1619)(SEQ. ID N0:1629) 5'-GGG GGB GTT TCB TCT TGG-3' (FRAG. N0:1620)(SEQ. ID N0:1630) 5'-GG GGB GTT TCB TCT TGG-3' (FRAG. N0:1621XSEQ. ID N0:1631) 5'-G GGB GTT TCB TCT TGG-3' (FRAG. N0:1622)(SEQ. ID N0:1632) 3O 5'-GGB GTT TCB TCT TGG-3' (FRAG. N0:1623)(SEQ. ID N0:1633) 5'-GB GTT TCB TCT TGG-3' (FRAG. N0:1624)(SEQ. ID N0:1634) 5'-B GTT TCB TCT TGG-3' (FRAG. N0:1625~(SEQ. ID N0:1635~
5'-GTT TCB TCT TGG-3' (FRAG. N0:162~(SEQ. ID N0:163~
5'-GGG GGB GTT TCB TCT TG-3' (P'RAG. N0:1627)(SEQ. ID N0:1637) 3 S 5'-GG GGB GTT TCB TCT TG-3' (FRAG. N0:1628)(SEQ. ID N0:1638) 5'-G GGB GTT TCB TCT TG-3' (FRAG. N0:1629)(SEQ. ID N0:1639) 5'-GGB GTT TCB TCT TG-3' (FRAG. N0:1630)(SEQ. ID N0:1640) 5'-GB GTT TCB TCT TG-3' (FRAG. N0:1631)(SEQ. ID N0:1641) 5'-B GTT TCB TCT TG-3' (FRAG. N0:1632)(SEQ. ID N0:1642) 4O 5'-GGG GGB GTT TCB TCT T-3' (FRAG. N0:1633)(SEQ. ID N0:1643) 5'-GG GGB GTT TCB TCT T-3' (FRAG. NO: L634xSEQ. >D N0:1644) 5'-G GGB GTT TCB TCT T-3' (FRAG. N0:1635)(SEQ. ID N0:1645) 5'-G GGB GTT TCB TCT T-3' (FRAG. N0:1636)(SEQ. ID N0:1646) 5'-GGB GTT TCB TCT T-3' (FRAG. N0:1637)(SEQ. ID N0:1647) 4S 5'-GB GTT TCB TCT T-3' (FRAG. N0:1638)(SEQ. ID NO:1648) 5'-GGG GGB GTT TCB TCT-3' (FRAG. N0:1639)(SEQ. ID N0:1649) 5'-GG GGB GTT TCB TCT-3' (FRAG. N0:1640)(SEQ. ID N0:1650) 5'-G GGB GTT TCB TCT-3' (FRAG. N0:1641)(SEQ. ID N0:1651) 5'-GGB GTT TCB TCT-3' (FRAG. N0:1642xSEQ. ID N0:1652) SO 5'-GGG GGB GTT TCB TC-3' (FRAG. N0:1643)(SEQ. ID N0:1653) 5'-GG GGB GTT TCB TC-3' (FRAG. N0:1644HSEQ. ID N0:1654) 5'-G GGB GTT TCB TC-3' (FRAG. N0:1645)(SEQ. ID N0:1655) 5'-GGG GGB GTT TCB T-3' (FRAG. N0:1646)(SEQ. ID N0:1656) 5'-GG GGB GTT TCB T-3' (FRAG. N0:1647)(SEQ. ID N0:1657) SS 5'-GGG GGB GTT TCB-3' (FRAG. N0:1648)(SEQ. ID N0:1658) 5'-TCT CCC CTT GTT CCT CCC C-3' (FRAG. N0:1649xSEQ. ID N0:1659) 5'-TCT CCT GCT CTG GTG TCT CCT C-3' (FRAG. N0:1650)(SEQ. ID N0:1660) 5'-TTC CCT CCC TCC CCT GCC-3' (FRAG. N0:1651)(SEQ. ID N0:1661) 5'-GTG TTG TCT GTG GGT GTC C-3' (FRAG. N0:1652)(SEQ. ID N0:1662) GO 5'-GTT TCG CTC TTG TTG CCC-3' -3' (FRAG. N0:1653)(SEQ. ID N0:1663) 5'-TGG GCC CTT CCC TGC TGG-3' (FRAG. N0:1654)(SEQ. ID N0:1664) 5'-GGG GGB G-3' (FRAG. N0:1912)(SEQ. ID N0:1913) 5'-GTG GGT GTC C-3' (FRAG. N0:1913) (SEQ. ID N0:1924) S'-CCGTGTTGTC BGTGGTGCTG CCCGTTTGBG GTBTGGCGCT CCBCCBBTTC CCTTTTCTCC
TTGTTTTCCG TTTCTCTTGC
CGTCTGTGGT T-3' (FRAG. N0:1914) (SEQ. ID N0:1925) 5'-CCCGTTTGBGGTBTGGC-3'(FRAG. N0:19I5) (SEQ. ID N0:1926) 5'-GCTCCBCCBBTTCCCTTTTCTCC-3'(FRAG. N0:1916) (SEQ. ID N0:1927) 5'-TTGTTTTCCGTTTCTCTTG-3'(FRAG. N0:1917) (SEQ. ID N0:1928) 5'-CCGTCTGTGGTT-3'(FRAG. N0:19I8) (SEQ, ID N0:1929) 5'-CCCGTTTGAGGTATGGC-3'(FRAG. N0:1919) (SEQ. ID N0:1930) 5'-GCTCCBCCAATTCCCTTTTCTCC-3'(FRAG. N0:1920) (SEQ. ID N0:1931) 5'-GGGCCCBGCCCCGCCGCCTTTTCTBGCCCC GGCC-3' (FRAG. N0:1921) (SEQ. ID N0:1932) 5'-GGGCCCBGCCCCGCCGCCTTTT(.'1'BGCCCC GGC-3' (FRAG. N0:1922) (SEQ. ID N0:1933) 5'-GGGCCCB GCCCCGCCGCCTTTTCTBGCCCCGG-3' (FRAG. N0:1923) (SEQ. ID N0:1934) 5'-GGGCCCBGCCCCGCCGCCTTTTCTBGCCCCG-3' (FRAG. N0:1924) (SEQ. ID N0:1935) 1 S 5'-GGGCCCBGCCCCGCCGCCTTTTCTBGCCCC-3' (FRAG. N0:1925) (SEQ. ID N0:1936) 5'-GGGCCCBGCCCCGCCGCCTTTTCTBGCCC-3' (FRAG. N0:1926) (SEQ. ID N0:1937) 5'-GGGCCCBGCCCCGCCGCCTTTTCTBGCC-3' (FRAG. N0:1927) (SEQ. iD N0:1938) 5'-GGGCCCBGCCCCGCCGCCTTTTCTBGC-3' (FRAG. N0:1928) (SEQ. ID N0:1939) 5'-GGGCCCBGCCCCGCCGCCTTTTCTBG-3' (FRAC. N0:1929) (SEQ. ID N0:1940) ZO 5'-GGGCCCBGCCCCGCCGCC7Tf'I'CTB-3' (FRAG. N0:1930) (SEQ. ID N0:1941) 5'-GGGCCCBGCCCCGCCGCCTTTTCT-3' (FRAG. N0:1931) (SEQ. ID N0:1942) S'-GGGCCCBGCCCCGCCGCCTTTTC-3' (FRAG. N0:1932) (SEQ. ID N0:1943) 5'-GGGCCCBGCCCCGCCGCCTTTT-3' (FRAG. N0:1933) (SEQ. ID N0:1944) 5'-GGGCCCBGCCCCGCCGCCTTT-3' (FRAG. N0:1934) (SEQ. ID N0:1945) 25 5'-GGGCCCBGCCCCGCCGCCTT-3' (FRAG. N0:1935) (SEQ. ID N0:1946) 5'-GGGCCCBGCCCCGCCGCCT-3' (FRAG. N0:1936) (SEQ. ID N0:1947) 5'-GGGCCCBGCCCCGCCGCC-3' (FRAG. N0:1937) (SEQ. ID N0:1948) 5'-GGGCCCBGCCCCGCCGC-3' (FRAG. N0:1938) (SEQ. ID N0:1949) 5'-GGGCCCBGCCCCGCCG-3' (FRAG. N0:1939) (SEQ. ID N0:1950) 5'-GGGCCCBGCCCCGCC-3' (FRAG. N0:1940) (SEQ. ID N0:1951) 5'-GGGCCCBGCCCCGC-3' (FRAG. N0:1941) (SEQ. ID N0:1952) 5'-GGGCCCBGCCCCG-3' (FRAG. N0:1942) (SEQ. ID N0:1953) 5'-GGGCCCBGCCCC-3' (FRAC. N0:1943) (SEQ. ID N0:1954) 5'-GGGCCCBGCCC-3' (FRAG. N0:1944) (SEQ. ID N0:1955) 3 S 5'-GGCCCBGCCCCGCCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1945) (SEQ. ID N0:1956) 5'-GCCCBGCCCCGCCGCCTTTfCTBGCCCCGGC-3' (FRAG. N0:1946) (SEQ. ID N0:1957) 5'-CCCBGCCCCGCCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1947) (SEQ. ID N0:1958) 5'-CCBGCCCCGCCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1948) (SEQ. ID N0:1959) 5'-CBGCCCCGCCGCCTTI'TCTBGCCCCGGC-3' (FRAG. N0:1g48) (SEQ. ID NO:I960) 4U 5'-BGCCCCGCCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1950) (SEQ. ID N0:1961) 5'-GCCCCGCCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1951) (SEQ. ID N0:1962) 5'-CCCCGCCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1952) (SEQ. ID N0:1963) 5'-CCCGCCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1953) (SEQ. ID N0:1964) 5'-CCGCCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1954) (SEQ. ID N0:1965) 4S 5'-CGCCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1955) (SEQ. ID N0:1966) 5'-GCCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1956) (SEQ. ID N0:1967) 5'-CCGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1957) (SEQ. ID N0:1968) 5'-CGCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1958) (SEQ. ID N0:1969) 5'-GCCTTTTCTBGCCCCGGC-3' (FRAG. N0:1959) (SEQ. ID N0:1970) SD 5'-CCTTTTCTBGCCCCGGC-3' (FRAG. N0:1960) (SEQ. ID N0:197i) 5'-C7TITCTBGCCCCGGC-3' (FRAG. N0:1961) (SEQ. ID N0:1972) 5'-TTTTCTBGCCCCGGC-3' (FRAG. N0:1962) (SEQ. ID N0:1973) 5'-TTTCTBGCCCCGGC-3' (FRAG. N0:1963) (SEQ. ID N0:1974) 5'-TTCTBGCCCCGGC-3' (FRAG. N0:1964) (SEQ. ID N0:1975) 55 5'-TCTBGCCCCGGC-3' (FRAG. N0:1965) (SEQ. iD N0:1976) 5'-CTBGCCCCGGC-3' (FRAG. N0:1966) (SEQ. ID N0:1977) 5'-GCGBGGCTGTCBCCTCGCTGGGCCC-3' (FRAG. NO:1967) (SEQ. ID N0:1978) 5'-GCGBGGC'fGTCBCCTCGCTGGGCC-3' (FRAG. N0:1968) (SEQ. ID N0:1979) 5'-GCGBGGCTGTCBCCTCGCTGGGC-3' (FRAG. N0:1969) (SEQ. ID N0:1980) 5'-GCGBGGCTGTCBCCTCGCTGGG-3' (FRAG. N0:1970) (SEQ. ID N0:1981) 5'-GCGBGGCTGTCBCCTCGCTGG-3' {FRAG. N0:1971) (SEQ. ID N0:1982) S 5'-GCGBGGCTGTCBCCTCGCTG-3' (FRAG. N0:1972) (SEQ. ID N0:1983) 5'-GCGBGGCTGTCBCCTCGCT-3' (FRAG. N0:1973) (SEQ. ID N0:1984) 5'-GCGBGGCTGTCBCCTCGC-3' (FRAG. N0:1974) (SEQ. ID N0:1985) 5'-GCGBGGCTGTCBCCTCG-3' (FRAG. N0:1975) (SEQ. ID N0:1986) 5'-GCGBGGCTGTCBCCTC-3' (FRAG. N0:1976) (SEQ. ID N0:1987) I O 5'-GCGBGGCTGTCBCCT-3' (FRAG. N0:1977) (SEQ. ID N0:1988) 5'-GCGBGGCTGTCBCC-3' (FRAG. N0:1978) (SEQ. ID N0:1989) 5'-GCGBGGCTGTCBC-3' (FRAG. N0:1979) (SEQ. ID N0:1990) 5'-GCGBGGCTGTCB-3' (FRAG. N0:1980) (SEQ. ID N0:1991) 5'-GCGBGGCTGTC-3' (FRAG. N0:1981) (SEQ. ID N0:1992) 1 S 5'-GCGBGGCTGT-3' (FRAG. N0:1982) (SEQ. ID N0:1993) 5'-CGBGGCTGTCBCCTCGCTGGGCCC-3' (FRAG. N0:1983) (SEQ. ID N0:1994) 5'-GBGGCTGTCBCCTCGCTGGGCCC-3' (FRAG. N0:1984) (SEQ. ID N0:1995) 5'-BGGCTGTCBCCTCGCTGGGCCC-3' (FRAG. N0:1985) (SEQ. ID N0:1996) 5'-GGCTGTCBCCTCGCTGGGCCC-3' (FRAG. N0:1986) (SEQ. ID N0:1997) ZO 5'-GCTGTCBCCTCGCTGGGCCC-3' (FItAG. N0:1987) (SEQ. ID N0:1998) 5'-CTGTCBCCTCGCTGGGCCC-3' (FRAG. N0:1988) (SEQ. ID N0:1999) 5'-TGTCBCCTCGCTGGGCCC-3' (FRAG. N0:1989) (SEQ. ID N0:2000) 5'-GTCBCCTCGCTGGGCCC-3' (FRAG. N0:1990) (SEQ. ID N0:2001) 5'-TCBCCTCGCTGGGCCC-3' (FRAG. N0:1991) (SEQ. ID N0:2002) ZS 5'-CBCCTCGCTGGGCCC-3' (FRAG. N0:1992) (SEQ. ID N0:2003) 5'-BCCTCGCTGGGCCC-3' (FRAG. N0:1993) (SEQ. ID N0:2004) 5'-CCTCGCTGGGCCC-3' (FRAG. N0:1994) (SEQ. ID N0:2005) 5'-C1'CGCTGGGCCC-3' (FRAG. N0:1995) (SEQ. ID N0:2006) 5'-TCGCTGGGCCC-3' (FRAG. N0:1996) (SEQ. ID N0:2007) 3O 5'-CGCTGGGCCC-3' (FRAG. N0:1997) (SEQ. ID N0:2008) 5'-GCGCGGCCGTCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:1998) (SEQ. iD N0:2009) 5'-GCGCGGCCGTCBTGGCGGCGTCGGGCCGGG-3' (FRAG. N0:1999) (SEQ. ID N0:2010) 5'-GCGCGGCCGTCBTGGCGGCGTCGGGCCGG-3' (FRAG. N0:2000) (SEQ. ID N0:2011) 5'-GCGCGGCCGTCBTGGCGGCGTCGGGCCG-3' (FRAG. N0:2001) (SEQ. ID N0:2012) 3 S 5'-GCGCGGCCGTCBTGGCGGCGTCGGGCC-3' (FRAG. N0:2002) (SEQ. ID N0:2013) 5'-GCGCGGCCGTCBTGGCGGCGTCGGGC-3' (FRAG. N0:2003) (SEQ. ID N0:2014) 5'-GCGCGGCCGTCBTGGCGGCGTCGGG-3' (FRAG. NO:Z004) (SEQ. ID N0:2015) 5'-GCGCGGCCGTCBTGGCGGCGTCGG-3' (FRAG. N0:2005) (SEQ. ID N0:2016) 5'-GCGCGGCCGTCBTGGCGGCGTCG-3' (FRAG. N0:2006) (SEQ. ID N0:2017) 4O 5'-GCGCGGCCGTCBTGGCGGCGTC-3' (FRAG. N0:2007) (SEQ. ID N0:2018) 5'-GCGCGGCCGTCBTGGCGGCGT-3' (FRAG. N0:2008) (SEQ. ID N0:2019) 5'-GCGCGGCCGTCBTGGCGGCG-3' (FRAG. N0:2009) (SEQ. ID N0:2020) 5'-GCGCGGCCGTCBTGGCGGC-3' (FRAG. N0:2010) (SEQ. ID N0:2021) 5'-GCGCGGCCGTCBTGGCGG3' (FRAG. N0:2011) (SEQ. ID N0:2022) 4S 5'-GCGCGGCCGTCBTGGCG-3' (FRAG. N0:2012) (SEQ. ID N0:2023) 5'-GCGCGGCCGTCBTGGC-3' (FRAG. N0:2013) (SEQ. ID N0:2024) 5'-GCGCGGCCGTCBTGG-3' (FRAG. N0:2014) (SEQ. ID N0:2025) 5'-GCGCGGCCGTCBTG-3' (FRAG. N0:2015) (SEQ. ID N0:2026) 5'-GCGCGGCCGTCBT-3' (FRAG. N0:2016) (SEQ. ID N0:2027) SO 5'-GCGCGGCCGTCB-3' (FRAG. N0:2017) (SEQ. ID N0:2028) 5'-GCGCGGCCGTC-3' (FRAG. N0:2018) (SEQ. ID N0:2029) 5'-GCGCGGCCGT-3' (FRAG. N0:2019) (SEQ. ID N0:2030) 5'-CGCGGCCGTCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2020) (SEQ. ID N0:2031) 5'-GCGGCCGTCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2021) (SEQ. ID N0:2032) SS 5'-CGGCCGTCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2022) (SEQ. ID N0:2033) 5'-GGCCGTCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2023) (SEQ. ID N0:2034) 5'-GCCGTCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2024) (SEQ. ID N0:2035) 5'-CCGTCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2025) (SEQ.1D N0:2036) 5'-CGTCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2026) (SEQ. ID N0:2037) 3'-GTCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2027) (SEQ. IB N0:2038) 5'-TCBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2028) (SEQ. ID N0:2039) 3'-CBTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2029) (SEQ. ID N0:2040) 3'-BTGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2030) (SEQ. ID N0:2041) S 3'-TGGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2031) (SEQ. ID N0:2042) 3'-GGCGGCGTCGGGCCGGGC-3' (FRAG. N0:2032) (SEQ. ID N0:2043) 3'-GCGGCGTCGGGCCGGGC-3' (FRAG. N0:2033) (SEQ. ID N0:2044) 3'-CGGCGTCGGGCCGGGC-3' (FRAG. N0:2034) (SEQ. ID N0:2045) 5'-GGCGTCGGGCCGGGC-3' (FRAG. N0:2035) (SEQ. ID N0:2046) 1 U 3'-GCGTCGGGCCGGGC-3' (FRAG. N0:2036) (SEQ. ID N0:2047) 3'-CGTCGGGCCGGGC-3' (FRAG. N0:2037) (SEQ. ID N0:2048) 3'-GTCGGGCCGGGC-3' (FRAG. NOd038) (SEQ.1D N0:2049) 5'-TCGGGCCGGGC-3' (FRAG. N0:2039) (SEQ. ID N0:2050) 3'-CGGGCCGGGC-3' (FRAG. N0:2040) (SEQ. ID N0:2051) I S 3'-CCGCBGGCCBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2041) (SEQ. ID N0:2052) 5'-CCGCBGGCCBGGGCGCGCCGCCGGCCGGGCC-3' (FRAG. N0:2042) (SEQ. ID N0:2053) 3'-CCGCBGGCCBGGGCGCGCCGCCGGCCGGGC-3' (FRAG. N0:2043) (SEQ. ID N0:2054) 3'-CCGCBGGCCBGGGCGCGCCGCCGGCCGGG-3' (FRAG. N0:2044) (SEQ. ID N0:2055) 5'-CCGCBGGCCBGGGCGCGCCGCCGGCCGG-3' (FRAG. N0:2045) (SEQ. ID N0:2056) ZO 5'-CCGCBGGCCBGGGCGCGCCGCCGGCCG-3' (FRAG. N0:2046) (SEQ. ID N0:2057) 3'-CCGCBGGCCBGGGCGCGCCGCCGGCC-3' (FRAG. N0:2047) (SEQ. ID N0:2058) 3'-CCGCBGGCCBGGGCGCGCCGCCGGC-3' (FRAG. N0:2048) (SEQ. ID N0:2059) 3'-CCGCBGGCCBGGGCGCGCCGCCGG-3' (FRAG. N0:2049) (SEQ. ID N0:2060) 3'-CCGCBGGCCBGGGCGCGCCGCCG-3' (FRAG. N0:2050) (SEQ. ID N0:2061) ZS 3'-CCGCBGGCCBGGGCGCGCCGCC-3' (FRAG. N0:2051) (SEQ. ID N0:2062) 3'-CCGCBGGCCBGGGCGCGCCGC-3' (FRAG. N0:2052) (SEQ. ID N0:2063) 3'-CCGCBGGCCBGGGCGCGCCG-3' (FRAG. N0:2053) (SEQ. ID N0:2064) 5'-CCGCBGGCCBGGGCGCGCC-3' (FRAG. N0:2054) (SEQ. ID N0:2065) 3'-CCGCBGGCCBGGGCGCGC-3' (FRAG. N0:2055) (SEQ. ID N0:2066) 3O 3'-CCGCBGGCCBGGGCGCG-3' (FRAG. N0:2056) (SEQ. ID N0:2067) 3'-CCGCBGGCCBGGGCGC-3' (FRAG. N0:2057) (SEQ. ID N0:2068) 3'-CCGCBGGCCBGGGCG-3' (FRAG. N0:2058) (SEQ. ID N0:2069) 5'-CCGCBGGCCBGGGC-3' (FRAG. N0:2059} (SEQ. ID N0:2070) 3'-CCGCBGGCCBGGG-3' (FRAG. N0:2060) (SEQ. ID N0:2071) 3 S 5'-CCGCBGGCCBGG-3' (FRAG. N0:2061) (SEQ. ID N0:2072) 5'-CCGCBGGCCBG-3' (FRAG. N0:2062) (SEQ. ID N0:2073) 3'-CCGCBGGCCB-3' (FRAG. N0:2063) (SEQ. ID N0:2074) 3'-CCGCBGGCC-3' (FRAG. N0:2064) (SEQ. ID N0:2075) 3'-CGCBGGCCBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2065) (SEQ. ID N0:2076) 4O 3'-GCBGGCCBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2066) (SEQ. ID N0:2077) 3'-CBGGCCBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2067) (SEQ. ID N0:2078) 3'-BGGCCBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2068) (SEQ. ID N0:2079) 5'-GGCCBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2069) (SEQ. ID N0:2080) 3'-GCCBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2070) (SEQ. ID N0:2081) 4S 3'-CCBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2071) (SEQ. ID N0:2082) 5'-CBGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2072) (SEQ. ID N0:2083) 5'-BGGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2073) (SEQ. ID N0:2084) 5'-GGGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2074) (SEQ. ID N0:2085) 5'-GGCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2075) (SEQ. ID N0:2086) SO 3'-GCGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2076) (SEQ. ID N0:2087) 3'-CGCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2077) (SEQ. ID N0:2088) 3'-GCGCCGCCGGCCGGGCCG-3' (FRAG. N0:2078) (SEQ. ID N0:2089) 3'-CGCCGCCGGCCGGGCCG-3' (FRAG. N0:2079) (SEQ. ID N0:2090) 3'-GCCGCCGGCCGGGCCG-3' (FRAG. N0:2080) (SEQ. ID N0:2091) SS 3'-CCGCCGGCCGGGCCG-3' (FRAG. N0:2081) (SEQ. ID N0:2092) 3'-CGCCGGCCGGGCCG-3' (FRAG. N0:2082) (SEQ. ID N0:2093) 5'-GCCGGCCGGGCCG-3' (FRAG. N0:2083) (SEQ. ID N0:2094) 3'-CCGGCCGGGCCG-3' (FRAG. N0:2084) (SEQ. ID N0:2095) 3'-CGGCCGGGCCG-3' (FRAG. N0:2085) (SEQ. ID N0:2096) 6O 3'-GGCCGGGCCG-3' (FRAG. N0:2086) (SEQ. ID N0:2097) 5'-GGGCGCBGGCTCCGCB-3' (FRAG. N0:2087) (SEQ. ID N0:2098) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' {FRAG. N0:2088) (SEQ. ID
N0:2099) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCG-3' (FRAG. N0:2089) (SEQ. ID
N0:2100) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCC-3' (FRAG. N0:2090) (SEQ. ID
N0:2101) S 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCC-3' (FRAG. N0:2091) (SEQ. ID
N0:2102) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGC-3' (FRAG. N0:2092) (SEQ. ID
N0:2103) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGG-3' (FRAG. N0:2093) (SEQ. ID
N0:2104) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCG-3' (FRAG. N0:2094) (SEQ. ID
N0:2105) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCC-3' {FRAG. N0:2095) (SEQ. ID
N0:2106) I O 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCC-3' (FRAG. N0:2096) (SEQ. ID
N0:2107) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGC-3' (FRAG. N0:2097) (SEQ. ID N0:2108) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCG-3' (FRAG. N0:2098) (SEQ. ID N0:2109) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCC-3' (FRAG. N0:2099) (SEQ. ID N0:2110) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCC-3' (FRAG. N0:2100) (SEQ. ID N0:2111) I S 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGC-3' (FRAG. N0:2101) (SEQ. ID N0:2112) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTTG-3' (FRAG. N0:2102) (SEQ. ID N0:2113) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCTT-3' (FRAG. N0:2103) (SEQ.1D N0:2114) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGCT3' (FRAG. N0:2104) (SEQ. ID N0:2115) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGGC-3' (FRAG. N0:2105) (SEQ. ID N0:2116) ZO 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCGG-3' (FRAG. N0:2106) (SEQ. ID N0:2117) 5'-GGGCCCCTGGCTCGGCCCCGCGGCCCG-3' (FRAG. N0:2107) (SEQ. ID N0:2118) S'-GGGCCCCTGGCTCGGCCCCGCGGCCC-3' (FRAG. N0:2108) (SEQ. ID N0:2119) 5'-GGGCCCCTGGCTCGGCCCCGCGGCC-3' (FRAG. N0:2109) (SEQ. ID N0:2120) 5'-GGGCCCCTGGCTCGGCCCCGCGGC-3' (FRAG. N0:2110) (SEQ. ID N0:2121) ZS 5'-GGGCCCCTGGCTCGGCCCCGCGG-3' (FRAG. N0:2111) (SEQ. ID N0:2122) 5'-GGGCCCCTGGCTCGGCCCCGCG-3' (FRAG. N0:2112) (SEQ. ID N0:2123) 5'-GGGCCCCTGGCTCGGCCCCGC-3' (FRAG. N0:2113) (SEQ. ID N0:2124) 5'-GGGCCCCTGGCTCGGCCCCG-3' (FRAG. N0:2114) (SEQ. ID N0:2125) 5'-GGGCCCCTGGCTCGGCCCC-3' (FRAG. N0:2115) (SEQ. ID N0:2126) 3O 5'-GGGCCCCTGGCTCGGCCC-3' (FRAG. N0:2116) (SEQ. ID N0:2127) 5'-GGGCCCCTGGCTCGGCC-3' (FRAG. N0:2117) (SEQ. ID N0:2128) 5'-GGGCCCCTGGCTCGGC-3' (FRAG. N0:2118) (SEQ. ID N0:2129) 5'-GGGCCCCTGGCTCGG-3' (FRAG. N0:2119) (SEQ. ID N0:2130) 5'-GGGCCCCTGGCTCG-3' (FRAG. N0:2120) (SEQ. ID N0:2131) 3 S 5'-GGGCCCCTGGCTC-3' (FRAG. N0:2121) (SEQ. ID N0:2132) 5'-GGGCCCCTGGCT-3' (FRAG. N0:2122) (SEQ. ID N0:2133) 5'-GGCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2123) (SEQ. ID
N0:2134) 5'-GCCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2124) (SEQ. ID
N0:2135) 5'-CCCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2125) (SEQ. ID
N0:2136) 4O 5'-CCCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2126) (SEQ. ID
N0:2137) 5'-CCTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2127) (SEQ. ID
N0:2138) S'-CTGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2128) (SEQ. ID
N0:2139) 5'-TGGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2129) (SEQ. ID
N0:2140) 5'-GGCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FItAG. N0:2130) (SEQ. ID
N0:2141) 4S 5'-GCTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2131) (SEQ.1D
N0:2142) 5'-CTCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2132) (SEQ. ID N0:2143) 5'-TCGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2133) (SEQ. ID N0:2144) 5'-CGGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2134) (SEQ. ID N0:2145) 5'-GGCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2135) (SEQ. ID N0:2146) SO 5'-GCCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2136) (SEQ. ID N0:2147) 5'-CCCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2137) (SEQ. ID N0:2148) 5'-CCCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2138) (SEQ. ID N0:2149) 5'-CCGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2139) (SEQ. ID N0:2150) 5'-CGCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2140) (SEQ. ID N0:2151) SS 5'-GCGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2141) (SEQ. ID N0:2152) 5'-CGGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2142) (SEQ. ID N0:2153) 5'-GGCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2143) (SEQ. ID N0:2154) 5'-GCCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2144) (SEQ. ID N0:2155) 5'-CCCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2145) (SEQ. ID N0:2156) 5'-CCGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2146) (SEQ. ID N0:2157) 5'-CGGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2147) (SEQ. ID N0:2158) 5'-GGCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2148) (SEQ. ID N0:2159) 5'-GCTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2149) (SEQ. ID N0:2160) S 5'-CTTGCCCGCCCGGCCCGG-3' (FRAG. N0:2150) (SEQ. ID N0:2161) 5'-TTGCCCGCCCGGCCCGG-3' (FRAG. N0:2151) (SEQ. ID N0:2162) 5'-TGCCCGCCCGGCCCGG-3' (FRAG. N0:2152) (SEQ. ID N0:2163) 5'-GCCCGCCCGGCCCGG-3' (FRAG. N0:2153) (SEQ. ID N0:2164) 5'-CCCGCCCGGCCCGG-3' (FRAG. N0:2154) (SEQ. ID N0:2165) 1 O 5'-CCGCCCGGCCCGG-3' (FRAG. N0:2155) (SEQ. ID N0:2166) 5'-CGCCCGGCCCGG-3' (FRAG. N0:2156) (SEQ. ID N0:2167) 5'-GCCCGGCCCGG-3' (FItAG. N0:2157) (SEQ. ID N0:2168) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2158) (SEQ. ID N0:2169) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGGGCCC-3' (FRAG. N0:2159) (SEQ. ID N0:2170) I S 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGGGCC-3' (FRAG. N0:2160) (SEQ. ID N0:2171) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGGGC-3' (FRAG. N0:2161) (SEQ. ID N0:2172) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGGG-3' (FRAG. N0:2162) (SEQ. ID N0:2173) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBGG-3' (FRAG. N0:21b3) (SEQ. ID N0:2174) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCTBG-3' (FRAG. N0:2164) (SEQ.1D N0:2175) 2O 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCC1B-3' (FRAG. N0:2165) (SEQ. ID N0:2176) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCCT-3' (FRAG. N0:2166) (SEQ. ID N0:2177) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGCC-3' (FRAG. N0:2167) (SEQ. ID N0:2178) 5'-GGCGGGGGCGGCGGCGCCTGGCTCGC-3' (FRAG. N0:2168) (SEQ. ID N0:2179) 5'-GGCGGGGGCGGCGGCGCCTGGCTCG-3' (FRAG. N0:2169) (SEQ. ID N0:2180) ZS 5'-GGCGGGGGCGGCGGCGCCTGGCTC-3' (FRAG. N0:2170) (SEQ. ID N0:2181) 5'-GGCGGGGGCGGCGGCGCCTGGCT-3' (FRAG. N0:2171) (SEQ.1D N0:2082) 5'-GGCGGGGGCGGCGGCGCCTGGC-3' (FRAG. N0:2172) (SEQ. ID N0:2183) 5'-GGCGGGGGCGGCGGCGCCTGG-3' (FRAG. N0:2173) (SEQ. ID N0:2184) 5'-GGCGGGGGCGGCGGCGCCTG-3' (FRAG. N0:2174) (SEQ. ID N0:2185) 5'-GGCGGGGGCGGCGGCGCCT-3' (FRAG. N0:2175) (SEQ. ID N0:2186) 5'-GGCGGGGGCGGCGGCGCC-3' (FRAG. N0:2176) (SEQ. ID N0:2187) 5'-GGCGGGGGCGGCGGCGC-3' (FRAG. N0:2177) (SEQ. ID N0:2188) 5'-GGCGGGGGCGGCGGCG-3' (FRAG. N0:2178) (SEQ. ID N0:2189) 5'-GGCGGGGGCGGCGGC-3' (FRAG. N0:2179) (SEQ.1D N0:2190) 3S 5'-GGCGGGGGCGGCGG-3' (FRAG. N0:2180) (SEQ. ID N0:2191) 5'-GGCGGGGGCGGCG-3' (FRAG. N0:2181) (SEQ. ID N0:2192) 5'-GGCGGGGGCGGC-3' (FRAG. N0:2182) (SEQ. ID N0:2193) 5'-GGCGGGGGCGG-3' (FRAG. N0:2183) (SEQ. ID N0:2194) 5'-GCGGGGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2184) (SEQ. ID N0:2195) 4O 5'-CGGGGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2185) (SEQ. ID N0:2196) 5'-GGGGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2186) (SEQ. ID N0:2197) 5'-GGGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2187) (SEQ. ID N0:2198) S'-GGGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2188) (SEQ. ID N0:2199) 5'-GGCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2189) (SEQ. ID N0:2200) 4S 5'-GCGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2190) (SEQ. ID N0:2201) 5'-CGGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2191) (SEQ. ID N0:2202) 5'-GGCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2192) (SEQ. ID N0:2203) 5'-GCGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2193) (SEQ. ID N0:2204) 5'-CGGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2194) (SEQ. ID N0:2205) SO 5'-GGCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2195) (SEQ. ID N0:2206) 5'-GCGCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2196) (SEQ. ID N0:2207) 5'-CGCCTGGCTCGCCTBGGGCCCC~3' (FRAG. N0:2197) (SEQ. ID N0:2208) 5'-GCCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2198) (SEQ. ID N0:2209) 5'-CCTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2199) (SEQ. ID N0:2210) S S 5'-CTGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2200) (SEQ.1D N0:2211) 5'-TGGCTCGCCTBGGGCCCC-3' (FRAG. N0:2201) (SEQ. ID N0:2212) S'-GGCTCGCCTBGGGCCCC-3' (FRAG. N0:2202) (SEQ. ID N0:2213) 5'-GCTCGCCTBGGGCCCC-3' (FRAG. N0:2203) (SEQ. ID N0:2214) 5'-CTCGCCTBGGGCCCC-3' (FRAG. N0:2204) (SEQ. ID N0:2215) 5'-TCGCCTBGGGCCCC-3' (FRAG. N0:2205) (SEQ. ID N0:2216) 5'-CGCCTBGGGCCCC-3' (FRAG. N0:2206) (SEQ. ID N0:2217) 5'-GCCTBGGGCCCC-3' (FRAG. N0:2207) (SEQ. ID N0:2218) 5'-CCTBGGGCCCC-3' (FRAG. N0:2208) (SEQ. ID N0:2219) S 5'-CZ'BGGGCCCC-3' (FRAG. N0:2209) (SEQ. ID N0:2220) 5'-GGGTGGGCBCGGCGGCC-3' (FRAG. N0:2210) (SEQ. ID N0:2221) 5'-GGTCGGCGBBGBGCTCGTCGTGGC-3' (FRAG. N0:2211) (SEQ. ID N0:2222) 5'-GGTCGGCGBBGHGCTCGTCGTGG-3' (FRAG. N0:2212) (SEQ. ID N0:2223) 5'-GGTCGGCGBBGBGCTCGTCGTG-3' (FRAG. N0:2I13) (SEQ. ID N0:2224) I O 5'-GGTCGGCGBBGBGCTCGTCGT-3' (FRAG. N0:2214) (SEQ. ID N0:2225) 5'-GGTCGGCGBHGHGCTCGTCG-3' (FRAG. N0:2215) (SEQ. ID N0:2226) 5'-GGTCGGCGBBGBGCTCGTC-3' (FRAG. N0:2216) (SEQ. ID N0:2227) 5'-GGTCGGCGBBGBGCTCGT-3' (FRAG. N0:2217) (SEQ. ID N0:2228) 5'-GGTCGGCGBBGBGCTCG-3' (FRAG. N0:2218) (SEQ. ID N0:2229) 1 S 5'-GGTCGGCGBBGBGCTC-3' (FRAG. N0:2219) (SEQ. ID N0:2230) 5'-GGTCGGCGBBGHGCT-3' (FRAG. N0:2220) (SEQ. ID N0:2231) 5'-GGTCGGCGBBGBGC-3' (FRAG. N0:2221) (SEQ. ID N0:2232) 5'-GGTCGGCGBBGBG-3' (FRAG. N0:2222) (SEQ. ID N0:2233) 5'-GGTCGGCGBBGB-3' (FRAG. N0:2223) (SEQ. ID N0:2234) 2O 5'-GGTCGGCGBBG-3' (FRAG. N0:2224) (SEQ. ID N0:2235) 5'-GTCGGCGBBGBGCTCGTCGTGGC-3' (FRAG. N0:2225) (SEQ. ID N0:2236) 5'-TCGGCGBBGBGCTCGTCGTGGC-3' (FH;AG. N0:2226) (SEQ. ID N0:2237) 5'-CGGCGBBGBGCTCGTCGTGGC-3' (FRAG. N0:2227) (SEQ. ID N0:2238) 5'-GGCGHBGBGCTCGTCGTGGC-3' (FRAG. N0:2228) (SEQ. fD N0:2239) ZS 5'-GCGHBGBGCTCGTCGTGGC-3' (FRAG. N0:2229) (SEQ. ID N0:2240) 5'-CGBBGBGCTCGTCGTGGC-3' (FRAG. N0:2230) (SEQ. iD N0:2241) 5'-GBBGBGCTCGTCGTGGC-3' (FRAG. N0:2231) (SEQ. tD N0:2242) 5'-BBGBGCTCGTCGTGGC-3' (FRAG. N0:2232) (SEQ. ID N0:2243) 5'-BGBGCTCGTCGTGGC-3' (FRAG. N0:2233) (SEQ. ID N0:2244) 30 5'-GBGCTCGTCGTGGC-3' (FRAG. N0:2234) (SEQ. ID N0:2245) 5'-BGCTCGTCGTGGC-3' (FRAG. N0:2235) (SEQ. ID N0:2246) 5'-GCTCGTCGTGGC-3' (FRAG. N0:2236) (SEQ. ID N0:2247) 5'-CTCGTCGTGGC-3' (FRAG. N0:2237) (SEQ. ID N0:2248) 5'-TCGTCGTGGC-3' (FRAG. N0:2238) (SEQ. ID N0:2249) 3S 5'-GGGGCCCCGCGCCGCCCGCC-3' (FRAG. N0:2239) (SEQ. ID N0:2250) 5'-GGGGCCCCGCGCCGCCCGC-3' (FRAG. N0:2240) (SEQ. ID N0:2251) 5'-GGGGCCCCGCGCCGCCCG-3' (FRAG. N0:2241) (SEQ. ID N0:2252) 5'-GGGGCCCCGCGCCGCCC-3' (FRAG. N0:2242) (SEQ. ID N0:2253) 5'-GGGGCCCCGCGCCGCC-3' (FRAG. N0:2243) (SEQ. ID N0:2254) 4O 5'-GGGGCCCCGCGCCGC-3' (FRAG. N0:2244) (SEQ. ID N0:2255) 5'-GGGGCCCCGCGCCG-3' (FRAG. N0:2245) (SEQ. ID N0:2256) 5'-GGGGCCCCGCGCC-3' (FRAG. N0:2246) (SEQ. ID N0:2257) 5'-GGGGCCCCGCGC-3' (FRAG. N0:2247) (SEQ. ID N0:2258) 5'-GGGCCCCGCGCCGCCCGCC-3' (FRAG. N0:2248) (SEQ. ID N0:2259) 4S 5'-GGCCCCGCGCCGCCCGCC-3' (FRAG. N0:2249) (SEQ. ID N0:2260) 5'-GCCCCGCGCCGCCCGCC-3' (FRAG. N0:2250) (SEQ. ID N0:2261) 5'-CCCCGCGCCGCCCGCC-3' (FRAG. N0:2251) (SEQ. ID N0:2262) 5'-CCCGCGCCGCCCGCC-3' (FRAG. N0:2252) (SEQ. ID N0:2263) 5'-CCGCGCCGCCCGCC-3' (FRAG. N0:2253) (SEQ. ID N0:2264) SO 5'-CGCGCCGCCCGCC-3' (FRAG. N0:2254) (SEQ. ID N0:2265) 5'-GCGCCGCCCGCC-3' (FRAG. N0:2255) (SEQ. ID N0:2266) 5'-CGCCGCCCGCC-3' (FRAG. N0:2256) (SEQ. ID N0:2267) 5'-GCCGCCCGCC-3' (FRAG. N0:2257) (SEQ. ID N0:2268) 5'-GGGGCGCGCGGGGCCGCCGGG-3' (FRAG. N0:2258) (SEQ. ID N0:2269) SS 5'-GGCGGGGBGCGGCBGGGCCCGGGCCC-3' (FRAG. N0:2259) (SEQ. ID N0:2270) 5'-GGCGCGTCGCCGTCGCCCCBGTCGGGCTCGCGC-3' (FRAG. N0:2260) (SEQ. ID N0:2271) 5'-GCGCGGGCBBCBGCGBGCCGGGCGCG-3' (FRAG. N0:2261) (SEQ. ID N0:2272) 5'-GCGCBCGGGCCCBCCTGCGCGGGC-3' (FRAG. N0:2262) (SEQ. ID N0:2273) 5'-GGGCGGGGTGGGCTGCCCTGCGGCCGCC-3' (FRAG. N0:2263) (SEQ. ID N0:2274) 5'-GGGCTGCTGCGCGGCGGCTCCGGCGA-3' (FRAG. N0:2264) (SEQ. ID N0:2275) 5'-CTCCCGGGCGGGGCCGGGCGCGGGG-3' (FRAG. N0:2265) (SEQ. ID N0:2276) 5'-GGGCTGCCGCGGTCCGGGCCCCTCTTGCCGGCG-3' (FRAG. N0:2266) (SEQ. ID N0:2277) 5'-GCGCTCGCGCCGCTGCCGG-3' (FRAG. N0:2267) (SEQ. ID N0:2278) S 5'-GCGCCGCTTGGCCTTGTCGCGGC-3' (FRAG. N0:2268) (SEQ. ID N0:2279) 5'-GCTGCTCCBCGCGCTGG-3' (FRAG. N0:2269) (SEQ. ID N0:2280) 5'-GCCGGBGGCCGGCCBGGTCCCGCG-3' (FRAG. N0:2270) (SEQ. ID N0:2281) 5'-CCCGGCGGCCGGCBGGBBGGGCGGGCTGGGC-3' (FRAG. N0:2271) (SEQ. ID N0:2282) 5'-GTCTCTCCCGCCCCGGCCGCGCG-3' (FRAG. N0:2272) (SEQ. ID N0:2283) I O 5'-GGGCGTCCGCTCCGGGCCGTCGGG-3' (FRAG. N0:2273) (SEQ. ID N0:2Z84) 5'-GCGGGCACGCGGCGGCTCTGGCGTCGGC-3' (FRAG. N0:2274) (SEQ. ID N0:2285) Where B is adenosine, or, more preferbly, replaces adenosine and is a universal base, and adenosine A2a receptor agonist, an adenosine A2b receptor antagonist, an adenosine A3 receptor antagonist, or an adenosine A1 receptor antagonist 1 S Brad~rkinin Receytor Anti-sense Oligonucleotide Fragments 5'-GGTGBCBTTG BGCBTGTCGG CGCGGTCCCG TTBBGBGTGG GCCCGCCAGC CCAGCCACTC
CACTTGGGGG CGGGTGGCCA
GCACGAACAG CACCCAGAGG AAGGGGGGCG GCCCAGAAGG GCAGCCCGCA GGCCAGGATC AGGTCTGCTG
CGGCCGGAGA
TAATGGCATT CACCACGCGG CGGCCCAGCG CACGCCGCGC ATCCGGCCCG GGTTCTGACC TGCAGCCCCC
GTCTCCTTGG
CATTCCTGGG CCCCAGTCAC TCCTCTCCCT GCCCCCCTTG CTGGGGCAGG GACGGGGTG BCBTTGBGCB
TGTCGGCGCG

GAACAGCACC CAGAGGAAGG
GGGGCGGCCC AGAAGGGCAG CCCGCAGGCC AGGATCAGGT CTGCTGCGGC CGGAGATAAT GGCATTCACC
ACGCGGCGGC
CCAGCGCACG CCGCGCATCC GGCCCGGGTT CTGACCTGCA GCCCCCGTCT CCTTGGCATT CCTGGGCCCC
AGTCACTCCT
CTCCCTGCCC CCCTTGCTGG GGCAGGGACG GCCGTGTTGT CBGTGGTGCT GCCCGTTTGB GGTBTGGCGC
TCCBCCBBTT
CCCTTTTCTC CTTGTTTTCC GTTTCTCTTG CCGTCTGTGG TT-3' (FRAG. N0:2275) (SEQ. ID
N0:2286) 2S 5'-GGTGBCBTTGBGCBTGTCGGCGC-3' (FRAG. N0:2276) (SEQ. ID N0:2287) 5'-GGTCCCGTTBBGBGTGGGCCC-3' (FRAG. N0:2277) (SEQ. ID N0:2288) 5'-GCCAGCCCAGCCACTCCACTTGGGGGC-3' (FRAG. N0:2278) (SEQ. ID N0:2289) 5'-GGGTGGCCAGCACGAACAGCACCCAGAGGAAGGGGGGC-3' (FRAG. N0:2279) (SEQ. ID N0:2290) 5'-GGCCCAGAAGGGCAGCCCGCAGGCCAGGATCAGGTCTGCTGCGGCC-3' (FRAG. N0:2280) (SEQ. ID
N0:2291) 3O 5'-GGAGATAATGGCATTCACCACGCGGC-3' (FRAG. N0:2281) (SEQ. ID N0:2292) 5'-GGCCCAGCGCACGCCGCGCATCCGGCCC-3' (FRAG. N0:2282) (SEQ. ID N0:2293) 5'-GGGTTCTGACCTGCAGCCCCC-3' (FRAG. N0:2283) (SEQ. ID N0:2294) 5'-GTCTCCTTGGCATTCCTGGGCCC-3' (FRAG. N0:2284) (SEQ. ID N0:2295) 5'-CAGTCACTCCTCTCCCTGCCCCC-3' (FRAG. N0:2285) (SEQ. ID N0:2296) 3 S 5'-C1TGCTGGGGCAGGGACGG-3' (FRAG. N0:2286) (SEQ. ID N0:2297) 5'-GGTGBCBTTGBGCBTGTCGGCGC-3' (FRAG. N0:2287) (SEQ. ID N0:2298) 5'-GGTCCCGTTBBGBGTGGGCCC-3' (FRAG. N0:2288) (SEQ. ID N0:2299) 5'-GCCAGCCCAGCCACTCCACTTGGGGGC-3' (FRAG. N0:2289) (SEQ. ID NO:Z300) 5'-GGGTGGCCAGCACGAACAGCACCCAGAGGAAGGG('~GGC-3' (FRAG. N0:2290) (SEQ. ID
N0:2301) 4O 5'-GGCCCAGAAGGGCAGCCCGCAGGCCAGGATCAGGTCTGCTGCGGCC-3' (FRAG. N0:2291) (SEQ.
ID N0:2302) 5'-GGAGATAATGGCATTCACCACGCGGC-3' (FRAG. N0:2292) (SEQ. ID N0:2303) 5'-GGCCCAGCGCACGCCGCGCATCCGGCCC-3' (FRAG. N0:2293) (SEQ. ID N0:2304) S'-GGGTTCTGACCTGCAGCCCCC-3' (FRAG. N0:2I94) (SEQ.1D N0:2305) 5'-GTCTCCTTGGCATTCCTGGGCCC-3' (FRAG. N0:2295) (SEQ. ID N0:2306) 4S 5'-CAGTCACTCCTCTCCCTGCCCCC-3' (FRAG. N0:2296) (SEQ. ID N0:2307) 5'-CTTGCTGGGGCAGGGACGG-3' (FRAG. N0:2297) (SEQ. ID N0:2308) 5'-CCGTGTTGTCBGTGGTGCTG-3' (FRAG. N0:2298) (SEQ. ID N0:2309) 5'-CCCGTTTGBGGTBTGGC-3' (FRAG. N0:2299) (SEQ. ID N0:2310) 5'-GCTCCBCCBBTTCCCTTTTCTCC-3' (FRAG. N0:2300) (SEQ. ED N0:2311) SO 5'-TTGTTTTCCGTTTCTCTTG-3' (FRAG. N0:2301) (SEQ. ID N0:2312) 5'-CCGTCTGTGGTT-3' (FRAG. N0:2302) (SEQ. ID N0:2313) In one preferred embodiment, the links between neighboring mononucleotides are phosphodiester links. In another preferred, at least one mononucleotide phosphodiester residue of the anti-sense oligonucleotide(s) is substituted by a methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, S sulfide, ~hydroxylamine, 2'-O-methyl, methylene(methyimino), methyleneoxy (methylimino), phosphoramidate residues, and combinations thereof. The MTA oligos having one or more phosphodiester residues substituted by one or more of the other residues are generally longer lasting, given that these residues are more resistant to hydrolysis than the phosphodiester residue. In some cases up to about 10% , about 30%, about 50% , about 75 % , and even all phosphodiester residues may be substituted (100%).
Typically, the multiple target anti-sense oligonucleotide (MTA oligo) of the invention comprises at least about 7 mononucleotides, in some instances up to 60 and more mononucleotides, preferably about 10 to about 36, and more preferably about 12 to about 21 mononucleotides. However, other lengths are also suitable depending on the length of the 1 S target macromolecule. Examples of the MTA oligos of the invention are provided in Table 3 below, which includes ninety-four sequences (SEQ ID NOS.: 2317 through 2411).
Table 3: MTA Oligos, Location Targeted & Target MTA SEQ . ID
Oligo Location Compound Target No. Targeted CCC GGC CCCGCCTCG TGCC 2317 5' EPI2192 =

CGT CCB TGCCGCGGG CCC 2318 5' =
28(AUG)EPI

TGC G 2319 5' EPI2199 CGG =

TCT GTG CTCCTCTCG CCTGGG 2320 5' EPI2195 -TGG TGG GGTGGGTCT TGGTGG 2321 5'=159 EPI2196 CTG TCC CTGGTCCTG TG 2322 5'=196 EPI2197 GGT CCC GCTTCTTC 2323 5'=362 EPI2198 GGG GTT GTTGTTGGT CTGG 2329 5'=901 EPI2199 TGT CCT CTTTCTGC 2325 5'=656 EPI2200 Table 3: MTA OGgos, Location Targeted & Target (Cont'd) MTA SEQ ID Location Oligo Compound Target No. Targeted GCC TCG GGCCTCCC 2326 5'=697 EPI 2201 GGC TGG~GGTCTGCGT 2327 5'=769 EPI 2202 GGC CGG GGGTCGGTG GGT

CCG 2328 5'=953 EPI 2203 CTG

1~ GGG CTG GGGTGCTGG CTT G 295'=1022 EPI2209 GGG GCT GGGGCCTGG GCC 23 305'=1208 EPI2205 GCC TGG GTGGGCTTG GGG 23 315'=1272 EPI2206 GC

GCT GGG TCTGTGCTG TTG 2 325'=1362 EPI220?
CC

GTT GTG TGGGGGGCC 2 5'= 1951 EPI2208 IS GCT GGG TCGGGGGGC CTC
TGG

GCT 2339 5'=1511 EPI 2209 GTC

GCC CCG GGGCCCCC 2335 5'=1550 EPI 2210 TGG CTC CCCCCTCC 2336 5'=1772 EPI 2211 GCT CCC CCCTTTCC 2337 5'=1863 EPI 2212 CGG ACG AAGACAGAG A 2338 5'=1979 EPI 2213 GGC TTT GTGGGCTC 2339 5'=2011 EPI 2219 GCC TGC TCTCCCCC 2340 5'=2312 EPI 2215 CCC GGC CCCGCCBCG BBC 2341 intron EPI 2192-OlA HSU50136 C

Synthase 25 CCC GGC CCCGCCBCG 2392 intron EPI 2192-O1B

CCC GGC CCCGCCBCG BBC 2343 5'untr EPI 2192-02A HUMLIPOX

CCC GGC CCCGCCBCG 2344 5'untr EPI 2192-02B

CCC GHC CCCGCCTCB BG 2345 trans EPI 2192-03A HSNFKBS

subunit CCC GBC CCCGCCTC 2346 trans EPI 2192-03B

CCG GCC CCGCCTC 2347 5'untr EPI 2192-04 TGF(~

CCC GBB CCCGCBTBG TGC 2348 5'trans EPI 2192-05A HSU58198 enhan CCC GCB TBGTGCC 2399 5'untr EPI 2192-058 35 CCC GGB CCCBCCBBG TGC 2350 3'trans EPI 2192-06 HSVECAD
C

CBG BBC CCGCCTCGT GCC 2351 intron EPI 2192-07A NFK B2 C 2352 intron EPI 2192-07B NFK B2 CCG
CCT
CGT
GCC

CCG GCB CCGCCTCBT GCC 2353 5'trans EPI 2192-OS Car boxypep CCG GCC CCGCCBCBT GCC 2354 3'trans EPI 2192-09 HUMADRAZC

40 a2adr kidney CCC GBC CCCGBCTCG 2355 5'untrs EPI 2192-10 HUMFK506B

CCC GGC CBCGBCTCG 2356 5'untrs EPI 2192-11 HSNBARKS1 Radr kinase CC CCBGCCTHG 2357 5'UTR EPI 2192-12 r riSNFXNl 45 (NFKB1) CCC GGC BCBGBCTCG TBC 2358 3'UTR EPI 2192-13 HSILF
C

(transcrp.

Factor ILF) $~ MynA/5-LO /TGF
T recl CC Syn MTA

TCC BTG CCGCGGGC 2361 3' trans EPI-2193-O1 MET
Oncogene SS TCC BTG CCBCGGGCC 2362 3' trans EPI-2 193-02 HSFGR2(IG) TCC BTG CCBCGGGCC 2363 mid cod EPI-2 193-03 5-LO

TCC BTG CCBCBGGCC 2364 mid cod EPI-2 193-09 HUMTK19 GTC CBT GBCGCGG 2365 3'trans EPI-2 193-05 HUMTNFR

CBT
GBC
GCG
GG

ProbI.HUMPTCH

cardiac K+channel TCT GBG CTCCTCTHB CCT 2367 intr EPI -2195-O1 HUMCSPA
GGG

cytotox.

ser.
protease CTG TGC BCCTBBCBC CTG 2368 intr EPI -2195-02 HSINOSX08 GG

inducible NOS

G

musc.
70 m2 acetylch.

rec.
TCT GTB CTCBBCTCB CCT 2370 EPI -2195-04 s86371s1 G

Neurokinin 7$ TGC TCC TCBCBBCTG GG 2371 EPI -2195-OS H~P1A
macro Table 3: MTA Oligos, Location Targeted & Target (Cont'd) MTA SEQ . ID
Oligo Location Compound Target No. T argeted inflam.

factor a-adr rec kinase GTG CBCCHBTCB CCTGGG 2374 EPI-2195-08 humfkbp bindi ng ~
rotein TCT GTGCBCCTC TBGBCT 2375 exon EPI-2195-09 ~
tiSNBARK$1 (3-adr.

receptor H

CTG TBBTCCT88 CHCCTG 2376 intron EPI-2195-10 UMIL8 G

G

E

GTG CBCCBCTCB CCTG 2378 intron/exon IL

2S CTG TGCBCCTCT C 2379 3'UTR EPI-2203-05 IL-6 R

CBG TGCBCCBCT CBCCTG 2380 intr/ex EPI-2203-06A HSIL2rG6 G 2381 intr/ex EPI-2203-06B HSIL2rG6 TGC

BCT
CBC
CTG

CBC CTCTCBCCT GGG 2382 coding EPI-2203-07A HUMIL71 C 2383 coding EPI-2203-07B IL-7 HUMIL71 CTC
TCB
CCT
GGG

GCT CCBCTCGCC T 2384 coding EPI-2203-08 IL-6 R

TGC TCCTCBCGC C 2385 intron 9 PDGF
A

chain HUMPDGFAB

GTT GTTGBTCTG G 2386 3'utr EPI-2199-Ol GATA-4 transcrip. Factor for GGT TGBBBTTGG TCTTGG 2387 Coding EPI-2199-02 TNFa HUMT~1FA

GGT TGTTG8TGB TCTG 2388 Far HSSUBP1G
5'UTR

(Sub P r?

GGG TTBBBGTTG BTCTGG 2389 Coding EPI-2199-04 Neutrophil adh.

4S ~~IA

GGG TTBBBGTTG BTCTGG 2390 HSHM2 EPI-2199-05 m2 muscarinic R

TTG TTGTBG8TC TGG 2391 HUML1CAM EPI-2199-06 L1 leuk.

adh.

SO prot.

GGG TBG BBGBGTCCG CTG 2392 coding EPI-2203-O1 HUMGATA2A

GGG TCB GBGGBTCBG CTG 2393 S7142452 EPI-2203-02 IGE eps GGG TBG GTGGGTC 2394 coding EPI-2203-03 HSGCSFR2 GGG TCG GBGGGTCBG C 2395 HUMITGF EPI-2203-04 TGF(33 & T

Cell Activating Protein f)0 Pr~ta 1.
g EP3 Receptor Table 3: MTA Oligos, Location Targeted& Target (Cont'd) MTA Oligo SEQ ID Location Compound Target No. T argeted NFKB/

Granulocyte CSF/Transcr.

l~ Factor NF2B

Leuk.Adhes.

Prot.

15 Endotheline Lymph. Ser Thr Prot. Kinase HSGCSFRl Rec.

/NK7TCELLACT.

Prot.

/HSTGFBl TGFB

N
~~1 3~ CTGGGTGGGBBTGGG 2405 EPI 2206-11FKBAS13/

Lym~h.Act.

Antig (Coding) 40 ~
as V
c.
Endoth.

Cell Adh. Molec.

4C D. VilIVCIJiIl DillC
The MTA oligos of Table 3 are suitable for use with two or more of the targets listed in Table 4 below.

Table 4: Targets for the MTA Oligos of Table 3 Com ound Ta et EPI 2010 Adenosine At teceeptor --EPI 2045 ., Adenosine A3 rece r S EPI 2873, EPI 2193 NFxB

EPI 1873 Interleulun-1 EPI 1857 ~ Interleultin -5 EPI 2945 Interleulatt -4 EPI 2977 Interleukin -8 1 EPI 2031 5-Li x erase ~

EPI 1898 Leukotriette C-4 S

EPI 1856 Eotaxin 1 EPI 2085 TNFa S

EPI1925 IL-4 r EPI 2643 2 aderener is race for ltinase EPI2934 T se EPI 2033 Ma'or Basic Protein EPI 2795 Eosino hil Peroxidase NfxH: nuclear factor xt3 ICAM: intracellular adhesion molecule VCAM: vascular cell adhesion molecule ZS TNF: tumor necrosis factor PAF: platelet activating factor In a most preferred embodiment for use in the lung, the MTA oligo of this invention comprises a desadenosine oligonucleotide, whether an anti-sense to a naturally occurring 30 desthymidine sequence, or by substitution with one or more universal bases in accordance with the invention. The methods for substituting nucleotide, as well as for synthesizing oligonucleotides of a specific sequence, and which bases to employ as universal bases are known in the art, and need not be further provided here, since they are within the knowledge of an artisan.
3S In a further embodiment of the agent of the invention, the MTA oligo is operatively linked to III agent or molecule which, itself, is internalized or up-taken by living cells. In this manner, the uptake of the agent of the invention is enhanced as is known in the art. Examples of agents or molecules suitable for use with the MTA oligos of this invention are transferrin, asialoglycoprotein, and streptavidin. Others, however, are also suitable.
40 The present agents are also provided as a pharmaceutical composition comprising an anti-sense oligonucleotide as given above in an amount effective to reduce expression of a target mRNA, by passing through a cell membrane and binding specifically with target mRNA
in the cell so as to prevent its translation are another aspect of the present invention. Such compositions are provided in a suitable pharmaceutically acceptable carrier, e.g. sterile 45 pyrogen-free saline solution. The agent of the invention may be formulated with a hydrophobic carrier capable of passing through a cell membrane, e.g. in a liposome, with the liposomes carried in a pharmaceutically acceptable aqueous carrier. The oligonucleotides may be coupled to an agent which inactivates mRNA, such as a ribozyme. Such oligonucleotides may be administered to a subject in need of such treatment to inhibit the activation of specific receptors, enzymes and/or proteins andlor factors, among other expression products. The pharmaceutical formulation may also comprise chimeric molecules comprising anti-sense oligonucleotides attached to molecules which are known to be internalized by cells. These oligonucleotide conjugates utilize cellular up-take pathways to increase intracellular concentrations of the oligonucleotide. Examples of molecules used in this manner are macromolecules including transferrin, asialoglycoprotein (bound to oligonucleotides via polylysine) and streptavidin, among others.
The anti-sense compound may be contained in the pharmaceutical formulation within a lipid particle or vesicle, such as a liposome or microcrystal. The particles may be of any suitable structure, such as unilamellar or plurilamellar. The one preferred embodiment, the anti-sense oligonucleotide is comprised within the liposome. Positively charged lipids such as N-[1-(2, 3 -dioleoyloxi) propyl] -N, N, N-trimethylammoniumethylsulfate, or "DOTAP," are particularly preferred for such particles and vesicles. However, others are also suitable. The preparation of such lipid particles is well known. See, e.g., US Patent Nos.
4,880,635 to Janoff et al., 4,906,477 to Kurono et al., 4,911,928 to Wallach, 4,917,951 to Wallach, 4,920,016 to Allen et al., 4,921,757 to Wheatley et al., the relevant sections of all of which are herein incorporated in their entireties by reference.
The composition of the invention may be administered by any means which transports the agent to the lungs. The present agents may be administered to the lungs of a patient by any suitable means, but are preferably administered through the respiratory system as a respirable formulation, more preferably in the form of an aerosol comprising respirable particles which, in turn, comprise the agent for respiration or inhalation by the subject. The respirable particles may be in gaseous, liquid or solid form, and they may, optionally, contain other therapeutic ingredients and formulation components.
The particles of the present invention are preferably particles of respirable size, preferably of a size sufficiently small to pass, upon inhalation, through the mouth and larynx and into the bronchi and alveoli of the lungs. In general, particles ranging from about 0.5 to 10 microns in diameter are respirable. However, other sizes may also be suitable. Particles of non-respirable size, of considerably larger diameter, which are included in the respirabie formulation tend to deposit in the throat and may be swallowed. Accordingly, it is desirable to minimize the quantity of non-respirable particles in the aerosol. For nasal administration, a particle size in the range of 10-500 ~,m is preferred to ensure their retention in the nasal cavity.

Liquid pharmaceutical compositions of the agent of the invention for producing a respirable formulation, e.g. an aerosol may be prepared by combining the anti-sense oligo with a suitable vehicle or carrier, such as sterile pyrogen-free water and/or other known pharmaceutically or veterinarily acceptable carrier. Other therapeutic compounds may be included as well as other formulation ingredients as is known in the art.
Solid particulate compositions comprising respirable dry particles of, e.g.
the micronized agent of the invention may be prepared by grinding the dry anti-sense compound with a mortar and pestle, and then passing the thus ground, e.g. micronized composition through a screen, e.g. 400 mesh screen, to break up or separate large agglomerates of particles. A solid particulate composition comprising the anti-sense compound may optionally also comprise a dispersant and other known agents, which serve to facilitate the formation of a mist or aerosol. A suitable dispersant is lactose, which may be blended with the anti-sense compound in any suitable ratio, about 1:1 w/w. Other ratios may be utilized as well, and other therapeutic and formulation agents may also be included.
Aerosols of liquid particles comprising the agent may be produced by any suitable means, such as with an insufflator or nebulizer. See, e.g., US Patent No.
4,501,729.
Nebulizers are commercially available devices which transform solutions or suspensions of an agent into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air or oxygen, e.g. through a narrow venturi orifice or by means of ultrasonic agitation. Suitable formulations for use in insufflators and nebulizers comprise the present agent, the agent of this invention, in an amount of about 0.01 to about 40 % , preferably less than 20 % w/w in a liquid carrier which is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Other carriers are also suitable. Optional additives include preservatives if the formulation is not prepared sterile, for example, methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils, buffering agents and surfactants, among others.
The pharmaceutical compositions provided herein comprise nucleic acids) comprising the anti-sense oligonucleotide(s) described above and one or more surfactants.
Suitable surfactants or surfactant components for enhancing the uptake of the anti-sense oligonucleotides of the invention include synthetic and natural as well as full and truncated forms of surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D
and surfactant Protein E, di-saturated phosphatidylcholine (other than dipalmitoyl), dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine;
phosphatidic acid, ubiquinones, lysophosphatidylethanolamine, lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, dehydroepiandrosterone, dolichols, sulfatidic acid, glycerol-3-phosphate, dihydroxyacetone phosphate, glycerol, glycero-3-phosphocholine, dihydroxyacetone, palmitate, cytidine diphosphate (CDP) diacylglycerol, CDP
choline, choline, choiine phosphate; as well as natural and artificial lamelar bodies which are the natural carrier vehicles for the components of surfactant, omega-3 fatty acids, polyenic acid, polyenoic acid, lecithin, palmitinic acid, non-ionic block copolymers of ethylene or propylene oxides, polyoxypropylene, monomeric and polymeric, polyoxyethylene, monomeric and polymeric, poly (vinyl amine) with dextran and/or alkanoyl side chains, Brij 35, Triton X-100 and synthetic surfactants ALEC, Exosurf, Survan and Atovaquone, among others.
These surfactants may be useed either as single or part of a multiple component surfactant in a formulation, or as covalently bound additions to the 5' and/or 3' ends of the anti-sense oligonucleotides (oligos).
The composition of the invention may be administered by any means which transports the anti-sense nucleotide and the surfactant composition to the lung. The anti-sense compounds disclosed herein may be administered to the lungs of a patient by any suitable means, but are preferably administered by inhalation of an aerosol comprised of respirable particles which comprise the anti-sense compound. The respirable particles may be liquid or solid, and they may optionally contain other therapeutic or diagnostic ingredients as well as other typical ingredients for a particular formulation. Examples of other agents are analgesics such as acetaminophen, anilerdine, aspirin, buprenorphine, butabital, butorpphanol, Choline Salicylate, Codeine, Dezocine, Diclofenac, Diflunisal, Dihydrocodeine, Elcatoninin, Etodolac, Fenoprofen, Hydrocodone, Hydromorphone, Ibuprofen, Ketoprofen, Ketorolac, Levorphanol, Magnesium Salicylate, Meclofenamate, Mefenamic Acid, Meperidine, Methadone, Methotrimeprazine, Morphine, Nalbuphine, Naproxen, Opium, Oxycodone, Oxymorphone, Pentazocine, Phenobarbital, Propoxyphene, Salsalate, Sodium Salicylate, Tramadol and Narcotic analgesics in addition to those listed above. See, Mosby's Physician's GenRx. Anti-anxiety agents are also useful including Alprazolam, Bromazepam, Buspirone, Chlordiazepoxide, Chlormezanone, Clorazepate, Diazepam, Halazepam, Hydroxyzine, Ketaszolam, Lorazepam, Meprobamate, Oxazepam and Prazepam, among others. Anti-anxiety agents associated with mental depression, such as Chlordiazepoxide, Amitriptyline, Loxapine Maprotiline and Perphenazine, among others. Anti-inflammatory agents such as non rheumatic Aspirin, Choline Salicylate, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Floctafenine, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Magnesium Salicylate, Meclofenamate, Mefenamic Acid, Nabumetone, Naproxen, Oxaprozin, Phenylbutazone, Piroxicam, Salsalate, Sodium Salicylate, Sulindac, Tenoxicam, Tiaprofenic Acid, Tolmetin, anti-inflammatories for ocular treatment such as Diclofenac, Flurbiprofen, Indomethacin, Ketorolac, Rimexolone (generally for post-operative treatment), anti-inflammatories for, non-infectious nasal applications such as Beclomethaxone, Budesonide, Dexamethasone, Flunisolide, Triamcinolone, and the like. Soporifics (anti-insomnia/sleep inducing agents) such as those utilized for treatment of insomnia, including Alprazolam, Bromazepam, Diazepam, Diphenhydramine, Doxylamine, Estazolam, Flurazepam, Halazepam, Ketazolam, Lorazepam, Nitrazepam, Prazepam Quazepam, Temazepam, Triazolam, Zolpidem and Sopiclone, among others. Sedatives including Diphenhydramine, Hydroxyzine, Methotrimeprazine, Promethazine, Propofol, Melatonin, Trimeprazine, and the like. Sedatives and agents used for treatment of petit mal and tremors, among other conditions, such as Amitriptyline HCI;
Chlordiazepoxide, Amobarbital; Secobarbital, Aprobarbital, Butabarbital, Ethchiorvynol, Glutethimide, L-Tryptophan, Mephobarbital, MethoHexital Na, Midazolam Hcl, Oxazepam, Pentobarbital Na, Phenobarbital, Secobarbital Na, Thiamylal Na, and many others. Agents used in the treatment of head trauma (Brain Injury/Ischemia), such as Enadoline HCl (e.g. for treatment of severe head injury; orphan status, Warner Lambert), cytoprotective agents, and agents for the treatment of menopause, menopausal symptoms (treatment), e.g.
Ergotamine, Belladonna Alkaloids and Phenobarbital, for the treatment of menopausal vasomotor symptoms, e.g. Clonidine, Conjugated Estrogens and Medroxyprogesterone, Estradiol, Estradiol Cypionate, Estradiol Valerate, Estrogens, conjugated Estrogens, esterified Estrone, Estropipate, and Ethinyl Estradiol. Examples of agents for treatment of pre menstrual syndrome (PMS) axe Progesterone, Progestin, Gonadotrophic Releasing Hormone, Oral contraceptives, Danazol, Luprolide Acetate, Vitamin B6. Examples of agents for treatment of emotional/psychiatric treatments such as Tricyclic Antidepressants, including Amitriptyline HCI (Elavil), Amitriptyline HCI, Perphenazine (Triavil) and Doxepin HCl (Sinequan). Examples of tranquilizers, anti-depressants and anti-anxiety agents are Diazepam (Valium), Lorazepam (Ativan), Alprazolam (Xanax), SSRI's (selective Ssrotonin reuptake inhibitors), Fluoxetine HCl (Prozac), Sertaline HCl (Zoloft), Paroxetine HCl (Paxil), Fluvoxamine Maleate (Luvox), Venlafaxine HCl (Effexor), Serotonin, Serotonin Agonists (Fenfluramine), and other over the counter (OTC) medications.
The composition of the present invention may be administered into the respiratory system as a formulation including particles of respirable size, e.g. particles of a size sufficiently small to pass through the nose, mouth and larynx upon inhalation and through the bronchi and alveoli of the lungs. In general, respirable particles range from about 0.5 to 10 microns in size. Particles of non-respirable size which are included in the aerosol tend to deposit in the throat and be swallowed, and the quantity of non-respirable particles in the aerosol is thus minimized. For nasal administration, a particle size in the range of 10-500 ~,m is preferred to ensure retention in the nasal cavity.

Aerosols or mists of solid particles comprising the agent of the invention may likewise be produced with any device that generates solid particulate medicament aerosols or mists.
Aerosol and mist generators are suitable for administering solid particulate medicaments.
These devices produce respirable particles, as explained above., and generate a volume of aerosol or mist containing a predetermined metered dose of a medicament at a rate suitable for human or animal administration. One illustrative type of solid particulate aerosol generator is an insufflator. Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff. In the insufflator, the powder, e.g. a metered dose of the agent effective to carry out the treatments described herein, is contained in a capsule or a cartridge.
These capsules or cartridges are typically made of gelatin or plastic, and may be pierced or opened in situ, and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator may consist either solely of the agent or of a powder blend comprising the agent, a suitable powder diluent, such as lactose, and an optional surfactant as well as other agents. The agent typically comprises from 0.01 to 100 w/w of the formulation. A second type of illustrative aerosol generator comprises a metered dose inhaler. Metered dose inhalers are pressurized aerosol dispensers, typically comprising a suspension or solution formulation of the active ingredient in a liquified propellant. During use these devices discharge the formulation through a valve adapted to deliver a metered volume, typically about 10 to 150 ~.1, although other volumes are also suitable, to produce a fine particle spray containing the active ingredient. Suitable propellants include solvents such as certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and/or mixtures thereof. The formulation may additionally comprise one or more co-solvents, for example, ethanol, surfactants, such as oleic acid or sorbitan trioleate, antioxidants and suitable flavoring agents. The aerosol, whether formed from solid or liquid particles, may be produced by the aerosol generator at a rate of from about 10 to 150 liters per minute, more preferably from about 30 to 150 liters per minute, and most preferably about 60 liters per minute. Aerosols containing greater amounts of medicament may be administered more rapidly.
As already indicated, the agent of this invention is also provided as a composition, comprising the agent of the invention, and a carrier. The carrier is preferably a biologically acceptable carrier, and more preferably a pharmaceutically or veterinarily acceptable carrier in the form of a gaseous, liquid, solid carriers, and mixtures thereof, which are suitable for the different routes of administration intended. The composition may optionally comprise other 3 5 agents such as other therapeutic compounds known in the art for the treatment of the condition or disease, antioxidants, flavoring and coloring agents, fillers, volatile oils, buffering agents, dispersants, surfactants, RNA inactivating agents, antioxidants, flavoring agents, propellants and preservatives, as well as other agents known to be utilized in therapeutic compositions. An example of the mRNA inactivating agent is an enzyme, such, as ribozyme.
The composition generally contains the anti-sense oligonucleotide in an amount of about 0.01 to about 99.99 w/w, preferably about 1 to about 40 w/w, and more preferably about 5 to about 20 w/w of the composition. However, other ingredients, and other amounts of the agent are also suitable within the confines of this invention.
The agent of the invention is also provided in various formulations which are tailored for different methods of administration and routes of delivery. The formulations that are contemplated are, for example, a transdermal formulation also containing carriers) and other agents suitable for delivery through the skin, mouth, nose, vagina, anus, eyes, ears, other body cavities, intradermally, as a sustained release formulation, intracranial, intrathecally, intravascularly, by inhalation, intrapulmonarily, into an organ, by implantation, including suppositories, cremes, gels, and the like, as is known in the art. In one particular formulation, the agent is suspended or dissolved in a solvent. In another the carrier comprises a hydrophobic carrier, such as lipid particles or vesicles, including liposomes and micro crystals. The preparation of all of these formulations, as well as the ingredients to be utilized are known in the art, and need not be further described here. In one particularly preferred embodiment of the vesicle formulation, the vesicles comprise liposomes containing the anti-sense oligonucleotide. The lipid vesicles may comprise N-(1-[ 2, 3-dioleoxyloxi]
propyl) -N,N,N-trimethyl- ammonium methylsulfate as well as other lipids known in the art to provide suitable delivery of DNA to target cells. In one embodiment, the formulation comprises a respirable formulation, such as an aerosol. The agent, composition, and formulation of the invention are provided in bulk, and in unit form, as well as in the form of an implant, a solution or suspension, a capsule or cartridge, which may be operable or piercable as is known in the art.
A kit is also provided, which comprises a delivery device, and in separate containers, the agent, composition or formulation of the invention, and optionally other agents, and instructions for the use of the kit components. In one preferred embodiment, the delivery device comprises a nebulizer which delivers single or multiple metered doses of the formulation. The single metered dose nebulizer may be provided as a disposable kit which is sterilely preloaded with enough agent for one application. The nebulizer may be provided as an insufflator, and the composition in a piercable or operable capsule or cartridge. In a different embodiment, the delivery device comprises a pressurized inhaler, and the agent is in the form of a suspension or solution. The kit may optionally also comprise in a separate container an agent selected from the group consisting of other therapeutic compounds, antioxidants, flavoring and coloring agents, fillers, volatile oils, buffering agents, dispersants, surfactants, cell internalized or up taken agents, RNA inactivating agents, antioxidants, flavoring agents, propellants and preservatives, among other suitable additives for the different formulations. When a solvent for the agent or the other ingredients is added, organic solvents and organic solvents mixed with one or more co-solvents may be utilized as well as aqueous solvents as is known in the art.
The agent of the invention may be provided in conjunction with a vector for delivery purposes, or for manufacturing copies thereof. The agent may be operatively linked to the vector as is known in the art. The agent may also be provided within a host cell for amplification of the MTA oligo, and for storage purposes.
The agent of this invention may be utilized by itself or in the form of a composition or various formulations in the treatment of a disease or condition associated with the mRNA
corresponding to at least one target gene(s), to genomic flanking regions, initiation codon, intron-exon borders and the like, or the entire sequence of precursor RNAs, including non-coding RNA segments, the 5'-end and the 3'-end, e.g. poly-A segment and oligos targeted to the juxta-section between coding and non-coding regions, and RNA regions encoding proteins, by administration to a subject afflicted with the disease or condition of an amount of the anti-sense oligonucleotide effective to reduce the production or availability, or to increase the degradation by the subject of at least one of the target mRNAs. Typically, the agent is administered in an amount effective to reduce the production or availability, or to increase the degradation of at least two of the target mRNAs. Optionally, the agent is administered directly to the lung (s) of the subject, preferably as a respirable aerosol. Although an artisan will know how to titrate the amount of agent to be administered by the weight of the subjected being treated in accordance with the teachings of this patent, the agent is preferably administered in an amount effective to attain an intracellular concentration of about 0.05 to about 10 ~M
multiple targeted anti-sense oligonucleotide, preferably in an amount effective to attain an intracellular concentration of up to about 5 ~,M multiple targeted anti-sense oligonucleotide.
The treatment provided in this patent is suitable for treating numerous diseases and conditions, and its application is solely limited by the availability of target molecules and their sequences. One type of disease or condition for which this technology is particularly well suited are lung diseases or conditions. For this type of application, at least one of the target mRNA encodes a protein such as the adenosine A, receptor, adenosine AZB
receptor, adenosine A3 receptor, and bradykinin B2 receptor. However, other targets are also suitable. In one application, the disease or condition is associated with obstruction of the subject's airways, in another specifically with asthma, etc. One of the preferred target proteins comprises the NfxB
transcription factor, although others which were described above are also suitable. In another preferred application, the disease or condition is associated with inflammation. For this type of application at least one of the target mRNA preferably encodes a protein selected from the group consisting of interleukins, chemokines, Rantes and receptors thereof.
Still another application is for treating a disease or condition associated with an allergy.
For this application, the mRNA preferably encodes a target selected from the group consisting of an antibody and an antiboiiy receptor. For the application of this technology to a disease or condition associated with a malignancy or cancer, the mRNA preferably encodes a target selected from the group consisting of oncogenes, an imrnunoglobulin and an antibody receptor.
Depending on the target organ or tissue, the agent of the invention may be delivered in one of many ways, for example, by a transdermal or systemic route, and more specifically orally, intracavitarily, intranasally, intraanally, intravaginally, transdermally, intrabucally, intravenously, subcutaneously, intramuscularly, intratumorously, into a gland, by implantation, intradermally, and many other routes of administration. The formulation may be, in addition, an implant, slow release, transdermal release, sustained release, and coated with one or more macromolecules to avoid destruction of the agent prior to reaching the selected target. The subject that may be treated by the present agent are varied, and include humans and other animals in general, and in particular vertebrates, and amongst these man;imals, and more specifically humans; and small and large, wild and domesticated, marine and farm animals, and preferably humans and domesticated and farm animals. In one aspect of the invention, at least one of the target mRNAs and the subject are of the same species, and in a preferred case they are of human origin. However, since in one embodiment mismatched nucleotides are replaced, mismatched species may also be utilized.
The multiple targeted anti-sense oligonucleotide of this invention may be administered in a broad dose range. Preferable is an amount of about 0.005 to about 150 mg/kg body weight per administration, and the agent may be administered from once in an acute treatment to several doses per day, to a continuous administration to maintain the level of a specific molecule. Preferred doses are about 0.01 to about 75 mg/kg body weight, more preferably about 1 to 50 mg/kg body weight. The method may be administered as a prophylactic or therapeutic method.
The agent of the invention may be produced by selecting two or more targets selected from the group consisting of genes, genomic flanking regions, mRNAs and proteins known to be associated with at least one disease or condition; obtaining RNAs selected from the group consisting of RNAs corresponding to the genes, to genomic flanking regions, initiation codon, intron-exon borders and the like, or the entire sequence of RNAs, including non-coding RNA
segments, the 5'-end and the 3'-end, e.g. the poly-A segment and oligos targeted to the juxta-3 5 section between coding and non-coding regions, and RNA segments encoding the target proteins; selecting a segment of a first RNA which is at least about 60 %
homologous to a segment of at least a segment of a second RNA; and synthesizing one or more anti-sense oligonucleotide(s) to the one or more RNA segments. In one preferred embodiment, the method further comprises substituting a universal base for at least one, and in some instances all , non-homologous nucleotide in the anti-sense oligonucleotide, and in another preferred embodiment the method further comprises substituting a methylated cytosine for cytosine in at least one CpG dinucleotide present in the anti-sense oligonucleodde. The technology involved in methylation is known in the art and need not be further described here.
Although the specific length of the MTA oligo is determined by the target's length, and its segments containing few thymidines, the anti-sense oligonucleotide(s) are preferably greater than about 7 nucleotides long, and up to about 60 nucleotides long, and longer. The specific backbone chemistry may by selected by an artisan based on the teachings provided here and the knowledge of the art at large. One factor that impinges on the selection of the nucleotide bridging residues is the level of nuclease resistance desired and other factors specific to one or the other method of administration. Another factor is the need for localization of the treatment, to minimize or fully avoid side effects which might otherwise be caused along with the therapeutic effect of the agent.
The following examples are provided to illustrate the present invention, and should not be construed as limiting thereon. In these examples, ~.M means micromolar, ml means milliliters, ~,M means micrometers, mm means millimeters, cm means centimeters, °C means degrees Celsius, ~.g means micrograms, mg means milligrams, g means grams, kg means kilograms, M means molar, and h means hours.
~~;am~de 1: Design and Synthesis of Anti-sense Oligonucleotides The design of anti-sense oligonucleotides against the A, and A3 adenosine receptors may require the solution of the complex secondary structure of the target A, receptor mRNA and the target A3 receptor mRNA. After generating this structure, anti-sense nucleotide are designed which target regions of mRNA which might be construed to confer functional activity or stability to the mRNA and which optimally may overlap the initiation codon.
Other target sites are readily usable. As a demonstration of specificity of the anti-sense effect, other oligonucleotides not totally complementary to the target mRNA, but containing identical nucleotide compositions on a w/w basis, are included as controls in anti-sense experiments.
The mRNA secondary structure of the adenosine A, receptor was analyzed and used as described above. to design a phosphorothioate anti-sense oligonucleotide.
The anti-sense oligonucleotide which was synthesized was designated HAdA,AS and had the following sequence:

5' -GAT GGA GGG CGG CAT GGC GGG-3' (SEQ ID NO:1) As a control, a mismatched phosphorothioate anti-sense nucleotide designated HAdAIMMI was synthesized with the following sequence:
5' -GTA GCA GGC GGG GAT GGG GGC-3' (SEQ ID N0:2) Each oligonucleotide had identical base content and general sequence structure.
Homology searches in GENBANK (release 85.0) and EMBL (release 40.0) indicated that the anti-sense oligonucleotide was specific for the human and rabbit adenosine A, receptor genes, and that the mismatched control was not a candidate for hybridization with any known gene sequence.
The secondary structure of the adenosine A3 receptor mRNA was similarly analyzed and used as described above to design two phosphorothioate anti-sense oligonucleotides. The first anti-sense oligonucleotide (HAdA3AS1) synthesized had the following sequence:
5' -GTT GTT GGG CAT CTT GCC-3' (SEQ ID N0:3) As a control, a mismatched phosphorothioate anti-sense oligonucleotide (HAdA3MM1) was synthesized, having the following sequence:
5' -GTA CTT GCG GAT CTA GGC-3' (SEQ ID N0:4) A second phosphorothioate anti-sense oligonucleotide (HAdA3AS2) was also designed and synthesized, having the following sequence:
5' -GTG GGC CTA GCT CTC GCC-3' (SEQ m NO:S) its control oligonucleotide (HAdA3MM2) had the sequence:
5' -GTC GGG GTA CCT GTC GGC-3' (SEQ ID N0:6) Phosphorothioate oligonucleotides were synthesized on an Applied Biosystems Model 396 Oligonucleotide Synthesizer, and purified using NENSORB chromatography (DuPont, MD).
pjg~: In Vivo Testing of Adenosine Al Receptor Anti-sense Oligos The anti-sense oligonucleotide against the human A, receptor (SEQ In N0:1) described above. was tested for efficacy in an in vitro model utilizing lung adenocarcinoma cells HTB-54. HTB-54 lung adenocarcinoma cells were demonstrated to express the At adenosine receptor using standard northern blotting procedures and receptor probes designed and synthesized in the laboratory.
HTB-54 human lung adenocarcinoma cells (106/100 mm tissue culture dish) were exposed to 5.0 ~,M HAdAIAS or HAdAIMMI for 24 hours, with a fresh change of media and oligonucleotides after 12 hours of incubation. Following 24 hour exposure to the oligonucleotides, cells were harvested and their RNA extracted by standard procedures. A 21-mer probe corresponding to the region of mRNA targeted by the anti-sense (and therefore having the same sequence as the anti-sense, but not phosphorothioated) was synthesized and used to probe northern blots of RNA prepared from HAdAIAS-treated, HAdAIMMl-treated and non-treated HTB-54 cells. These blots showed clearly that HAdAIAS but not HAdAIMMl effectively reduced human adenosine receptor mRNA by > 50 % . This result showed that S HAdAIAS is a good candidate for an anti-asthma drug since it depletes intracellular mRNA for the adenosine A1 receptor, which is involved in asthma.
~x;tmpl~: In Vivo Efficacy of Adenosine Al Receptor Anti-sense Oligos A fortuitous homology between the rabbit and human DNA sequences within the adenosine A, gene overlapping the initiation codon permitted the use of the phosphorothioate anti-sense oligonucleotides initially designed for use against the human adenosine AI receptor in a rabbit model.
Neonatal New Zealand white Pasteurella-free rabbits were immunized intraperitoneally within 24 hours of birth with 312 antigen units/ml house dustmite (D. farinae) extract (Berkeley Biologicals, Berkeley, CA), mixed with IO % kaolin. Immunizations were repeated weekly for the first month and then biweekly for the next 2 months. At 3-4 months of age, eight sensitized rabbits were anesthetized and relaxed with a mixture of ketamine hydrochloride (44 mg/kg) and acepromazine maleate (0.4 mg/kg) administered intramuscularly.
The rabbits were then laid supine in a comfortable position on a small molded, padded animal board and intubated with a 4.0-mm intratracheal tube (Mallinkrodt, Inc., Glens Falls, NY). A polyethylene catheter of external diameter 2.4 mm with an attached latex balloon was passed into the esophagus and maintained at the same distance (approximately 16 cm) from the mouth throughout the experiments. The intratracheal tube was attached to a heated Fleisch pneumotachograph (size 00; DOM Medical, Richmond, VA), and flow was measured using a Validyne differential pressure transducer (Model DP-45161927; Validyne Engineering Corp., Northridge, CA) driven by a Gould carrier amplifier (Model 11-4113; Gould Electronic, Cleveland, OH). The esophageal balloon was attached to one side of the differential pressure transducer, and the outflow of the intratracheal tube was connected to the opposite side of the pressure transducer to allow recording of transpulmonary pressure. Flow was integrated to give a continuous tidal volume, and measurements of total lung resistance (RL) and dynamic compliance (Cdyn) were calculated at isovolumetric and flow zero points, respectively, using an automated respiratory analyzer (Model 6; Buxco, Sharon, CT).
Animals were randomized and on Day 1 pretreatment values for PC50 were obtained for aerosolized adenosine. Anti-sense (HAdAIAS) or mismatched control (HAdAIMM) oligonucleotides were dissolved in sterile physiological saline at a concentration of 5000 ~.g (5 mg) per 1.0 ml. Animals were subsequently administered the aerosolized anti-sense or mismatch oligonucleotide via the intratracheal tube (approximately 5000 ~,g in a volume of 1.0 ml), twice daily for two days. Aerosols of either saline, adenosine, or anti-sense or mismatch oligonucleotides were generated by an ultrasonic nebulizer (DeVilbiss, Somerset, PA), producing aerosol droplets 80% of which were smaller than 5 ~,m in diameter.
In the first arm of the experiment, four randomly selected allergic rabbits were administered anti-sense oligonucleotide and four the mismatched control oligonucleotide. On the morning of the third day, PC50 values (the concentration of aerosolized adenosine in mg/ml required to reduce the dynamic compliance of the bronchial airway 50 %
from the baseline value) were obtained and compared to PC50 values obtained for these animals prior to exposure to oligonucleotide.
Following a 1 week interval, animals were crossed over, with those previously administered mismatch control oligonucleotide now administered anti-sense oligonucleotide, and those previously treated with anti-sense oligonucleotide now administered mismatch control oligonucleotide. Treatment methods and measurements were identical to those employed in the first arm of the experiment. It should be noted that in six of the eight animals treated with anti-sense oligonucleotide, adenosine-mediated bronchoconstriction could not be obtained up to the limit of solubility of adenosine, 20 mg/ml. For the purpose of calculation, PC50 values for these animals were set at 20 mg/ml. The values given therefore represent a minimum figure for anti-sense effectiveness. Actual effectiveness was higher.
The results of this experiment are illustrated in Table 3 below.

Table 3: Effect of Adenosine A1 Receptor Anti-sense Oligo upon PC50 Values in Asthmatic Rabbits Mismatch Control A, Receutor Anti-sense s Pre Oligonucleotide ~'ost Oligonucleotide ~re Oligonucleotide ~ Post Oligonucleotide ~i.56 t 1.02 ~.16 ~ 1.03 ~.36 t 0.68 I > 19.5 f 0.34**
The results are presented as the mean (n=8) f SEM.
The significance was determined by repeated-measures analysis of variance (ANOVA), and Tukey's protected test.
**Significantly different from all other groups, p < 0.01.
In both arms of the experiment, animals receiving the anti-sense oligonucleotide showed an order of magnitude increase in the dose of aerosolized adenosine required to reduce dynamic compliance of the lung by 50% . No effect of the mismatched control oligonucleotide upon PC50 values was observed. No toxicity was observed in any animal receiving either anti-sense or control inhaled oligonucleotide.
These results show clearly that the lung has exceptional potential as a target for anti-sense oligonucleotide-based therapeutic intervention in lung disease. They further show, in a model system which closely resembles human asthma, that downregulation of the adenosine A, receptor largely eliminates adenosine-mediated bronchoconstriction in asthmatic airways.
Bronchial hyperresponsiveness in the allergic rabbit model of human asthma is an excellent endpoint for anti-sense intervention since the tissues involved in this response lie near to the point of contact with aerosolized oligonucleotides, and the model closely simulates an important human disease.
E:~amnile 4: Specificity of A,-adenosine Receptor Anti-sense Oligonucleotide At the conclusion of the cross-over experiment of Example 3 above, airway smooth muscle from all rabbits was quantitatively analyzed for adenosine At receptor number. As a control for the specificity of the anti-sense oligonucleotide, adenosine A2 receptors, which should not have been affected, were also quantified.
Airway smooth muscle tissue was dissected from each rabbit and a membrane fraction prepared according to the method of Kleinstein et al. (Kleinstein, J. and Glossmann, H., Naunyn-Schmiedeberg's Arch. Pharmacol. 305: 191-200 (1978)), the relevant portion of which is hereby incorporated in its entirety by reference, with slight modifications. Crude plasma membrane preparations were stored at 70°C until the time of assay. Protein content was determined by the method of Bradford (M. Bradford, Anal. Biochem. 72, 240-254 (1976), the relevant portion of which is hereby incorporated in its entirety by reference). Frozen plasma membranes were thawed at room temperature and were incubated with 0.2 U/ml adenosine deaminase for 30 minutes at 37°C to remove endogenous adenosine. The binding of [~H]
DPCPX (At receptor-specific) or [3H] CGS-21680 (At receptor-specific) was measured as previously described by Ali et al. (Ali, S. et al., J. Pharmacol. Exp. Ther.
268, Am. J. Physiol 266, L271-277 (1994), the relevant portion of which is hereby incorporated in its entirety by reference).
The animals treated with adenosine A1 anti-sense oligonucleotide in the cross-over experiment had a nearly 75 % decrease in A, receptor number compared to controls, as assayed by specific binding of the At-specific antagonist DPCPX. There was no change in adenosine AZ receptor number, as assayed by specific binding of the AZ receptor-specific agonist 2- [p-(2-carboxyethyl)-phenethylamino] -5' - (N-ethylcarboxamido) adenosine (CGS-21680). This is illustrated in Table 4 below.
Table 4: Specificity of Action of Adenosine A1 Receptor Anti-sense Oligonucleotide Mismatch Control At Anti-sense Olignnucientidp (lli~nnnrlrntirlP
Al-Specific Binding 1105 t 48** 293 t i8 A2-Specific Binding 302 t 22 442 t 171 me ~c~wW arc prc~cmcu as me mcan ~n = °~ * ~rivl.
The significance was determined by repeated-measures analysis of variance (ANOVA), and Tukey's protected test.
**Significantly different from mismatch control, p<0.01.
The above results illustrate the effectiveness of anti-sense oligonucleoddes in treating airway disease. Since the anti-sense oligos described above. eliminate the receptor systems responsible for adenosine-mediated bronchoconstriction, it may be less imperative to eliminate adenosine from them. However, it would be preferable to eliminate adenosine from even these oligonucleoddes to reduce the dose needed to attain a similar effect.
Described above are other anti-sense oligonucleotides targeting mRNA of proteins involved in inflammation. Adenosine has been eliminated from their nucleotide content to prevent its liberation during degradation.
F~;aninle 5: Anti-sense Oligos directed to other Target Nucleic Acids This work was conducted to demonstrate that the present invention is broadly applicable to anti-sense oligonucleotides ("oligos") specific to nucleic acid targets broadly. The following experimental studies were conducted to show that the method of the invention is broadly suitable for use with anti-sense oligos designed as taught by this application and targeted to any and all adenosine receptor mRNAs. For this purpose, various anti-sense oligos were porepared to adenosine receptor mRNAs exemplified by the adenosine A,, A~ and A3 receptor mRNAs.
Anti-sense Oligo I was disclosed above (SEQ. ID NO:1).Five additional anti-sense phosphorothioate oligos were designed asnd synthesized as indicated above.
1-~Oligo II (SEQ. iD NO: ~) also targeted to the adenosine A, receptor, but to a different region than Oligo I.
2- Oligo V (SEQ. iD NO: 1o) targeted to the adenosine A~ receptor.
3- Oligos III (SEQ. ID NO: 8) and IV (SEQ. ID No: 9) targeted to different regions of the adenosine A3 receptor.
4- Oligo I-PD (SEQ. ID No:168i)(a phosphodiester oligo of the same sequence as Oligo I).
These anti-sense oligos were designed for therapy on a selected species as described above and are generally specific for that species, unless the segment of the target ml2NA of other species happens to contain a similar sequences. All anti-sense oligos were prepared as described below, and tested in vivo in a rabbit model for bronchoconstriction, inflammation and allergy, which have breathing difficulties and impeded lung airways, as is the case in ailments such as asthma, as described in the above-identified application.
Ex~mpll~~: Design & Sequences of other Anti-sense Oligos Six oligos and their effects in a rabbit model were studied and the results of these studies are reported and discussed below. Five of these oligos were selected for this study to complement the data on Oligo I (SEQ ~D NO: i) provided in Examples 1 to 4 above. This oligo is anti-sense to one region of the adenosine A1 receptor mltNA.
The oligos tested are identified as anti-sense Oligos I (SEQ in NO:1) and II
(SEQ. ID No:
~) targeted to a different region of the adenosine A1 receptor mRNA, Oligo V
(SEQ. >D No:B) targeted to the adenosine A~, receptor mRNA, and anti-sense Oligos III and IV
(SEQ. ID NOS:
9 and io) targeted to two different regions of the adenosine A~ receptor mRNA.
The sixth oligo (Oligo I-PD) is a phosphodiester version of Oligo I (SEQ. m NO:1). The design and synthesis of these anti-sense oligos was performed in accordance with Example 1 above.
(n Anti-sense Oligo I
The anti-sense oligonucleodde I referred to in Examples 1 to 4 above is targeted to the human A, adenosine receptor mRNA (EPI 2010). Anti-sense oligo I is 21 nucleotide long, overlaps the initiation codon, and has the following sequence.
5'- GAT GGA GGG CGG CAT GGC GGG -3' (:SEQ. ID No 1) The oligo I was previously shown to abrogate the adenosine-induced bronchoconstriction in allergic rabbits, and to reduce allergen-induced airway obstruction and bronchial hyperresponsiveness (BHR), as discussed above and shown by Nyce, J.
W. &
Metzger, W. J., Nature, 385:721 (1977), the relevant portions of which reference are incorporated in their entireties herein by reference.
(In Anti-sense Oligo II
S A phosphorothioate anti-sense oligo (SEQ, in No:'7) was designed in accordance with the invention to target the rabbit adenosine A1 receptor mRNA region +936 to +956 relative to the initiation codon (start site). The anti-sense oligo II is 21 nucleotide long, and has the following sequence.
5'-CTC GTC GCC GTC GCC GGC GGG-3' (SEQ. ID NO:'n (III) Anti-sense Oligo III
A phosphorothioate anti-sense oligo other than that provided in Example 1 above (SEQ.
m N0:8) was designed in accordance with the invention to target the anti-sense As receptor mRNA region +3 to + 22 relative to the initiation codon start site. The anti-sense oligo III
is 20 nucleotide long, and has the following sequence.
5'-GGG TGG TGC TAT TGT CGG GC-3' (SEQ. ID N0:8) (IV) Anti-sense Oligo IV
Yet another phosphorothioate anti-sense oligo (SEQ. m No:9) was designed in accordance with the invention to target the adenosine A3 receptor mRNA region + 386 to +
401 relative to the initiation codon (start site). The anti-sense oligo IV is 15 nucleotide long, and has the following sequence.
5'-GGC CCA GGG CCA GCC-3' (SEQ. ID N0:9) (V) Anti-sense Oligo V
A phosphorothioate anti-sense oligo (SEQ. ID NO:10) was designed in accordance with the invention to target the adenosine A2b receptor mRNA region -21 to -1 relative to the initiation codon (start site). The anti-sense oligonucleotide V is 21 nucleotide long, and has the following sequence.
5'-GGC CGG GCC AGC CGG GCC CGG-3' (SEQ. ID NO:10) (Vn A1 Mismatch Oligos Two different mismatched oligonucleotides having the following sequences were used as controls for anti-sense oligo I (SEQ. In N0:1) described in Example 5 above.
A1 MM2 5'-GTA GGT GGC GGG CAA GGC GGG-3' (SEQ. ID N0:1682) A1 MM3 5'-GAT GGA GGC GGG CAT GGC GGG3' (SEQ. ID N0:1683) Anti-sense oligo I and the two mismatch anti-sense oligos had identical base content and general sequence structure. Homology searches in GENBANK (release 85.0) and EMBL
(release 40.0) indicated that the anti-sense oligo I was specific, not only for the human, but also for the rabbit, adenosine A, receptor genes, and that the mismatched controls were not candidates for hybridization with any known human or animal gene sequence.

(VIn Anti-sense Oligo A,-PD (Oligo Vn A phosphodiester anti-sense oligo (Oligo VI; SEQ. m No:1681) having the same nucleotide sequence as Oligo I was designed as disclosed in the above-identified application.
Anti-sense oligo I-PD is 21 nucleotide long, overlaps the initiation codon, and has the following sequence.
5'- GAT GGA GGG CGG CAT GGC GGG -3' (SEQ. ID N0:1681) l;In Controls Each rabbit was administered 5.0 ml aerosolized sterile saline following the same schedule as for the anti-sense oligos in (II), (III), and (IV) above.
Examyle : Synthesis of Anti-sense Oligos Phosphorothioate anti-sense oligos having the sequences described in (a) above, were synthesized on an Applied Biosystems Model 396 Oligonucleotide Synthesizer, and purified using NENSORB chromatography (DuPont, DE). TETD (tetraethylthiuram disulfide) was used as the sulfurizing agent during the synthesis. Anti-sense oligonucleotide II (sE(~. m NO:~), 1 S anti-sense oligonucleotide III (SEQ. ID No: 8) and anti-sense oligonucleotide IV (sEQ. ID No:
9) were each synthesized and purified in this manner.
Exam~~le 8: Preparation of Allergic Rabbits Neonatal New Zealand white Pasturella-free rabbits were immunized intraperitoneally within 24 hours of birth with 0.5 ml of 312 antigen units/ml house dust mite (D. farinae) extract (Berkeley Biologicals, Berkeley, CA) mixed with 10 % kaolin as previously described (Metzger, W. J., in Late Phase Allergic Reactions, Dorsch, W., Ed., CRC
Handbook, pp.
347-362, CRC Press, Boca Raton (1990); Ali, S., Metzger, W. J. and Mustafa, S.
J., Am. J.
Resp. Crit. Care Med. 149: 908 (1994)), the relevant portions of which are incorporated in their entireties here by reference. immunizations were repeated weekly for the first month and then biweekly until the age of 4 months. These rabbits preferentially produce allergen-specific IgE antibody, typically respond to aeroallergen challenge with both an early and late-phase asthmatic response, and show bronchial hyper responsiveness {BHR). Monthly intraperitoneal administration of allergen (312 units dust mite allergen, as above) continues to stimulate and maintain allergen-specific IgE antibody and BHR. At 4 months of age, sensitized rabbits were prepared for aerosol administration as described by Ali et al. (Ali, S., Metzger, W. J. and Mustafa, S. J., Am. J. Resp. Crit. Care Med. 149 (1994)), the relevant section being incorporated in its entirety here by reference.

Fx~mple 9: Experimental Setup Aerosols of either adenosine (0-20 mg/ml), or anti-sense or one of two mismatch oligonucleotides (5 mg/ml) were separately prepared with an ultrasonic nebulizer (Model 646, DeVilbiss, Somerset, PA), which produced aerosol droplets, 80% of which were smaller than Sum in diameter. Equal volumes of the aerosols were administered directly to the lungs via an intratracheal tube.
The animals were randomized, and administered aerosolized adenosine. Day 1 pre-treatment values for sensitivity to adenosine were calculated as the dose of adenosine causing a 50% loss of compliance (PCB Adenosine). The animals were then administered either the aerosolized anti-sense or one of the mismatch anti-sense oligos via the intratracheal tube (5 mg/1.0 ml), for 2 minutes, twice daily for 2 days (total dose, 20 mg). Post-treatment PCB
values were recorded (post-treatment challenge) on the morning of the third day. The results of these studies are provided in Example 21 below.
E.x_ample 10: Crossover Experiments For some experiments utilizing anti-sense oligo I (SEQ ID NO: i) and a corresponding mismatch control oligonucleotide A1MM2, following a 2 week interval, the animals were crossed over, with those previously administered the mismatch control A1MM2, now receiving the anti-sense oligo I, and those previously treated with the anti-sense oligo I, now receiving the mismatch control A1MM2 oligo.
The number of animals per group was as follows. For mismatch A,MM2 (Control 1), n=7, since one animal was lost in the second control arm of the experiment due to technical difficulties, for mismatch A,MM3 n=4 (Control 2) and for A,AS anti-sense oligo I, n=8. The AIMM3 oligo-treated animals were analyzed separately and were not part of the cross-over experiment. The treatment methods and measurements employed following the cross-over were identical to those employed in the first arm of the experiment.
In 6 of the 8 animals treated with the anti-sense oligo I (SEQ. in NO: 1), no PCB value could be obtained for adenosine doses of up to 20 mg/ml, which is the limit of solubility of adenosine. Accordingly, the PCB values for these animals were assumed to be 20 mg/ml for calculation purposes. The values given, therefore, represent a minimum figure for the effectiveness of the anti-sense oligonucleotides of the invention. Other groups of allergic rabbits (n=4 for each group) were administered 0.5 or 0.05 mg doses of the anti-sense oligo I (SEQ ID NO: i), or the A,MM2 oligo in the manner and according to the schedule described above (the total doses being 2.0 or 0.2 mg). The results of these studies are provided in Example 22 below.

Anti-sense Oligo Formulation Each one of anti-sense oligos were separately solubilized in an aqueous solution and administered as described for anti-sense oligo I (SEQ. ID Noa) in (e) above, in four 5 mg aliquots (20 mg total dose) by means of a nebulizer via endotracheal tube, as described above.
The results obtained for anti-sense oligo I and its mismatch controls confirmed that the mismatch controls are equivalent to saline, as described in Example 19 below and in Table 1 of Nyce & Metzger, Nature 385, 721-725 (1997). Because of this fording, saline was used as a control for pulmonary function studies employing anti-sense oligos II, III
and IV (SEQ. IS
NOS; 7, 8 and 9) .
dam In a 12: Specificity of Oligo I for Adenosine A1 Receptor (Receptor Binding Studies) Tissue from airway smooth muscle was dissected to primary, secondary and tertiary bronchi from rabbits which had been administered 20 mg oligo I (SEQ m NO: i) in 4 divided doses over a period of 48 hours as described above. A membrane fraction was prepared according to the method of Ali et al. (All, S., et al., Am. J. Resp. Crit.
Care Med. 149: 908 (1994), the relevant section relating to the preparation of the membrane fraction is incorporated in its entirety hereby by reference).
The protein content was determined by the method of Bradford and plasma membranes were incubated with 0.2 U/ml adenosine deaminase for 30 minutes at 37°C
to remove endogenous adenosine. See, Bradford, M. M. Anal. Biochem. 72, 240-254 (1976), the relevant portion of which is hereby incorporated in its entirety by reference.
The binding of [3H]DPCPX, [3H]NPC17731, or [3H]CGS-21680 was measured as described by Jarvis et al.
See, Jarvis, M.F., et al., Pharmacol. Exptl. Ther. 251, 888-893 (1989), the relevant portion of which is fully incorporated herein by reference. The results of this study are shown in Table 8 and discussed in Example 20 below.
F,~cam ly a 13: Pulmonary Function Measurements (Compliance cDl.,,, and Resistance) At 4 months of age, the immunized animals were anesthetized and relaxed with 1.5 ml of a mixture of ketamine HCl (35 mg/kg) and acepromazine maleate (1.5 mg/kg) administered intramuscularly. After induction of anesthesia, allergic rabbits were comfortably positioned supine on a soft molded animal board. Salve was applied to the eyes to prevent drying, and they were closed. The animals were then intubated with a 4.0 mm intermediate high-low cuffed Murphy 1 endotracheal tube (Mallinckrodt, Glen Falls, NY), as previously described by Zavala and Rhodes. See, Zavala and Rhodes, Proc. Soc. Exp. Biol. Med. 144: 509-WO 99/13886 . PCT/US98/19419 (1973), the relevant portion of which is incorporated herein by reference in its entirety. A
polyethylene catheter of OD 2.4 mm (Becton Dickinson, Clay Adams, Parsippany NJ) with an attached thin-walled latex balloon was passed into the esophagus and maintained at the same distance (approximately 16 cm) from the mouth throughout the experiment. The endotracheal tube was attached to a heated Fleisch pneumotach (size 00; DEM Medical, Richmond, VA), and the flow (v) measured using a Validyne differential pressure transducer (Model DP-45-16-1927, Validyne Engineering, Northridge, CA), driven by a Gould carrier amplifier (Model 11-4113, Gould Electronics, Cleveland, OIT).
An esophageal balloon was attached to one side of the Validyne differential pressure transducer, and the other side was attached to the outflow of the endotracheal tube to obtain transpulmonary pressure (P~). The flow was integrated to yield a continuous tidal volume, and the measurements of total lung resistance (R~) and dynamic compliance (Cdy,~
were made at isovolumetric and zero flow points. The flow, volume and pressure were recorded on an eight channel Gould 2000 W high-frequency recorder and C~," was calculated using the total volume and the difference in P~ at zero flow, and . R, was calculated as the ratio of Ptp and V at midtidal lung volumes. These calculations were made automatically with the Buxco automated pulmonary mechanics respiratory analyzer (Model 6, Buxco Electronics, Sharon, CT), as previously described by Giles et al. See, Giles et al., Arch. Int.
Pharmacodyn. Ther. 194: 213-232 (1971), the relevant portion of which describing these calculations is incorporated in toto hereby by reference. The results obtained upon administration of oligo II on allergic rabbits are shown and discussed in Example 26 below.
Exam lni a 14: Measurement of Bronchial Iiyperresponsiveness (BHR) Each allergic rabbit was administered histamine by aerosol to determine their baseline hyperresponsiveness. Aerosols of either saline or histamine were generated using a DeVilbiss nebulizer (DeVilbiss, Somerset, PA) for 30 seconds and then for 2 minutes at each dose employed. The ultrasonic nebulizer produced aerosol droplets of which 80% were < 5 micron in diameter. The histamine aerosol was administered in increasing concentrations (O.lSb to 80 mg/ml) and measurements of pulmonary function were made after each dose. The B4R was then determined by calculating the concentration of histamine (mg/ml) required to reduce the 3O Cdy~ 50% from baseline (PCso H~~,;"~.
Exam ln~ a 15: Cardiovascular Effect of Anti-sense Oligo I
The measurement of cardiac output and other cardiovascular parameters using Cardiomax~' utilizes the principal of thermal dilution in which the change in temperature of the blood exiting the heart after a venous injection of a known volume of cool saline is monitored.
A single rapid injection of cool saline was made into the right atrium via cannulation of the right jugular vein, and the corresponding changes in temperature of the mixed injectate and blood in the aortic arch were recorded via cannulation of the carotid artery by a temperature-sensing miniprobe.
Twelve hours after the allergic rabbits had been treated with aerosols of oligo I (EPI
2010; SEQ. ID NO: 1) as described in (d) above, the animals were anesthetized with 0.3 ml/kg of 80% Ketamine and 20% Xylazine. This time point coincides with previous data showing efficacy for SEQ. ID NO: 1, as is clearly shown by Nyce & Metzger, (1997), supra, the pertinent disclosure being incorporated in its entirety here by reference. A
thermocouple was then inserted into the left carotid artery of each rabbit, and was then advanced 6.5 cm and secured with a silk ligature. The right jugular vein was then cannulated and a length of polyethylene tubing was inserted and secured.
A thermodilution curve was then established on a Cardiomax'~ II (Columbus Instruments, Ohio) by injecting sterile saline at 20°C to determine the correctness of positioning of the thermocouple probe. After establishing the correctness of the position of the thermocouple, the femoral artery and vein were isolated. The femoral vein was used as a portal for drug injections, and the femoral artery for blood pressure and heart rate measurements. Once constant baseline cardiovascular parameters were established, Cardiomax~' measurements of blood pressure, heart rate, cardiac output, total peripheral resistance, and cardiac contractility were made.

~m_~~le 16: Duration of Action of Oligo I
(SEQ. ID NO: 1) Eight allergic rabbits received initially increasing log doses of adenosine by means of a nebulizer via an infra-tracheal tube as described in (f) above, beginning with O.1S6 mg/ml S until compliance was reduced by SO% (PCso ,~"~;"~ to establish a baseline.
Six of the rabbits then received four S mg aerosolized doses of (SEQ. ID N0:1) as described above. Two rabbits received equivalent amounts of saline vehicle as controls. Beginning 18 hours after the last treatment, the PCso pd~ine values were tested again. After this point, the measurements were continued for all animals each day, for up to 10 days. The results of this study are discussed in Example 2S below.
Exani~ile 17: Reduction of Adenosine A26 Receptor Number by Anti-sense Oligo V
Sprague Dawley rats were administered 2.0 mg respirable anti-sense oligo V
(SEQ m No:lo) three times over two days using an inhalation chamber as described above. Twelve 1 S hours after the last administration, lung parenchymal tissue was dissected and assayed for adenosine A2b receptor binding using [311]-NECA as described by Nyce & Metzger (1997), supra. Controls were conducted by administration of equal volumes of saline.
The results are significant at p < O.OS using Student's paired t test, and are discussed in Example 28 below.
Comparison of Oligo I & Corresponding Phosphodiester Oligo VI (SEQ. m No:1681) Oligo I (sEQ m Noa) countered the effects of adenosine and eliminated sensitivity to it for adenosine amounte up to 20 mg adenosine/S.0 ml (the limit of solubility of adenosine).
Oligo VI (SEQ ID No:1681), the phosphodiester version of the oligonucleotide sequence, was completely ineffective when tested in the same manner. Both compounds have identical 2S sequence, differing only in the presence of phosphorothioate residues in Oligo I (SEQ ID NOa), and were delivered as an aerosol as described above and in Nyce & Metzger (1997), supra.
Significantly different at p < 0.001, Student's paired t test. The results are discussed in Example 29 below..
BESULTS OBTAINED FO~, NTI- '.NSF OLI = I (SEQ. m NO: i) Exam lp a 19: Results of Prior Work The nucleotide sequence and other data for anti-sense oligo I (SEQ. m No: 1), which is specific for the adenosine A, receptor, were provided above. The experimental data showing the effectiveness of oligo I in down regulating the receptor number and activity were also provided above.
Further information on the characteristics and activities of anti-sense oligo I is provided in Nyce,-J. W. and Metzger, W. J., Nature 385:721 (1997), the relevant parts of which relating to the following results are incorporated in their entireties herein by reference. The Nyce & Metzger (1997) publication provided data showing that the anti-sense oligo I (SE(2. m NO: 1):
(1) The anti-sense oligo I reduces the number of adenosine A, receptors in the bronchial smooth muscle of allergic rabbits in a dose-dependent manner as may be seen in Table 5 below.
{2) Anti-sense Oligo I attenuates adenosine-induced bronchoconstriction and allergen-induced bronchoconstriction.
(3) The Oligo I attenuates bronchial hyperresponsiveness as measured by PCB
histamine, a standard measurement to assess bronchial hyperresponsiveness.
This result clearly demonstrates anti-inflammatory activity of the anti-sense oligo I as is shown in Table 5 above.
(4) As expected, because it was designed to target it, the anti-sense oligo I
is totally specific for the adenosine A, receptor, and has no effect at all at any dose on either the very closely related adenosine AZ receptor or the related bradykinin BZ receptor.
This is seen in Table 5 below.
(5} In contradistinction to the above effects of the Oligo I, the mismatch control molecules MM2 and MM3 (SEQ. ID N0:1682 and SEQ. m No:~683) which have identical base composition and molecular weight but differed from the anti-sense oligo I (SEQ
In NO: 1) by 6 and 2 mismatches, respectively. These mismatches, which are the minimum possible while still retaining identical base composition, produced absolutely no effect upon any of the targeted receptors (A,, AZ or B2).
These results, along with a complete lack of prior art on the use of anti-sense oligonucleotides, such as oligo I, targeted to the adenosine A, receptor, are unexpected results.
The showings presented in this patent clearly enable and demonstrate the effectiveness, for their intended use, of the claimed agents and method for treating a disease or condition associated with lung airway, such as bronchoconstriction, inflammation, allergy(ies), and the like.
F~m~lg?~Q: Oligo I Significantly Reduces Response to Adenosine Challenge WO 99!13886 . PCT/IJS98/19419 The receptor binding experiment is described in Example 12 above, and the results shown in Table 5 below which shows the binding characteristics of the adenosine A,-selective ligand [~H]DPCPX and the bradylcinin Bz -selective ligand [3H]NPC 17731 in membranes isolated from airway smooth muscle of A, adenosine receptor and BZ bradylcinin receptor anti-sense- and mismatch-treated allergic rabbits.

Table 5: Binding Characteristics of Three Anti-Sense Oligos reatment 1 receptor 2 receptor K
enosme A, eceptor 20 mg 0.3610.029 ttM 1911.52 fmoles* 0.3910.031 ttM 14.8t0.99fmoles 2 mg 0.38 f 0.030 t~Ivl 32 t 2.56 fmoles* 0.41 t 0.028 ttM 15.5 t 1.08 fmoles 0.2 mg 0.37(0.030 493.43 fmoles 0.3410.02415.01 1.06 nM nIVI fmoles A,MMI (Control) 20 mg 0.3410.027 52.013.64 fmoles 0.3510.02414.0f 1.0 fmoles ttM nM

2 mg 0.37(0.033 51.813.88 fmoles 0.3810.02814.611.02 fmoles ttM ttM

B=A (BradylcininReceptor) mg 0.3610.028 45.013.15 fmoles 0.3810.0278.7 f0.62 fmoles*
nM nM

2 mg 0.3910.035 44.312.90 fmoles 0.340.02411.910.76 fmoles**
ttM ttM

0.2 mg 0.4010.028 47.03.76 fmoles 0.35(0.02815.1 t 1.05 ttM ttM fmoles BZMM (Control) 15 20 mg 0.3910.031 42.012.94 fmoles 0.4110.02914.010.98 fmola ttM t~lul 2 mg 0.41 (0.035 40.013.20 fmoles 0.3710.03014.810.99 fmoles ttM nM

0.2 mg 0.3710.029 43.013.14 fmoles 0.3610.02515.111.35 fmoles nM nM

Saline Control 0.3710.041 46.015.21 0.3910.047 14.211.35 fmoles ttM

Refers to total oligo administered in four equivalently divided doses over a 48 hour period.
Treatments and analyses were performed as described in methods. Significance was determined by repeated-measures analysis of variance (ANOVA) and ' Tukey , s protected t test.
n = 4-6 for all groups.

* Significantly different from mismatch control-and saline-treated groups, p<0.001;

**Significantly different from mismatch control-and saline-treated groups, p <0.05.

E~mpl~..Zl: Dose-response Effect of Oligo I
Anti-sense oligo I (SEQ >m NO:1) was found to reduce the effect of adenosine administration to the animal in a dose-dependent manner over the dose range tested as shown in Table 6 below.

Table 6: Dose-Response Effect to Anti-sense Oligo I
Total DOSe PC50 enosine (m A~
) g (mg enoslne) ta-sense igo 0.2 8.3217.2 2.0 14.017.2 20 19.510.34 A1MM2 oligo (control) 0.2 2.SI 10.46 2.0 3.13 t 0.71 3.25 t 0.34 15 The above results were studied with the Student's paired t test and found to be statistically different, p=0.05 The oligo I (SEQ. >D NO:1), an anti-adenosine A1 receptor oligo, acts specifically on the adenosine A1 receptor, but not on the adenosine AZ receptors. These results stem from the 20 treatment of rabbits with anti-sense oligo I (sEQ. in No.1) or mismatch control oligo (SEQ. m NO:1682; A,MM2) as described in Example 9 above and in Nyce & Metzger (1997), supra (four doses of 5 mg spaced 8 to 12 hours apart via nebulizer via endotracheal tube), bronchial smooth muscle tissue excised and the number of adenosine A1 and adenosine A2 receptors determined as reported in Nyce & Metzger (1997), supra.
~~: Specificity of Otigo I (sEQ. m NO:1) for Target Gene Product Oligo I (SEQ. ID No:l) is specific for the adenosine A, receptor whereas its mismatch controls had no activity. Figure 1 depicts the results obtained from the cross-over experiment described in Example 10 above and in Nyce & Metzger (1997), supra. The two mismatch controls (SEQ. >D N0:1682 and SEQ. ID N0:1683) evidenced no effect on the PCB
Ad~"~"~ value.
On the contrary, the administration of anti-sense oligo I (SEQ. ID NOa) showed a seven-fold increase in the PC~,;,~ value. The results clearly indicate that the anti-sense oligo I (SEQ.
ID NO: i) reduces the response (attenuates the sensitivity) to exogenously administered adenosine when compared with a saline control. The results provided in Table 2 above clearly establish that the effect of the anti-sense oligo I is dose dependent (see, column 3 of Table 1).
The Oligo I was also shown to be totally specific for the adenosine A, receptor, (see, top 3 rows of Table), inducing no activity at either the closely related adenosine A3 receptor or the bradykinin B2 receptor (see, lines 8-10 of Table 2 above).
In addition, the results shown in Table 2 establish that the anti-sense oligo I (SEQ. ID

No:1) decreases sensitivity to adenosine in a dose dependent manner, and that it does this in an anti-sense oligo-dependent manner since neither of two mismatch control oligonucleotides (A1MM2; SEQ. m No:1682 and A,MM3; sEQ. m Noa6s3) show any effect on PCsa Adenosine values or on attenuating the number of adenosine A, receptors.
~pl,~: Effect on Aeroallergen-induced Bronchoconstriction & Inflammation The Oligo I (SEQ. m Noa) was shown to significantly reduce the histamine-induced effect in the rabbit model when compared to the mismatch oligos. The effect of the anti-sense Oligo I (SEQ. TD No: l) and the mismatch oligos (A,MM2, SE(~. In No:1682 and A,MM3, SE(~.
ID Noa682) on allergen-induced airway obstruction and bronchial hyperresponsiveness was assessed in allergic rabbits.
The effect of the anti-sense oligo I (SEQ. in No:1) on allergen-induced airway obstruction was assessed. As calculated from the area under the plotted curve, the anti-sense oligo I significantly inhibited allergen-induced airway obstruction when compared with the mismatched control (55 %, p < 0.05; repeated measures ANOVA, and Tukey's t test).
A complete lack of effect was induced by the mismatch oligo A1MM2 (Control) on allergen induced airway obstruction.
The effect of the anti-sense oligo I (SE(2. in No:1) on allergen-induced BHR
was determined as above. As calculated from the 1'Cso H;~~ value , the anti-sense oligo I (SEQ.
ID No:1) significantly inhibited allergen induced BHR in allergic rabbits when compared to the mismatched control (61 % , p < 0.05; repeated measures ANOVA, Tukey's t test).
A complete lack of effect of the A,MM mismatch control on allergen-induced BHR
was observed.
The results indicated that anti-sense oligo I (SEQ. >D No:1) is effective to protect against aeroallergen-induced bronchoconstriction (house dust mite). In addition, the anti-sense oligo I (sEQ. m No:1) was also found to be a potent inhibitor of dust mite-induced bronchial hyper responsiveness, as shown by its effects upon histamine sensitivity which indicates anti-inflammatory activity for anti-sense oligo I (SEQ. ID No:1).
Exam !p a 24: Anti-sense Oligo I is fee of Deleterious Side Effects The Oligo I (SEQ. m Noa) was shown to be free of side effects that might be toxic to the recipient. No changes in arterial blood pressure, cardiac output, stroke volume, heart rate, total peripheral resistance or heart contractility (dPdT) were observed following administration of 2.0 or 20 mg oligo I (sEQ. ID No:1). The addition, the results of the measurement of cardiac output {CO), stroke volume {S~, mean arterial pressure (MAP), heart rate (HR), total peripheral resistance {TPR), and contractility (dPdT) with a Cardiomax'"
apparatus (Columbus Instruments, Ohio) were assessed.
These results evidenced that oligo I {SEQ. in No:1) has no detrimental effect upon critical cardiovascular parameters. More particularly, this oligo does not cause hypotension.
This finding is of particular importance because other phosphorothioate anti-sense oligonucleotides have been shown in the past to induce hypotension in some model systems.
Furthermore, the adenosine A1 receptor plays an important role in sinoatrial conduction within the heart. Attenuation of the adenosine A1 receptor by anti-sense oligo I
(SEQ. ID No:1) might be expected to result, therefore, in deleterious extrapulmonary activity in response to the downregulation of the receptor. This is not the case. The anti-sense oligo I
(SEQ. m N0:1) does not produce any deleterious intrapulmonary effects and renders the administration of the low doses of the present anti-sense oligo free of unexpected, undesirable side effects.
This demonstrates that when oligo I (sEQ. In NOa) is administered directly to the lung, it does not reach the heart in significant quantities to cause deleterious effects. This is in contrast to traditional adenosine receptor antagonists like theophylline which do escape the lung and can cause deleterious, even life-threatening effects outside the lung.
F~g,~: Long Lasting Effect of Oligo I
The Oligo I (SEQ. m No:1) evidenced a long lasting effect as evidenced by the PCB and Resistance values obtained upon its administration prior to adenosine challenge.
The duration of the effect was measured for with respect to the PCjo of adenosine anti-sense oligo I when administered in four equal doses of 5 mg each by means of a nebulizer via an endotracheal tube, as described above. The effect of the agent is significant over days 1 to 8 after administration. When the effect of the anti-sense oligo I (SEQ. 1D
N0:1) had disappeared, the animals were administered saline aerosols (controls), and the PC~o "a~"~
values for all animals were measured again. Saline-treated animals showed base line PCso adenosine values (n=6).
The duration of the effect {with respect to Resistance) was measured for six allergic rabbits which were administered 20 mg of anti-sense oligo I (SEQ. m NO: 1) as described above, upon airway resistance measured as also described above. The mean calculated duration of effect was 8.3 days for both PC~o adenosine (p < 0.05) and resistance (p < 0.05).
These results show that anti-sense oligo I (SEQ. ID N0:1) has an extremely long duration of action, which is completely unexpected.
Exam In a 26: Anti-sense Oligo II

Anti-sense oligo II, targeted to a different region of the adenosine A, receptor mRNA, was found to be highly active against the adenosine A,-mediated effects. The experiment measured the effect of the administration of anti-sense oligo II (SEQ. m NO:~) upon compliance and resistance values when 20 mg anti-sense oligo II or saline (control) were administered to two groups of allergic rabbits as described above. Compliance and resistance values were measured following an administration of adenosine or saline as described above in Example 13. The effect of the anti-sense oligo of the invention was different from the control in a statistically significant manner, p < 0.05 using paired t-test, compliance; p < 0.01 for resistance.
The results showed that anti-sense oligo II (SEQ. ID NO:~), which targets the adenosine A, receptor, effectively maintains compliance and reduces resistance upon adenosine challenge.
E,xamyle 27: Antisense Oligos III and IV
Oligos III (SEQ. ID N0:8) and IV (SEQ. ID N0:9) were shown to be in fact specifically targeted to the adenosine A3 receptor by their effect on reducing inflammation and the number of inflammatory cells present upon separate administration of 20 mg of the anti-sense oligos III {SEQ. in N0:8) and IV (SEQ. ID No:9) to allergic rabbits as described above. The number of inflammatory cells was determined in their bronchial lavage fluid 3 hours later by counting at least 100 viable cells per lavage.
The effect of anti-sense oligos III (SEQ. in N0:8) and IV (SE(2. m N0:9) upon granulocytes, and upon total cells in bronchial lavage were assessed following exposure to dust mite allergen. The results showed that the anti-sense oligo IV (SEQ. in N0:9) and anti-sense oligo III (SEQ. iD N0:8) are very potent anti-inflammatory agents in the asthmatic lung following exposure to dust mite allergen. As is known in the art, granulocytes, especially eosinophils, are the primary inflammatory cells of asthma, and the administration of anti-sense oligos III (SEQ. in N0:8) and IV (sEQ. m No:9) reduced their numbers by 40%
and 66%, respectively. Furthermore, anti-sense oligos IV (SEQ. m NO:9) and III (sEQ. In N0:8) also reduced the total number of cells in the bronchial lavage fluid by 40 % and 80 % , respectively.
This is also an important indicator of anti-inflammatory activity by the present anti-adenosine A3 agents of the invention. Inflammation is known to underlie bronchial hyperresponsiveness and allergen-induced bronchoconstriction in asthma. Both anti-sense oligonucleotides III (S>~.
m N0:8) and IV (SEQ. m N0:9), which are targeted to the adenosine A3 receptor, are representative of an important new class of anti-inflammatory agents which may be designed to specifically target the lung receptors of each species.
Exam~ile 28: Anti-sense Oligo V
The anti-sense oligo V (SF(~. m N0:10) , targeted to the adenosine AZb adenosine receptor mRNA was shown to be highly effective at countering adenosine Azb mediated effects and at reducing the number of adenosine A2b receptors present to less than half.
Exam ly a 29: Unexpected Superiority of Substituted over Phosphodiester-residue Oligo I-DS
(SEQ. ID N0:1681) Oligos I (SEQ. in No:l) and I-DS (sEQ. in No:1681) were separately administered to allergic rabbits as described above, and the rabbits were then challenged with adenosine. The phosphodiester oligo I-DS (SEQ. ID No:1681) was statistically significantly less effective in countering the effect of adenosine whereas oligo I (SEQ. m No:1) showed high effectiveness, evidencing a PCB A,~,~,;M of 20 mg.
Examp]'.e 30: Anti-sense Oligo VI
For the present work, I designed an additional anti-sense phosphorothioate oligo targeted to the adenosine A, receptor (Oligo VI). This anti-sense oligo was designed for therapy on a selected species as described in the above patent application and is generally specific for that species, unless the segment of the adenosine receptor mRNA of other species elected happens to have a similar sequence. The anti-sense oligos were prepared as described below, and tested in vivo in a rabbit model for bronchoconstriction, inflammation and lung allergy, which have breathing difficulties and impeded lung airways, as is the case in ailments such as asthma, as described in the above-identified application.
One additional oligo and its effect in a rabbit model was studied and the results of the study are reported and discussed below. The present oligo (anti-sense oligo VI) was selected for this study to complement the data on SEQ ID NO: 1 (Oligo I), which is anti-sense to the adenosine A, receptor mRNA provided in the above-identified patent application. This additional oligo is identified as anti-sense Oligo VI, and is targeted to a different region of the adenosine A, receptor mRNA than Oligo I. The design and synthesis of this anti-sense oligo was performed in accordance with the teaching, particularly Example 1, of the above-identified patent application.
The anti-sense Oligo VI is a phosphorothioate designed to target the coding region of the rabbit adenosine A, receptor mRNA region +964 to +984 relative to the initiation codon (start site). The Oligo VI was prepared as described in the above-indicated application, and is 20 nucleotides long. The OligoVI is directed to the adenosine A, receptor gene, and has the following sequence.
5'-CGC CGG CGG GTG CGG GCC GG-3' (SEQ. ID NO _) The phosphorothioate anti-sense Oligo VI having the sequence described in (5) above, was synthesized on an Applied Biosystems Model 396 Oligonucleotide Synthesizer, and purified using NENSORB chromatography (DuPont, DE). TETD (tetraethylthiuram disulfide) was used as the sulfurizing agent during the synthesis.
Preparation of Allergic Rabbits Neonatal New Zealand white Pasturella-free rabbits were immunized intraperitoneally within 24 hours of birth with 0.5 ml of 312 antigen units/ml house dust mite (D.
farinae) extract (Berkeley Biologicals, Berkeley, CA) mixed with 10% kaolin as previously described (Metzger, W. J., in Late Phase Allergic Reactions, Dorsch, W., Ed., CRC Handbook, pp 347-362, CRC
Press, Boca Raton, 1990; Ali, S. Et al., Am. J. Resp. Crit. Care Med. 149: 908 (1994)).
The immunizations were repeated weekly for the first month and then bi-weekly until the animals were 4 months old. These rabbits preferentially produce allergen-specific IgE antibody, typically respond to aeroallergen challenge with both an early and late-phase asthmatic response, and show bronchial hyper responsiveness (BHR). Monthly intraperitoneal administration of allergen (312 units dust mite allergen, as above) continues to stimulate and maintain allergen-specific IgE antibody and BHR. At 4 months of age, sensitized rabbits were prepared for aerosol administration as described by Ali et al. (1994), supra.
~;xan1 Ini a 32: Adenosine Aerosol Preparation An adenosine aerosol (20 mg/ml) was prepared with an ultrasonic nebulizer (Model 646, DeVilbiss, Somerset, PA), which produced aerosol droplets, 80 % of which were smaller than S~cm in diameter. Equal volumes of the aerosols were administered directly to the lungs via an intratracheal tube to all three rabbits.
The animals were then administered the aerosolized adenosine and Day 1 pre-treatment values for sensitivity to adenosine were calculated as the dose of adenosine causing a 50 % loss of compliance (PC~o Adenosine). The animals were then administered the aerosolized anti-sense via the intratracheal tube (5 mg/1.0 ml), for 2 minutes, twice daily for 2 days (total dose, 20 mg).
Post-treatment PCso values were recorded (post-treatment challenge) on the morning of the third day. The results of these studies are provided in (9) below.
pj~,~: Anti-sense Oligo Formulation Each one of anti-sense oligos were separately solubilized in an aqueous solution and administered as described for anti-sense oligo I in (e) above, in four 5 mg aliquots (20 mg total dose) by means of a nebulizer via endotracheal tube, as described above.
Examp]e 34: Oligo VI Reduces Response to Adenosine Challenge as well or Better than Oligo I
Oligo VI was tested in three allergic rabbits of the characteristics and readied as described in (7) above and in the above-indicated patent application. Oligo VI targets a section of the coding region of the A, receptor which is different from Oligo I. Both these target sequences were selected randomly from many possible coding region target sequences.
The three rabbits were treated identically as previously indicated for Oligo I. Briefly, 5 mg of Oligo VI were nebulized to the rabbits twice per day at 8 hour intervals, for two days. Thereafter, PCso adenosine studies were performed on the morning of the third day and compared to pre-treatment PCso values. This protocol is described in more detail in Nyce and Metzger (Nyce &
Metzger, Nature 385: 721-725 ( 1997)).
The results obtained for the three rabbits are shown in Table 1 below.
Table 1. Ae o olizedsAd o sine T ea ment rea men ime Y (mg) enos~ne Pre-treatment 3.0 t2.1 Post-treatment >20.0*
* maximum achievable dose due to adenosine insolubility in saline All three animals treated with Oligo VI completely eliminated sensitivity to adenosine up to the measurable level of the agent shown in Table 1 above. That is, the administration of the Oligo VI abrogated the adenosine-induced bronchoconstriction in the three allergic rabbits. The actual efficacy of Oligo VI is, therefore, greater than could be measured in the experimental system used.
By comparing with the previously submitted results for the Oligo I, it may be seen that the Oligo VI was found to be as effective, or more, than Oligo I.
Examn~le 34: Conclusions The work described and results discussed in the examples clearly indicates that all anti-I S sense oligonucleotides designed in accordance with the teachings of the above-identified application were found to be highly effective at countering or reducing effects mediated by the receptors they are targeted to. That is, each and all of the two anti-sense oligos targeting an adenosine A1 receptor mltNA, 1 anti-sense oligo targeting an adenosine A2b receptor mRNA, and the 2 anti-sense oligos targeting an A3 receptor mRNA were shown capable of countering the effect of exogenously administered adenosine which is mediated by the specific receptor they are targeted to.
The activity of the anti-sense oligos of this invention, moreover, is specific to the target and substitutively fails to inhibit another target.
In addition, the results presented also show that the administration of the present agents results in extremely low or non-existent deleterious side effects or toxicity.
This represents 100% success in providing agents that are highly effective and specific in the treatment of bronchoconstriction and/or inflammation. This invention is broadly applicable in the same manner to all genes) and corresponding mRNAs encoding proteins involved in or associated with airway diseases.
A comparison of the phosphodiester and a version of the same oligonucleotide wherein the phosphodiester bonds are substituted with phosphorothioate bonds evidenced an unexpected superiority for the phosphothiorate oligonucleotide over the phosphodiester anti-sense oligo.
The foregoing examples are illustrative of the present invention, and are not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims (58)

1. An agent, comprising an oligonucleotide which is anti-sense to at least two mRNAs selected from the group consisting of target genes, coding and non-coding regions of RNAs corresponding to target genes, the genes' initiation codons, genomic flanking regions, intron-exon borders, the 5'-end, the 3'-end and the juxta-section between coding and non-coding regions and all segments of RNAs encoding proteins associated with one or more disease(s) or condition(s) or mixtures thereof.

2. The agent of claim 1, wherein one mRNA encodes a protein selected from the group consisting of transcription factors, stimulating and activating factors, interleukins, interleukin receptors, chemokines, chemokine receptors, endogenously produced specific and non-specific enzymes, immunoglobulins, antibody receptors, central nervous system (CNS) and peripheral nervous and non-nervous system receptors, CNS and peripheral nervous and non-nervous system peptide transmitters, adhesion molecules, defensines, growth factors, vasoactive peptides and receptors, and binding proteins, or corresponds to an oncogene.

3. The agent of claim 2, wherein the encoded receptors and peptide transmitters selected from the group consisting of sympathomimetic receptors, parasympathetic receptors, GABA receptors, adenosine receptors, bradykinin receptors, insulin receptors, glucagon receptors, prostaglandin receptors, thyroid receptors, androgen receptors, anabolic receptors, estrogen receptors, progesterone receptors, receptors associated with the coagulation cascade, adenohypophyseal receptors, adenohypophyseal peptide transmitters, and histamine receptors (HisR).

4. The agent of claim 2, wherein the encoded sympathomimetic receptors and parasympathomimetic receptors are selected from the group consisting of acetylcholinesterase receptors (AcChaseR) acetylcholine receptors (AcChR), atropine receptors, muscarinic receptors, epinephrine receptors (EpiR), dopamine receptors (DOPAR), tachychinnen receptors, and norepinephrine receptors (NEpiR).

5. The agent of claim 2, wherein the encoded enzymes are selected from the group consisting of synthetases, kinases, oxidases, phosphatases, reductases, polysaccharide, triglyceride, and protein hydrolases, esterases, elastases, and , polysaccharide, triglyceride, lipid, and protein syntheses.

6. The agent of claim 5, wherein the encoded enzymes are selected from the group consisting of tryptase, inducible nitric oxide synthase, cyclooxygenase (Cox), MAP
kinase, eosinophil peroxidase, .beta.2-adrenergic receptor kinase, leukotriene c-4 synthase, 5-lipoxygenase, phosphodiesterase IV, metalloproteinase, CSBP/p38 MAP kinase, neutrophil elastase, phospholipase A2, cyclooxygenase 2 (Cox-2), fucosyl transferase, IkB
kinase 1 and 2, chymase, protein kinase C, thymidylate synthetase, tryptase, dihydrofolate reductase, tryptase, thymidine kinase, deoxycytidine kinase, and ribonucleotide reductase.

7. The agent of claim 2, wherein the encoded factor is selected from the group consisting of NfKB transcription factor, granulocyte macrophage colony stimulating factor (GM-CSF), AP-1 transcription factor, monocyte activating factor, neutrophil chemotactic factor, granulocyte colony-stimulating-factor (G-CSF), NFAT
transcription factors, platelet activating factor, tumor necrosis factor .alpha. (TNF
.alpha.), and basic fibroblast growth factor (BFGF).

8. The agent of claim 2, wherein the encoded adhesion molecule is selected from the group consisting of the intracellular adhesion molecules 1 (ICAM-1), 2 (ICAM-2) and 3 (ICAM-3), vascular cellular adhesion molecule (VCAM), endothelial leukocyte adhesion molecule-1 (SLAM-1), GATA transcription factor, neutrophil adherence receptor, mad CAM-1,

9. The agent of claim 2, wherein the encoded cytokines, lymphokines and chemokines are selected from the group consisting of the interleukin-1 (IL-1), interleukin-1.beta.
(IL-1)interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-8 (IL-8), interleukin-9 (IL-9), interleukin-11 (IL-11),CCR-5 CC chemokine, and Rantes.

10. The agent of claim 2, wherein the encoded receptor is selected from the group consisting of the adenosine A1 receptor, adenosine A2B receptor, adenosine A3 receptor, endothelin receptor A, endothellin receptor B, IgE high affinity receptor, muscarinic acetylcholine receptors, substance P receptor, histamine receptor, CCR-1 CC
chemokine receptor, substance P, NK-1, and NK-3 receptors, CCR-2 CC chemokine receptor, chemokine receptor (Eotaxin Receptor) , interleukin-1.beta. receptor (IL-1.beta.R), interleukin-1 receptor (IL-1R), interleukin-1.beta. receptor (IL-1.beta.R), interleukin-3 receptor (IL-3R), CCR-4 CC
chemokine receptor, cysteinyl leukotriene receptors, prostanoid receptors, interleukin-1 receptor (IL-1R), interleukin-4 receptor (IL-4R), interleukin-5 receptor (IL-5R), interleukin-8 receptor (IL-8R), interleukin-9 receptor (IL-9R), interleukin-11 receptor (IL-11R), bradykinin B2 receptor, sympathomimetic receptors, parasympathomimetic receptors, GABA
receptors, adenosine receptors, bradykinin receptors, insulin receptors, glucagon receptors, prostaglandin receptors, thyroid receptors, androgen receptors, anabolic receptors, estrogen receptors, progesterone receptors, receptors associated with the coagulation cascade, adenohypophyseal receptors, and histamine receptors (HisR).

11. The agent of claim 2, wherein the encoded protein is selected from the group consisting of the eotaxin, major basic protein, preproendothelin, eosinophil cationic protein, P-selectin, STAT 4, STAT 6, c-mas, NF-Interleukin-6 (NF-IL-6), MIP-1.alpha., MCP-2, MCP-3, MCP-4, cyclophillins, PDG2, cyclosporin A-binding protein, FK5-binding protein, fibronectin, LFA-1 (CD11a/CD18), PECAM-1, C3bi, PSGL-1,CD-34, substance P, p150,95, Mac-1 (CD11b/CD18), VLA-4, CD-18/CD11a, CD11b/CD18, C5a, CCR1, CCR2, CCR4, CCR5, and LTB-4.

12. The agent of claim 2, wherein the encoded defensin is selected from the group consisting of the defensin 1, defensin 2, and defensin 3.

13. The agent of claim 2, wherein the encoded selectin is selected from the group consisting of .alpha.4.beta.1 selectin, .alpha.4.beta.7 selectin, LFA-1 selectin, E-selectin, P-selectin, and L-selectin.

14. The agent of claim 2, wherein the mRNA corresponds to an oncogene selected from the group consisting of ras, src, myc, and bcl-2.

15. The agent of claim 1, wherein at least one mononucleotide linking phosphodiester residue of the anti-sense oligonucleotide(s) is substituted by a residue selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methyleneoxy (methylimino), 2'-O-methyl, phosphoramidate residues, and combinations thereof.

16. The agent of claim 15, wherein all phosphodiester residues are substituted.

17. The agent of claim 1, wherein the anti-sense oligonucleotide comprises about 7 to 60 mononucleotides.

18. The agent of claim 1, wherein the oligo consists of up to and including about 15 % A.

19. The agent of claim 1, wherein the oligo is adenosine-free.

20. The agent of claim 1, wherein the anti-sense oligo is selected from the group consisting of oligos comprising SEQ ID NOS.: _through_, SEQ. ID NO:s _to_ and SEQ. ID NOS: _ to _ (FRAGMENTS NOS: _ to _).

21. The agent of claim 1, wherein at least one A is substituted by a universal base selected from the group consisting of heteroaromatic bases which bind to a thymidine base but have antagonist activity and less than about 0.3 of the adenosine base agonist activity at the adenosine A1, A2b and A3 receptors, and heteroaromatic bases which have no activity or have an agonist activity at the adenosine A2a receptor.

22. The agent of claim 21, wherein the heteroaromatic bases are selected from the group consisting of pyrimidines and purines, which may be substituted by O, halo, NH2, SH, SO, SO2, SO3, COOH and branched and fused primary and secondary amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkenoxy, acyl, cycloacyl, arylacyl, alkynoxy, cycloalkoxy, aroyl, arylthio, arylsulfoxyl, halocycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkynylcycloalkyl, haloaryl, alkylaryl, alkenylaryl, alkynylaryl, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, which may be further substituted by O, halo, NH2, primary, secondary and tertiary amine, SH, SO, SO2, SO3, cycloalkyl, heterocycloalkyl and heteroaryl.

23. The agent of claim 22, wherein the pyrimidines and purines are substituted at positions 1, 2, 3, 4, 7 and 8.

24. The agent of claim 23, wherein the pyrimidines and purines are selected from the group consisting of theophylline, caffeine, dyphylline, etophylline, acephylline piperazine, bamifylline, enprofylline and xantine having the chemical formula wherein R1 and R2 are independently H, alkyl, alkenyl or alkynyl and R3 is H, aryl, dicycloalkyl, dicycloalkenyl, dicycloalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, O-cycloalkyl, O-cycloalkenyl, O-cycloalkynyl, NH2-alkylamino-ketoxyalkyloxy-aryl and mono and dialkylaminoalkyl-N-alkylamino-SO2 aryl.

25. The agent of claim 24, wherein the universal base is selected from the group consisting of 3-nitropyrrole-2'-deoxynucleoside, 5-nitro-indole, 2-deoxyribosyl-(5-nitroindole), 2-deoxyribofuranosyl-(5-nitroindole), 2'-deoxyinosine, 2'-deoxynebularine, 6H, 8H-3,4-dihydropyrimido [4,5-c] oxazine-7-one or 2-amino-6-methoxyaminopurine.

26. The agent of claim 1, where a methylated cytocine (m C) is substituted for at least one CpG dinucleotide if present in the oligo(s).

27. The agent of claim 1, wherein the anti-sense oligonucleotide is operatively linked to a cell internalized or up-taken agent or to a eukaryotic or prokaryotic vector.

28. The agent of claim 27, wherein the cell internalized or up taken agent is selected from the group consisting of transferrin, asialoglycoprotein, and streptavidin.

29. A composition, comprising the agent of claim 1 and a pharmaceutically or veterinarily acceptable carrier.

30. The composition of claim 29, wherein the carrier is selected from the group consisting of gaseous, liquid and solid carriers.

31. The composition of claim 29, further comprising an agent selected from the group consisting of other therapeutic compounds, surfactants, antioxidants, flavoring and coloring agents, fillers, volatile oils, buffering agents, dispersants, RNA
inactivating agents, antioxidants, flavoring agents, propellants and preservatives.

32. The composition of claim 29, wherein the anti-sense oligonucleotide is present in an amount of about 0.01 to about 99.99 w/w of the composition.

33. The composition of claim 32, comprising the nucleic acid, a surfactant and a carrier.

34. The composition of claim 33, wherein the surfactant is selected from the group consisting of surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant protein and active fragments thereof, non-dipalmitoyl disaturated phosphatidylcholine, dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, ubiquinones, lysophosphatidylethanolamine, lysophosphatidylcholine, palmitoyl-lysophosphatidylcholin, dehydroepiandrosterone, dolichols, sulfatidic acid, glycerol-3-phosphate, dihydroxyacetone phosphate, glycerol, glycero-3-phosphocholine, dihydroxyacetone, palinitate, cytidine diphosphate (CDP) diacylglycerol, CDP
choline, choline, choline phosphate, artificial lamellar bodies vehicles for surfactant components, omega-3 fatty acids, polyenic acid, polyenoic acid, lecithin, palmitic acid, non-ionic ethylene and/or propylene oxide block copolymers, polyoxypropylene, polyoxyethylene, poly (vinyl amine) with dextran and/or alkanoyl side chains, Brij 35, Triton X-100, ALEC, Exosurf, Survant and Atovaquone.

35. A formulation, comprising the composition of claim 26, wherein the carrier comprises a hydrophobic carrier.

36. The formulation of claim 35, wherein the carrier comprises lipid particles or vesicles.

37. The formulation of claim 36, wherein the vesicles comprise liposomes and the particles comprise micro crystals.

38. The formulation of claim 35, wherein the lipid vesicles comprise N-(1-[2, 3-dioleoxyloxi] propyl) -N,N,N- trimethyl- ammonium methylsulfate.

39. The formulation of claim 34, comprising a respirable formulation.

40. The formulation of claim 34, comprising an aerosol.

41. The formulation of claim 34, in single or multiple unit form.

42. The formulation of claim 34, in bulk.

43. A capsule or cartridge, comprising the composition of claim 26.

44. A kit, comprising a delivery device, in a separate container, the composition of claim 26 and instructions for its use.

45. The kit of claim 44, wherein the delivery device comprises a nebulizer which delivers single metered doses of the formulation.

46. The kit of claim 44, wherein the nebulizer comprises an insufflator, and the composition is provided in a piercable or openable capsule or cartridge.

47. The kit of claim 44, wherein the delivery device comprises a pressurized inhaler, and the composition comprises a suspension or solution of the agent.

48. The kit of claim 44, further comprising in a separate container an agent selected from the group consisting of other therapeutic compounds, surfactants, antioxidants, flavoring and coloring agents, fillers, volatile oils, buffering agents, dispersants, cell internalized or up taken agents, RNA inactivating agents, antioxidants, flavoring agents, propellants and preservatives.

49. The kit of claim 48, wherein the surfactant is selected from the group consisting of surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant protein and active fragments thereof, non-dipalmitoyl disaturated phosphatidylcholine, dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, ubiquinones, lysophosphatidylethanolamine, lysophosphatidylcholine, palmitoyl-lysophosphatidylcholin, dehydroepiandrosterone, dolichols, sulfatidic acid, glycerol-3-phosphate, dihydroxyacetone phosphate, glycerol, glycero-3-phosphocholine, dihydroxyacetone, palmitate, cytidine diphosphate (CDP) diacylglycerol, CDP
choline, choline, choline phosphate, artificial lamellar bodies vehicles for surfactant components, omega-3 fatty acids, polyenic acid, polyenoic acid, lecithin, palmitic acid, non-ionic ethylene and/or propylene oxide block copolymers, polyoxypropylene, polyoxyethylene, poly (vinyl amine) with dextran and/or alkanoyl side chains, Brij 35, Triton X-100, ALEC, Exosurf, Survant and Atovaquone.

50. The kit of claim 44, wherein the composition is provided in a capsule or carnidge.

51. A cell, comprising the agent of claim 1.

52. A method of treating a disease or condition associated with the mRNA
corresponding to at least one target gene(s), genomic flanking regions, or proteins, comprising administering to a subject afflicted with the disease or condition the agent of claim 1, comprising an amount of the anti-sense oligonucleotide effective to reduce the production or availability, or to increase the degradation by the subject of at least one of the target mRNA.

53. The method claim 52, wherein the agent is administered in an amount effective to reduce the production or availability, or to increase the degradation of at least two of the target mRNAs.

54. The method of claim 52, wherein the agent is administered directly to the lung (s) of the subject.

55. The method of claim 54, wherein the agent is administered as a respirable aerosol.

56. The method of claim 52, wherein the disease or condition is a lung disease or condition, and at least one of the target mRNA encodes a protein selected from the group consisting of the adenosine A1 receptor, adenosine A2B receptor, adenosine A3 receptor, and bradykinin B2 receptor.

57. The method of claim 56, wherein the disease or condition is associated with obstruction of the subject's airways.

58. The method of claim 57, wherein the disease or condition is associated with asthma.