HIGH-AFFINITY NUCLEIC ACID LIGANDS OF CYTOKINES

Abstract: Methods for identifying and preparing high-affinity nucleic acid ligands to cytokines and the ligands obtained thereby are disclosed.

Description: HIGH AFFINITY NUCLEIC ACID LIGANDS OF CYTOKINES FIELD OF THE INVENTION Described herein are methods for identifying and preparing high-affinity nucleic acid ligands to cytokines. The method utilized herein for identifying such nucleic acid ligands is called SELEX, an acronym for Systematic Evolution of Ligands by Exponential enrichment. This invention specifically includes methods for the identification of high affinity nucleic acid ligands of the following cytokines: IFN-gamma, IL-4, IL-10, TNFα, and RANTES. Further disclosed are RNA ligands to IFN-gamma, IL-4, IL- 10, and TNFα. Also disclosed are DNA ligands to RANTES. Specific examples are provided of oligonucleotides containing nucleotide derivatives chemically modified at the 2'-positions of pyrimidines. The oligonucleotides of the present invention are useful as pharmaceuticals or diagnostic agents. BACKGROUND OF THE INVENTION Cytokines are a diverse group of small proteins that mediate cell signaling/communication. They exert their biological functions through specific receptors expressed on the surface of target cells. Cytokines can be subdivided into several groups, including the immune/hematopoietins, interferons, tumor necrosis factor (TNF)-related molecules, and the chemokines. Representative immune/hematopoietins include erythropoietin (EPO), granulocyte/macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), leukemia inhibition factor (LIF), oncostatin-M (OSM), cilary neurotrophic factor (CNTF), growth hormone (GH), prolactin (PRL), interleukin (IL)-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, and IL-12. Representative interferons (IFN) include IFNα, IFNβ , and IFN-gamma. Representative TNF family members include TNF α, interferon (IFN) β , gp 39 (CD40-L), CD27-L, CD30-L, and nerve growth factor (NGF). Representative chemokines include platelet factor (PF)4, platelet basic protein (PBP), groα , MIG, ENA-78, macrophage inflammatory protein (MIP)l α , MIPl β, monocyte chemoattractant protein (MCP)-l, 1-309, HCl 4, CIO, Regulated on Activation, Normal T-cell Expressed, and Secreted (RANTES), and IL-8. IFN-gamma IFN-gamma was first described 30 years ago as an antiviral agent (Wheelock, 1965). Since that time the protein has been shown to be a remarkably pleiotropic cytokine which plays important roles in modulating virtually all phases of. immune and inflammatory responses. The cDNAs for murine IFN-gamma (Gray and Goeddel, 1983) and human IFN-gamma (Gray and Goeddel, 1982) have been cloned, sequenced, and characterized. IFN-gamma is a member of a family of proteins related by their ability to protect cells from viral infection. This family has been divided into three distinct classes based on a variety of criteria, IFN-alpha (originally known as Type I IFN or Leukocyte IFN), IFN-beta (also originally known as Type I IFN or Fibroblast IFN) and IFN-gamma (originally known as Type II IFN or Immune IFN). IFN-gamma is unrelated to the Type I interferons at both the genetic and protein levels (Gray et al., 1982). The human and murine IFN-gamma proteins display a strict species specificity in their ability to bind to and activate human and murine cells. This is due at least in part to their modest homologies at both the cDNA and amino acid levels (60% and 40% respectively). IFN-gamma is produced by a unique set of stimuli and only by T lymphocytes and natural killer (NK) cells. The human and murine genes for IFN-gamma are 6 kb in size, and each contain four exons and three introns. These genes have been localized to human chromosome 12 (12q24.1) and murine chromosome 10. Activation of the human gene leads to the transcription of a 1.2 kb mRNA that encodes a 166 amino acid polypeptide (Derynck et al., 1982). The human protein contains a 23 residue amino terminal hydrophobic signal sequence which gets proteolytically removed, giving rise to a mature 143 residue positively charged polypeptide with a predicted molecular mass of 17 kDa. Variable post-translational enzymatic degradation of the positively charged carboxy terminus (Rinderknecht et al., 1984) is responsible for the charge heterogeneity of the fully mature molecule. Proteins with six different carboxy termini have been detected for both natural and recombinant forms of IFN-gamma. Two polypeptides self-associate to form a homodimer with an apparent molecular mass of 34 kDa (Scahill et al., 1983). The homodimer is the biologically active form of the protein. Mature human IFN-gamma contains no cysteine residues, thus the homodimer is held together entirely by noncovalent forces. This quaternary structure of the native protein explains its characteristic sensitivity to extremes of heat (protein denatured at temperatures above 56°), and pH (activity rapidly lost at pH values less than 4.0 and greater than 9.0) (Mulkerrin and Wetzel, 1989). The remarkable pleiotropic effects of IFN-gamma are mediated through binding to a single type of IFN-gamma receptor. The structure and function of murine and human IFN-gamma receptors have been described (Schreiber et al., 1992). These receptor proteins are expressed on nearly all cells (except erythrocytes), and platelets (Anderson et al, 1982). The receptor binds ligand with high affinity (Kd = 10" 9 - 10-'°M) and is expressed on most cells at modest levels (200 - 25,000 sites/cell). Upon IFN-gamma . binding to the receptor at the cell surface, the intracellular domain of the receptor is phosphorylated at serine and threonine residues (Hershey et al., 1990). One of -the major physiologic roles of IFN-gamma is as a regulator of immune response induction, specifically its ability to regulate expression of class I and II major histocompatibility (MHC) antigens on a variety of immunologically important cell types (Trinchieri and Perussia, 1985) Functionally, IFN-gamma dependent upregulation of MHC gene expression is an important step in promoting antigen presentation during the inductive phase of immune responses and may play a role in antitumor activity of IFN-gamma (Buchmeier and Schreiber, 1985). Another major physiologic role for IFN-gamma is its ability to activate human macrophage cytotoxicity (Schreiber and Celada, 1985). Therefore, IFN-gamma is the primary cytokine responsible for inducing nonspecific cell-mediated mechanisms of host defense toward a variety of intracellular and extracellular parasites and neoplastic cells (Bancroft et al., 1987). This activation is a result of several distinct functions of IFN-gamma. IFN-gamma has been shown to effect the differentiation of immature myeloid precursors into mature monocytes (Adams and Hamilton, 1984). IFN-gamma promotes antigen presentation in macrophages, through the induction of MHC class II expression as described above, but also by increasing levels of several intracellular enzymes important for antigen processing (Allen and Unanue, 1987). Macrophage cell surface proteins such as ICAM-1 are upregulated by IFN-gamma, thus enhancing the functional results of the macrophage-T cell interaction during antigen presentation (Mantovani and Dejana, 1989). IFN-gamma activates the production of macrophage derived cytocidal compounds such as reactive oxygen- and reactive nitrogen-intermediates and tumor necrosis factor-a (TNF-a) (Ding et al., 1988). IFN-gamma also reduces the susceptibility of macrophage populations to microbial infections .(Bancroft et al., 1989). Animal models have been used to study the role of IFN-gamma in the clearance of microbial pathogens. Neutralizing monoclonal antibodies to IFN-gamma were injected into mice before infecting them with sublethal doses of various microbial pathogens. These mice lost their ability to resolve the infection initiated with Listeria monocytogenes (Buchmeier and Schreiber, 1985), Toxoplasma gondii (Suzuki et al., 1988), or Leishmania major (Green et al, 1990). Besides these nonspecific cell mediated cytocidal activities, IFN-gamma also enhances other macrophage immune response effector functions. IFN-gamma up-regulates expression of Fc receptors on monocytes/macrophages (FcgRI), thus enhancing the capacity of the macrophage for antibody dependent cell killing (Erbe et al, 1990). IFN-gamma also promotes humoral immunity through enhancement of complement activity. It does this in two ways, i) by promoting the synthesis of a variety of complement proteins (ie., C2, C4, and Factor B) by macrophages and fibroblasts, and ii) by regulating the expression of complement receptors on the mononuclear phagocyte plasma membrane (Strunk et al, 1985). IFN-gamma also exerts its effects on other cells of the immune system. It regulates immunoglobulin isotype switching on B cells (Snapper and Paul, 1987). IFN-gamma plays a positive role in the generation of CD8 + cytolytic T cells (CTLs) (Landolfo et al, 1985) and enhances NK cell activity. Recently, it has been unequivocally established that CD4 + T cells do not constitute a homogeneous class of cells. Indeed, a paradigm of lymphokine biology and of the function of CD4 + T cells has arisen, the so-called Thl/Th2 paradigm (for a review see Paul and Seder, 1994). The T HI clones, through their production of IFN-gamma, are well suited to induce enhanced microbicidal and antitumor activity in macrophages as detailed above (enhanced cellular immunity), while the Th2 clones make products (IL-4, IL-5, IL-6, IL-10, IL-13) that are well adapted to act in helping B cells develop into antibody-producing cells (enhanced humoral immunity). The role played by IFN-gamma at this crucial nexus of T cell effector function is fundamental to the success or failure of the immune response. IFN-gamma plays a major role in promoting inflammatory responses both directly, and indirectly through its ability to enhance TNF- α production. During an inflammatory response, cells leave the circulation and migrate to the point of infection. During this process they must first bind to and then extravasate through vascular endothelium. Both IFN-gamma and TNF-α can promote the expression of overlapping sets of cell adhesion molecules (ICAM-1, E-selectin, and others) that play an important role in this process (Pober et al, 1986; Thornhill et al, 1991). In fact, experiments have shown that these two cytokines exhibit synergistic effects in up-regulating cell adhesion molecules in vivo (Munro et al, 1989). One can envision microbial infections in which the microorganism is already widespread at the time the immune response develops or in which the response does not quickly rid the host of the infectious agent. This results in continued T cell activation inducing both local inflammation and tissue damage with ensuing loss of normal function. Indeed, when the infectious agent is of little intrinsic pathogenicity, the disease induced by the infection may largely reflect the consequences of such a response. Excessive production of IFN-gamma may play a role in autoimmune disorders (for review see Paul and Seder, 1994 and Steinman, 1993). The mechanism for this may involve excessive tissue damage due to aberrant or enhanced expression of class I and class II MHC molecules or the role of an excessive T H1 cellular response. A role for IFN-gamma and the tissue-damaging effects of immune responses mediated by T H ,-like cells has been suggested in autoimmune disorders such as rheumatoid arthritis (Feldmann, 1989), juvenile diabetes (Rapoport et al, 1993), myasthenia gravis (Gu et al, 1995), severe inflammatory bowel disease (Kuhn et al, 1993), and multiple sclerosis (Traugott, 1988). IL-4 Interleukin-4 (IL-4) is a remarkably pleiotropic cytokine first identified in 1982 as a B cell growth factor (BCGF) (Howard et al, 1982). In that same year, IL-4 was identified as an IgGl enhancing factor (Isakson et al, 1982). Because of the effect IL-4 has on B cells, it was first called BCGF-1 , later termed BSF-1 (B-cell stimulatory factor- 1), and in 1986 it was given the name IL-4. The cDNAs for murine IL-4 (Noma et al, 1986; Lee et al, 1986) and human IL-4 (Yokota et al, 1986) have been cloned, sequenced, and characterized. IL-4 can be regarded as the prototypic member of a family of immune recognition-induced lymphokines designated the "IL-4 family" (for a review see Paul, 1991). This family consists of IL-4, IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). The properties shared by these proteins leads to this grouping and include, i) the linkage of the genes for the members of the family (van Leeuwen et al, 1989), ii) the action of each member of the family as a hematopoietic growth factor in addition to any effects it may exert on lymphoid cells, iii) the receptors for these proteins are all members of the hematopoietin family of receptors (Bazan, 1990a), and iv) coexpression of these factors by a subpopulation of cloned CD4 + T cells (the so-called T^ cells) (Mosmann et al, 1989) and by mast cells (Plaut et al, 1989). The remarkable pleiotropic effects of IL-4 are mediated through binding to cell surface receptors (IL-4R). The murine IL-4R (Mosely et al, 1989; Harada et al, 1990), and the human IL-4R (Idzerda et al, 1990; Galizzi et al, 1990) have been cloned, sequenced, and characterized. IL-4R are present on a variety of hematopoietic (Park et al, 1987) and nonhematopoietic cells (Lowenthal et al, 1988). On both human and murine resting T and B cells, IL-4R are present in low numbers (<400) and are regulated by cytokines and other factors. The receptor binds IL-4 with high affinity (Kd = 10" 10 M). Now that most of the receptors for immunoregulatory and hematopoietic cytokines have been cloned, it is apparent that the majority of these receptors fall into a large family. This hematopoietic cytokine receptor superfamily includes receptors for IL-4, IL-2 ( b and g chains), IL-7, IL-9, and IL-13 which modulate the lymphoid system; and receptors for erythropoietin, granulocyte-colony stimulating factor (G-CSF), GM-CSF, IL-3, and IL-5 which modulate the hemopoietic system. The superfamily also includes receptors for factors believed to normally function outside the immune and hematopoietic systems, including receptors for growth hormone (GH), prolactin, leukemia inhibitory factor (LIF), IL-6, IL-11, and ciliary neurotrophic factor (CNF) (for a review see Kishimoto et al, 1994). A general first step in the signaling processes of immune and hematopoietic cytokines may be ligand-induced dimerization of receptor components whose cytoplasmic regions interact to initiate a downstream signaling cascade. The IL-4 receptor has a long putative intracellular domain (553 amino acids in mouse, 569 in human) with no known consensus sequences for kinase activity or for nucleotide-binding regions. The biochemical nature of signals induced by the binding of IL-4 to its receptor have not been elucidated. It does appear that the cytosolic domain of the receptor is essential for its signaling function (Mosely et al, 1989). Ligand induced dimerization of the IL-4 receptor appears to be a critical first step in IL-4 mediated signal transduction. One of the major physiologic roles of IL-4 is as a B lymphocyte activation and differentiation factor (Rabin et al, 1985; Oliver et al, 1985). The protein was first isolated based on this activity. In this regard, IL-4 activates production of IgGl (Vitetta et al, 1985), but is also responsible for isotype switching in B cells from production of IgG to IgE immunoglobulins (Coffinan et al, 1986; Lebman and Coffman, 1988, Del Prete et al, 1988). The effect of IL-4 on the in vivo regulation of IgE has been clearly demonstrated. Neutralization of IL-4 by treatment with a monoclonal anti-IL-4 antibody (Finkelman et al, 1986) or a monoclonal antibody to the IL-4 receptor (Finkelman et al, 1990) will block the IgE response. A recombinant soluble IL-4 receptor has been shown to inhibit IgE production by up to 85% in vivo (Sato et al, 1993). IL-4 deficient mice produced by gene-targeting in murine embryonic stem cells have normal B and T cell development, but serum levels of IgGl and IgE are strongly reduced (Kuhn et al, 1991). IL-4 augmented IgE production leads to an atopic state (allergy/asthma) (Finkelman et al, 1989; Katona et /., 1991). The IL-4 mediated up-regulation of IgGl may play a role in the inflammation cascade. IgGl has recently been shown to form immune complexes which bind to the cellular receptors for the Fc domain of immunoglobulins (FcRs) leading to an inflammatory response (Sylvestre and Ravetch, 1994; Ravetch, 1994). IL-4 transgenic mice have been produced that hyperexpress IL-4 (Tepper et al, 1990). These mice have elevated levels of serum IgGl and IgE and they develop allergic inflammatory disease. These findings demonstrate the critical role IL-4 plays in the humoral immune response. Another major physiologic role for IL-4 is as a T lymphocyte growth factor (Hu-Li et al, 1987; Spits et al, 1987). IL-4 enhances the proliferation of precursors of cytotoxic T cells (CTLs) and their differentiation into active CD8 * CTLs (Widmer and Grabstein, 1987; Trenn, 1988). IL-4 appears to augment the IL-2 driven induction of lymphokine-activated killer (LAK) cells (Higuchi et al, 1989), which have been shown to lyse a variety of tumor cell targets without major histocompatibility complex (MHC) restriction. The role played by IL-4 at this crucial nexus of T cell effector function is fundamental to the success or failure of the immune response. IL-4 has been shown to affect nonlymphoid hematopoietic cells in a variety of ways. IL-4 has been shown to modulate monocyte/macrophage growth (Mclnnes and Rennick, 1988; Jansen et al, 1989) while enhancing their differentiation and cytotoxic activity for certain tumor cells (Crawford,et al, 1987; Te Velde et al, 1988). IL-4 also has activity as a stimulant of mast cell growth (Mosmann et al, 1986; Brown et al, 1987), and increases production and recruitment of eosinophils (Tepper et al, 1989). IL-4 alone or in conjunction with other cytokines can promote the expression of a variety of cell-surface molecules on various cell types with diverse implications for disease. Specifically, IL-4 can interact with tumor necrosis factor (TNF) to selectively enhance vascular cell adhesion molecule- 1 (VCAM-1) expression contributing to T cell extravasation at sites of inflammation (Briscoe et al, 1992). IL-4 alone or in combination with TNF or IFN-gamma has been shown to increase both MHC antigen and tumor-associated antigen expression on a variety of neoplastic cells (Hoon et al, 1991). As detailed above, IgGl immune complexes bind to the cellular receptors for the Fc domain of immunoglobulins (FcRs) leading to an inflammatory response. Inhibition of IL-4 and the subsequent reduction in IL-4 mediated IgGl expression may prove efficacious against immune complex inflammatory disease states. Indeed, inhibitory ligands to IL-4 might also prevent the IL-4 mediated overexpression of VCAM-1, thus attenuating the ability of T cells to extravasate at sites of inflammation. Inhibition of IL-4 activity with a monoclonal antibody, a recombinant soluble IL-4 receptor, or gene knock-out, results in a reduction of serum IgE levels. An inhibitory oligonucleotide ligand to IL-4 could be clinically effective against allergy and allergic asthma. A recent report has described a disorder in bone homeostasis in transgenic mice that inappropriately express IL-4 under the direction of the lymphocyte-specific proximal promoter for the lck gene (Lewis et al, 1993). Bone disease in these mice resulted from markedly decreased bone formation by osteoblasts, features identical to those found in human osteoporosis. Inhibiting this IL-4 mediated reduction in osteoblast activity may prove beneficial against osteoporosis. Graft-versus-host disease (GVHD) is a major complication of human tissue transplantation. GVHD does not exist as a single clinical manifestation but can involve immunologic abnormalities ranging from immunodeficiency to systemic autoimmunities (Ferrara et al, 1991). These systemic autoimmunities include clinical and serological manifestations of human systemic lupus erythematosus (SLE). Several murine models of SLE have been developed (Gleichmann et al, 1982; van Rappard-van Der Veen et al, 1982), and the induction of systemic GVHD in mice has been described (Via et al, 1988). Two recent studies have shown in vivo efficacy of a mouse monoclonal antibody to IL-4 in preventing GVHD and SLE in these murine model systems (Umland et al, 1992; Ushiyama et al, 1995). These observations suggest that an inhibitor of human IL-4 may be effective in treatment of chronic systemic autoimmunities such as SLE and GVHD. A variety of microbicidal infections are characterized by depressed cellular but enhanced humoral immune responses, which suggests a T m type of response to infection. This T m phenotype is characterized by T cell secretion of IL-4, as detailed earlier. IL-4 blocks the microbicidal activity of IFN-gamma activated macrophages in fighting Leishmania major infection (Liew et al, 1989; Leal et al, 1993). Inhibition of IL-4 would enhance the T H , effector arm of the immune response enhancing cellular immunity and leading to the resolution of infection. Neutralization of IL-4 in vivo allows mice otherwise susceptible to Leishmania major infection to fight off the parasite and clear the infection (Heinzel et al, 1989). Several informative studies have looked at the T m IT m phenotypic distinction in infected mice, and suggest a T H , dominated response being most effective in fighting microbial infection (for a review, see Sher and Coffman, 1992). IL-10 IL-10 is a cytokine produced by the Th2 cells, but not Thl cells, and inhibits synthesis of most of all cytokines produced by Thl cells but not Th2 cells (Mosmann et al, 1991). In addition to the effect on CD4 + cells with Thl phenotype, IL-10 also inhibits CD8 + T cells with "Thl -like" phenotype. IL-10 is a potent suppressor of macrophage activation. It can suppress the production of proinflammatory cytokines, including TNFα , IL-1, IL-6, IL-8 and IFN-gamma. Overall, these results suggest that IL-10 is a potent macrophage deactivator and an effective anti-inflammatory reagent. In addition, IL-10 prevents the IFN- g -induced synthesis of nitric oxide, resulting in decreased resistance to intracellular parasites (Gazzinelli et al, 1992). Both human and mouse (hIL-10 and mIL-10, respectively) have been cloned and expressed (Moore et al, 1990; Vieira et al, 1991). The two cDNAs exhibit high degree of nucleotide sequence homology (>80%) throughout and encode very similar open reading frames (73% amino acid homology). Both proteins are expressed as noncovalent homodimers that are acid labile (Moore et al, 1993). Whether monomers are equally bioactive is not clear yet. Based on the primary structure IL-10 has been categorized into the four a-helix bundle family of cytokines (Shanafelt et α/.,1991). Possibly due to high degree of sequence homology and similar structure hIL-10 has been shown to be active on mouse cells (Moore et al, 1993) but not vice versa. hIL-10 is an 18 kDa polypeptide with no detectable carbohydrate; however, in mIL-10 there is one N-linked glycosylation. The recombinant hIL-10 has been expressed in CHO cells, COS7 cells, mouse myeloma cells, the baculovirus expression system and E. coli. The rIL-10 expressed in these systems have indistinguishable biological behavior (Moore etal.,1993). Parasitic infection often leads to polarized immune response of either Thl or Th2 type which can mediate protection or susceptibility. The outcome of a parasitic infection depends on the nature of the parasite and the host. The best understood example is Leishmania major infection in mice. L. major is a protozoan parasite that establishes an intracellular infection in macrophages, where it is mainly localized in phagolysosomes. Activated macrophages can efficiently destroy the intracellular parasite and thus parasitic protection is achieved by macrophage activation. Nonactivated macrophages do not kill these organisms. As expected, activation of macrophages upon IFN-gamma treatment enhanced the protection, whereas IL-4 and IL-10 blocked the increased microbicidal activity induced by IFN-gamma (Liew et al, 1989). In most inbred strains (example, C57/BL6) cutaneous infection of L. major often leads to localized infection with spontaneous healing and confers resistance to reinfection. However, in B ALB/c mice, L. major infection induces nonprotective immune response by producing IL-4. The antibody response mediated by IL-4 is ineffective and leads to death (Howard et al, 1980). In healing strains a strong Thl response has been noticed with high level of IFN- g , whereas in susceptible B ALB/c mice a nonproductive Th2 response with significant levels of IL-4 was found (Heinzel et al, 1991). Further it was shown that a single injection of monoclonal anti-IFN-gamma antibody can convert a resistance into a susceptible mouse (Belosevic et al, 1989). As expected, the treatment of BALB/c mice with anti-IL-4 antibody led to the development of Thl response and healing (Sher & Coffrnan, 1992). Thus, depending on the nature of the pathogen, changing the immune response to a T cell subset with a protective phenotype can lead to therapeutic intervention of the disease state. Understanding the regulation between the Thl and Th2 phenotype mediated by cytokines will help in designing cytokine-antagonist in therapeutics. The production of IL-10 is strongly increased in mice infected with various pathogens such as Leishmania major, Schistosoma mansoni, Trypanosoma cruzi and Mycobacterium Leprae (Sher et al, 1992; Salgame et al, 1991, Heinzel et al, 1991). When designing immune therapy to facilitate mounting the right arm of defense mechanism toward pathogens, it is important to maintain a balance between the two arms also. Th2-type responses may be important in controlling the tissue damage mediated by Thl cells during the response to an intracellular infectious agent. Keeping some Thl cells functioning in a predominantly Th2 environment can help abrogate damaging effects of Thl by secreting IL-10 and IL-4. One extreme of the spectrum of Thl/Th2 is reflected in transgenic mice lacking the IL-10 gene (Kuhn et al, 1993). The IL-10 deficient mouse is normal with respect to its development of T and B cell subsets. However these mice develop chronic enterocolitis (or inflammatory bowel disease) due to chronic inflammation via continuous overproduction of cytokines such as TNFα and IFN-gamma(Thl response). IL-12 can also induce the development of the Thl subset. By using Lysteria monocytogen, an intracellular gram-positive bacterium, infection in antibody T cell receptor transgenic mice as a model it has been shown that IL-10 can block the production of IL-12 from macrophages (Hsieh et α/.,1993) . Thus an IL-10-antagonist will tip the Thl/Th2 population predominantly to Th2 type environment by 1 , preventing the inhibition of the production of Thl cytokines 2 by allowing the production of a cytokine that induces the development of Thl subset. With experimental evidence in hand it has been proposed that the resistance and/or progression to AIDS is dependent on a Thl/Th2 stage of an individual (Clerici & Shearer, 1993). This hypothesis is based on the findings that progression to AIDS is characterized by loss of IL-2 and IFN-gamma production (loss of Thl response) with increase in IL-4 and IL-10 (acquired Th2 response). Many seronegatives (HIV-exposed individuals) generate a strong Thl -type response. It is important to note that after seroconversion both IL-4 and IL-10 levels go up at the expense of IL-4 and IFN-gamma. However, in full-blown AIDS patients, Th2 response seems to be mediated by high levels of IL-10 but not with IL-4, the level of which goes down to normal in these individuals. An anti-IL-10 reagent may serve as a potential therapeutic in shifting the Th2 response to Thl in AIDS patients to offer protection. TNFα TNFα is an extracellular cytokine and a central mediator of the immune and inflammatory response (Beutler et al, 1989; Vassalli, 1992). It is a homo-trimer (Smith et al, 1987, Eck et al, 1988), and has a subunit size of 17 kD. It circulates at concentrations of less than 5 pg/ml in healthy individuals (Dinarello et al, 1993) and it can go as high as 1000 pg/ml in patients with sepsis syndrome (Casey et al, 1993). The human TNFα is nonglycosylated, whereas in some other species (notably the mouse) glycosylation occurs on a single N-linked site in the mature protein, but the sugar moiety is not essential for biological activity (Beutler et al, 1989). The human TNFα is acidic with a pH of 5.3 (Aggarwal et al, 1985). Each TNFα subunit consists of an anti parallel β-sandwich and it participates in a trimer formation by an edge-to-face packing of β-sheets. The structure of the TNFα trimer resembles the "jelly-roll" structural motif characteristic of viral coat proteins (Jones et al, 1989). TNFα is a relatively stable molecule and may be exposed to chaotropic agents such as urea, SDS, or guanidinium hydrochloride, and renatured with recovery of as much as 50% of the initial biological activity. The TNFα renaturability may reflect the limited number of internal disulfide bonds (one per monomer) required for maintenance of structure (Beutler et al, 1989). Another related molecule, TNFβ, has the same bioactivity as TNFa . The interspecies sequence identity within the TNFα and TNFβ families is 71% and 61%, respectively (Beutler et al, 1989). The sequence identity between hTNF-α and hTNF-β is only 29% (Beutler et al, 1989). Despite their low similarity, both hTNFα and hTNFβ bind to the same receptors with comparable affinities. TNFα mediates its bioactivity through binding to cell surface receptors. The TNFα receptors are found on the surface of virtually all somatic cells tested (Vassalli, 1992). Two distinct TNFα receptors have been characterized of apparent molecular weights 55kD (p55 TNFα-Rl) and 75kD (p75 TNFα-R2) (Hohmann et al, 1989; Brockhaus et al, 1990; Loetscher et al, 1991). Both receptors bind TNFα and TNFβ with high affinities (Kd=0.3-0.6 nM) (Loetscher et al, 1990; Schall et al, 1990; Pennica et al, 1992). TNFα has diverse activities, and thus is implicated in several diseases as follows: Septic shock. Sepsis incidents have been increasing for the last 60 years and is the most common cause of death in intensive care units in the United States (Parrillo, 1991). The mortality of septic shock remains at approximately 50% despite the standard use of aggressive antibiotics and cardiovascular support for the past 10 years (Parrillo, 1991). The evidence implicating TNFα in sepsis is as follows. Pretreatment of mice or baboons with monoclonal antibodies to TNFα protects them from lethal doses of E. coli LPS (Beutler et al, 1985). Anti-TNFα antibodies protect primates against lethal endotoxin sepsis and against lethal S. αwews-induced shock (Fiedler et al, 1992; Hinshaw et al, 1992). Soluble-TNFα-receptor (p55)-IgG-Fc fusions (TNFα receptor immunoadhesin) were found to protect mice from endotoxic shock, even when administered lhr after endotoxin infusion. The same immunoadhesin was also effective against listeriosis in mice (Haak-Frendscho et al, 1994). Another immunoadhesin based on the p75 receptor was also shown to be effective in lethal endotoxemia and it was functioning simultaneously as both TNFα carrier and TNFα antagonist (Mohler et al, 1993). Cachexia. In vivo administration of TNFα causes cachexia in mice (Oliff et al, 1987). Therefore, TNFα antagonists may protect cancer or AIDS infected patients from cachexia. Cerebral malaria. High levels of TNFα are associated with poor prognosis in children with cerebral malaria, and antibodies to TNF a protect mice from cerebral complications of Plasmodium berghei infection (Grau et al, 1987). Arthritis. Antibodies to TNFα reduce the production of the inflammatory cytokine, IL-1 in synovial cells (Brennan et al, 1989). TNF α is an inducer of collagenase, the major destructive protease in rheumatoid arthritis (Brennan et al, 1989). Anti-TNF α antibodies were found to ameliorate joint disease in murine collagen-induced arthritis (Williams et al, 1992). Transgenic mice carrying the hTNFα gene develop arthritis which can be prevented by in vivo administration of a monoclonal antibody against hTNF α (Keffer et al, 1991 ). Graft Rejection and Graft versus Host Reaction (GVHR). TNFα has been implicated in the acute phase of graft- versus-host disease and in renal allograft rejection. Antagonists of TNFα may then be able to prevent these life-threatening conditions. Anti-TNFα antibodies have been found to delay graft rejection in experimental animals (Piguet, 1992). Also, injection of anti-TNFα antibodies during the acute phase of GVHR reduces mortality, and the severity of intestinal, epidermal, and alveolar lesions (Piguet, 1992). Clinical trials of the efficacy of anti-TNFα antibody in human bone marrow transplantation are underway. AIDS. Studies of intracellular signal transduction pathways revealed that TNFα induces proteins that bind to kB-like enhancer elements and thus takes part in the control of NF-kB-inducible genes (Lenardo et al, 1989; Lowenthal et al, 1989; Osborn et al, 1989). The antiviral activity of TNFα at least in part is mediated by the interaction of NF-kB with a virus-inducible element in the β-interferon gene (Goldfeld et al, 1989; Visvanathan et al, 1989). By an analogous mechanism, TNFα appears to activate human immunodeficiency virus type I (Duh et al, 1989; Folks et al, 1989). Therefore, TNFα antagonists may prove useful in delaying the activation of the AIDS virus and may work in conjunction with other treatments in the cure of AIDS. Parkinson's disease. Recently, elevated TNFα levels have been found in the brain and the cerebrospinal fluid of Parkinsonian patients (Mogi et al,.1994). This report speculates that elevated TNFα levels may be related to neuronal degeneration associated with the disease. RANTES RANTES is a small (MW 8-kD) highly basic (pl~9.5) chemokine that belongs to the CC group (Schall, 1991 ; Baggiolini et al, 1994). It does not appear to be glycosylated (Schall, 1991) and is a chemoattractant for monocytes (Schall et al, 1990; Wang et al, 1993; Wiedermann et al, 1993), basophils (Bischoff et al, 1993; Kuna et al, 1993), eosinophils (Rot et al, 1992), and CD47UCHL1 + T lymphocytes which are thought to be prestimulated or primed helper T cells involved in memory T cell function (Schall et al, 1990). RANTES is not only a chemoattractant but it also stimulates cells to release their effectors leading to tissue damage. For example, RANTES causes histamine release from basophils (Kuna et al, 1992; Kuna et al, 1993; Alam et al, 1993). It also causes the secretion of eosinophil basic peptide (Alam et al, 1993) and the production of oxygen free radicals (Rot et al, 1992) by eosinophils. Initially, it was thought that RANTES was synthesized by activated T cells but recently other cells were found to synthesize it very fast upon stimulation. RANTES mRNA is expressed late (3 to 5 days) after activation of resting T cells, whereas in fibroblasts, renal epithelial and mesangial cells, RANTES mRNA is quickly up-regulated by TNFα stimulation (Nelson et al, 1993). Receptors for RANTES have been identified. There is a promiscuous receptor on the surface of erythrocytes that binds all chemokines with a Kd=5nM (Horuk et al, 1993; Neote et al, 1993). This receptor is thought to be a sink for chemokines to help in the establishment of chemotactic gradients. Signal transducing receptors have also been identified and cloned (Gao et al, 1993; Neote et al, 1993; Van-Riper et al, 1993; Wang et al, 1993). Monocytes carry a G-protein coupled receptor that binds RANTES with estimated Kd of 400 pM, but also MCAF and MlP-la with lower affinities (estimated Kd of 6 and 1.6 nM respectively) (Wang et al, 1993). A receptor molecule has been cloned from neutrophils that can bind RANTES with a lower affinity of about 50 nM (Gao et al, 1993). Disease State. RANTES antagonists may have therapeutic application in inflammation. Blockage of the chemoattractant and effector cell activation properties of RANTES would block local inflammation and tissue damage. The mechanism of action of the RANTES antagonist will be the inhibition of RANTES binding to cell surface receptors. RANTES is chemoattractant for monocytes, basophils, eosinophils and memory lymphocytes. Basophils are the major source of mediators such as histamine and peptido-leukotrienes, and are an essential element of the late-phase responses to allergens in hypersensitivity diseases. These cells are also involved in other inflammatory pathologies, including certain autoimmune reactions, parasitic infections and inflammatory bowel diseases. In these conditions, basophil recruitement and activation is independent of IgE. Numerous reports have accumulated over the years that describe the effects of a group of elusive stimuli operationally called "histamine-releasing factors." A large number of these elusive stimuli may well be contributed by RANTES. Eosinophiles also are important in allergic inflamation, and together with lymphocytes, form prominent infiltrates in the bronchial mucosa of patients with asthma. They are believed to be the cause of epithelial damage and the characteristic airway hyper-reactivity. The recruitement of lymphocytes of the Th2 type, which comigrate with eosinophiles into sites of late-phase reactions, is an important source of other chemoattractant cytokines and growth factors that prime eosinophils. RANTES, with its effects on monocytes, basophils, eosinophils and lymphocytes appears to be a potent stimulator of effector-cell accumulation and activation in chronic inflammatory diseases and in particular, allergic inflammation. The recruitement system of inflammatory cells has some redundancy built into it. However, RANTES has some unique properties. It is a more potent chemoattractant than MCP-1 and MIP-1 a , while MCP-1 is more potent stimulator of histamine release from basophils (Baggiolini et al, 1994). RANTES causes the production of oxygen radicals by eosinophiles while MIP-1 a cannot (Rot et al, 1992). RANTES is as potent as C5a in the recruitement of eosinphiles, but not as potent a trigger of the eosinophil oxydation burst (Rot et al., 1992). C5a is a very potent chemoattractant: however, it lacks the specificity of RANTES. It attracts not only basophils and eosinophils but also neutrophils. Since the eosinophils, but not the neutrophils, are important in the pathophysiology of some inflammatory conditions, such as the allergen-induced late-phase reaction and asthma, specific chemoattractants such as RANTES are expected to be involved. Using in situ hybridization, RANTES expression has been found in interstitial mononuclear cells and proximal tubular epithelial cells in human kidney transplants undergoing rejection. Antibody staining revealed the presence of RANTES not only within the interstitial infiltrate and renal tubular epithelial cells but also in high abundance in inflamed endothelium (Wiedermann et al, 1993). Based on these results a haptotactic mechanism was postulated. Haptotaxis is defined as cell migration induced by surface-bound gradients. The haptotactic mechanism was supported by in vitro experiments and anti-RANTES antibodies have been found to prevent that in vitro haptotaxis. Human rheumatoid synovial fibroblasts express mRNA for RANTES and IL-8 after stimulation with TNFa and IL-lβ (Rathanaswami et al, 1993). There is a differential regulation of expression of IL-8 and RANTES mRNA. Cycloheximide enhanced the mRNA levels for IL-8 and RANTES after stimulation with IL-lβ but reduced the levels of RANTES mRNA after stimulation with TNFα. Also, IL-4 down-regulates and IFN-gamma enhances the TNFα and IL-lβ induced increase in RANTES mRNA, whereas the induction of IL-8 mRNA by TNFα or IL-lβ was inhibited by IFN-gamma and augmented by IL-4. Moreover, the combination of TNFα and IL-lβ synergistically increased the level of IL-8 mRNA, whereas under the same conditions, the levels of RANTES mRNA were less than those induced with TNFα alone. These studies suggest that the synovial fibroblasts may participate in the ongoing inflammatory process in rheumatoid arthritis, and RANTES might be one of the participating effectors. The observed differential regulation of IL-8 and RANTES indicates that the type of cellular infiltrate and the progress of the inflammatory disease is likely to depend on the relative levels of stimulatory and inhibitory cytokines. RANTES has also been implicated in atherosclerosis and possibly in postangioplasty restenosis (Schall, 1991). The participation of MCP-1 in atherosclerosis has been studied to a greater extent. Recently mRNAs for RANTES, MIP-1 a and MP-lβ have been detected in in situ in normal carotid plaque and heart transplant atherosclerosis. RANTES mRNA is not detected in the same cells expressing MlP-la and MlP-lβ, but it is expressed in lymphocytes and macrophages typically more proximal to the lumen. The data argue for positive feed-back mechanisms for the CC chemokines and possible differential expression of these chemokines at various stages in the progression of arterial disease. Finally, elevated RANTES levels have been correlated with endometriosis (Khorram et al, 1993). RANTES levels were elevated in pelvic fluids from women with endometriosis, and these levels correlate with the severity of the disease. Protein Homology between Human and Animal. The murine RANTES has been cloned (Schall et al, 1992). Sequence analysis revealed 85% amino acid identity between the human and mouse proteins. The human and murine RANTES exhibit immune crossreactivity. Boyden chamber chemotaxis experiments reveal some lack of species specificity in monocyte chemoattractant potential, as recombinant muRANTES attracts human monocytes in a dose-dependent fashion in vitro. Also, hRANTES transfection into mouse tumor cell lines produce tumors in which the secretion of hRANTES by those tumors correlates with increased murine monocyte infiltration in vivo (Schall et al, 1992). SELEX A method for the in vitro evolution of nucleic acid molecules with highly specific binding to target molecules has been developed. This method, Systematic Evolution of Ligands by Exponential enrichment, termed SELEX, is described in United States Patent Application Serial No. 07/536,428, entitled "Systematic Evolution of Ligands by Exponential Enrichment," now abandoned, United States Patent Application Serial No. 07/714,131, filed June 10, 1991, entitled "Nucleic Acid Ligands," United States Patent Application Serial No. 07/931,473, filed August 17, 1992, entitled "Nucleic Acid Ligands," now United States Patent No. 5,270,163 (see also PCT/US91/04078), each of which is herein specifically incoφorated by reference. Each of these applications. collectively referred to herein as the SELEX Patent Applications, describes a fundamentally novel method for making a nucleic acid ligand to any desired target molecule. The SELEX method involves selection from a mixture of candidate oligonucleotides and step-wise iterations of binding, partitioning and amplification, using the same general selection scheme, to achieve virtually any desired criterion of binding affinity and selectivity. Starting from a mixture of nucleic acids, preferably comprising a segment of randomized sequence, the SELEX method includes steps of contacting the mixture with the target under conditions favorable for binding, partitioning unbound nucleic acids from those nucleic acids which have bound specifically to target molecules, dissociating the nucleic acid-target complexes, amplifying the nucleic acids dissociated from the nucleic acid-target complexes to yield a ligand-enriched mixture of nucleic acids, then reiterating the steps of binding, partitioning, dissociating and amplifying through as many cycles as desired to yield highly specific, high affinity nucleic acid ligands to the target molecule. The basic SELEX method has been modified to achieve a number of specific objectives. For example, United States Patent Application Serial No. 07/960,093, filed October 14, 1992, entitled "Method for Selecting Nucleic Acids on the Basis of Structure," describes the use of SELEX in conjunction with gel electrophoresis to select nucleic acid molecules with specific structural characteristics, such as bent DNA. United States Patent Application Serial No. 08/123,935, filed September 17, 1993, entitled "Photoselection of Nucleic Acid Ligands" describes a SELEX based method for selecting nucleic acid ligands containing photoreactive groups capable of binding and/or photocrosslinking to and/or photoinactivating a target molecule. United States Patent Application Serial No. 08/134,028, filed October 7, 1993, entitled "High-Affinity Nucleic Acid Ligands That Discriminate Between Theophylline and Caffeine," describes a method for identifying highly specific nucleic acid ligands able to discriminate between closely related molecules, termed Counter-SELEX. United States Patent Application Serial No. 08/143,564, filed October 25, 1993, entitled "Systematic Evolution of Ligands by Exponential Enrichment: Solution SELEX," describes a SELEX-based method which achieves highly efficient partitioning between oligonucleotides having high and low affinity for a target molecule. United States Patent Application Serial No. 07/964,624, filed October 21, 1992, entitled "Methods of Producing Nucleic Acid Ligands" describes methods for obtaining improved nucleic acid ligands after SELEX has been performed. United States Patent Application Serial No. 08/400,440, filed March 8, 1995, entitled "Systematic .Evolution of Ligands by Exponential Enrichment: Chemi-SELEX," describes methods for covalently linking a ligand to its target. The SELEX method encompasses the identification of high-affinity nucleic acid ligands containing modified nucleotides conferring improved characteristics on the ligand, such as improved in vivo stability or improved delivery characteristics. Examples of such modifications include chemical substitutions at the ribose and/or phosphate and/or base positions. SELEX-identified nucleic acid ligands containing modified nucleotides are described in United States Patent Application Serial No. 08/117,991, filed September 8, 1993, entitled "High Affinity Nucleic Acid Ligands Containing Modified Nucleotides," that describes oligonucleotides containing nucleotide derivatives chemically modified at the 5- and 2'-positions of pyrimidines. United States Patent Application Serial No. 08/134,028, supra, describes highly specific nucleic acid ligands containing one or more nucleotides modified with 2'-amino (2'-NH 2 ), 2'-fluoro (2'-F), and/or 2'-O-methyl (2'-OMe). United States Patent Application Serial No. 08/264,029, filed June 22, 1994, entitled "NoveJ Method of Preparation of 2 1 Modified Pyrimidine Intramolecular Nucleophilic Displacement," describes oligonucleotides containing various 2'-modified pyrimidines. The SELEX method encompasses combining selected oligonucleotides with other selected oligonucleotides and non-oligonucleotide functional units as described in United States Patent Application Serial No. 08/284,063, filed August 2, 1994, entitled "Systematic Evolution of Ligands by Exponential Enrichment: Chimeric SELEX" and United States Patent Application Serial No. 08/234,997, filed April 28, 1994, entitled "Systematic Evolution of Ligands by Exponential Enrichment: Blended SELEX," respectively. These applications allow the combination of the broad array of shapes and other properties, and the efficient amplification and replication properties, of oligonucleotides with the desirable properties of other molecules. Each of the above described patent applications which describe modifications of the basic SELEX procedure are specifically incorporated by reference herein in their entirety. BRIEF SUMMARY OF THE INVENTION The present invention includes methods of identifying and producing nucleic acid ligands to cytokines and the nucleic acid ligands so identified and produced. In particular, RNA sequences are provided that are capable of binding specifically to IFN-gamma, IL-4, IL-10, and TNFα. In addition, DNA sequences are provided that are capable of binding specifically to RANTES. Specifically included in the invention are the RNA ligand . sequences shown in Tables 3, 4, 7, 8, 10, and 12 (SEQ ID NOS:7-73; 79-185; 189-205; 209-255). Further included in this invention is a method of identifying nucleic acid ligands and nucleic acid ligand sequences to a cytokine comprising the steps of (a) preparing a candidate mixture of nucleic acids, (b) contacting the candidate mixture of nucleic acids with a cytokine, (c) partitioning between members of said candidate mixture on the basis of affinity to the cytokine, and (d) amplifying the selected molecules to yield a mixture of nucleic acids enriched for nucleic acid sequences with a relatively higher affinity for binding to the cytokine. Further included in this invention is a method of identifying nucleic acid ligands and nucleic acid ligand sequences to a cytokine selected from the group consisting of IFN-gamma, IL-4, IL-10, TNFα, and RANTES comprising the steps of (a) preparing a candidate mixture of nucleic acids, (b) contacting the candidate mixture of nucleic acids with said cytokine, (c) partitioning between members of said candidate mixture on the basis of affinity to said cytokine, and (d) amplifying the selected molecules to yield a mixture of nucleic acids enriched for nucleic acid sequences with a relatively higher affinity for binding to said cytokine. More specifically, the present invention includes the RNA ligands to IFN-gamma, IL-4, IL-10, and TNFα identified according to the above-described method, including those ligands shown in Tables 3, 4, 7, 8, 10, and 12 (SEQ ID NOS:7-73; 79-185; 189-205; 209-255). Also included are RNA ligands to IFN-gamma, IL-4, IL-10, and TNFα that are substantially homologous to any of the given ligands and that have substantially the same ability to bind IFN-gamma, IL-4, IL-10, and TNFα and inhibit the function of IFN-gamma, IL-4, IL-10, and TNFα. Further included in this invention are nucleic acid ligands to IFN-gamma, IL-4, IL-10, and TNFα that have substantially the same structural form as the ligands presented herein and that have substantially the same ability to bind IFN-gamma, IL-4, IL-10, and TNFα and inhibit the function of IFN-gamma, IL-4, IL-10, and TNFα. The present invention also includes modified nucleotide sequences based on the nucleic acid ligands identified herein and mixtures of the same. DETAILED DESCRIPTION OF THE INVENTION This application describes high-affinity nucleic acid ligands to cytokines identified through the method known as SELEX. SELEX is described in U.S. Patent Application Serial No. 07/536,428, entitled Systematic Evolution of Ligands by Exponential Enrichment, now abandoned, U.S. Patent Application Serial No. 07/714,131, filed June 10, 1991 , entitled Nucleic Acid Ligands, United States Patent Application Serial No. 07/931,473, filed August 17, 1992, entitled Nucleic Acid Ligands, now United States Patent No. 5,270,163, (see also PCT/US91/04078). These applications, each specifically incoφorated herein by reference, are collectively called the SELEX Patent Applications. In its most basic form, the SELEX process may be defined by the following series of steps: 1) A candidate mixture of nucleic acids of differing sequence is prepared. The candidate mixture generally includes regions of fixed sequences (i.e., each of the members of the candidate mixture contains the same sequences in the same location) and regions of randomized sequences. The fixed sequence regions are selected either: (a) to assist in the amplification steps described below, (b) to mimic a sequence known to bind to the target, or (c) to enhance the concentration of a given structural arrangement of the nucleic acids in the candidate mixture. The randomized sequences can be totally randomized (i.e., the probability of finding a base at any position being one in four) or only partially randomized (e.g., the probability of finding a base at any location can be selected at any level between 0 and 100 percent). 2) The candidate mixture is contacted with the selected target under conditions favorable for binding between the target and members of the candidate mixture. Under these circumstances, the interaction between the target and the nucleic acids of the candidate mixture can be considered as forming nucleic acid-target pairs between the target and those nucleic acids having the strongest affinity for the target. 3) The nucleic acids with the highest affinity for the target are partitioned from those nucleic acids with lesser affinity to the target. Because only an extremely small number of sequences (and possibly only one molecule of nucleic acid) corresponding to the highest affinity nucleic acids exist in the candidate mixture, it is generally desirable to set the partitioning criteria so that a significant amount of the nucleic acids in the candidate mixture (approximately 5-50%) are retained during partitioning. 4) Those nucleic acids selected during partitioning as having the relatively higher affinity to the target are then amplified to create a new candidate mixture that is enriched in nucleic acids having a relatively higher affinity for the target. 5) By repeating the partitioning and amplifying steps above, the newly formed candidate mixture contains fewer and fewer weakly binding sequences, and the average degree of affinity of the nucleic acids to the target will generally increase. Taken to its extreme, the SELEX process will yield a candidate mixture containing one or a small number of unique nucleic acids representing those nucleic acids from the original candidate mixture having the highest affinity to the target molecule. The SELEX Patent Applications describe and elaborate on this process in great detail. Included are targets that can be used in the process; methods for partitioning nucleic acids within a candidate mixture; and methods for amplifying partitioned nucleic acids to generate enriched candidate mixture. The SELEX Patent Applications also describe ligands obtained to a number of target species, including both protein targets where the protein is and is not a nucleic acid binding protein. The nucleic acid ligands described herein can be complexed with a lipophilic compound (e.g., cholesterol) or attached to or encapsulated in a complex comprised of lipophilic components (e.g., a liposome). The complexed nucleic acid ligands can enhance the cellular uptake of the nucleic acid ligands by a cell for delivery of the nucleic acid ligands to an intracellular target. U.S. Patent Application No. 08/434,465, filed May 4, 1995, entitled "Nucleic Acid Ligand Complexes," which is incoφorated in its entirety herein, describes a method for preparing a therapeutic or diagnostic complex comprised of a nucleic acid ligand and a lipophilic compound or a non-immunogenic, high molecular weight compound. The methods described herein and the nucleic acid ligands identified by such methods are useful for both therapeutic and diagnostic puφoses. Therapeutic uses include the treatment or prevention of diseases or medical conditions in human patients. Diagnostic utilization may include both in vivo or in vitro diagnostic applications. The SELEX method generally, and the specific adaptations of the SELEX method taught and claimed herein specifically, are particularly suited for diagnostic applications. SELEX identifies nucleic acid ligands that are able to bind targets with high affinity and with suφrising specificity. These characteristics are, of course, the desired properties one skilled in the art would seek in a diagnostic ligand. The nucleic acid ligands of the present invention may be routinely adapted for diagnostic puφoses according to any number of techniques employed by those skilled in the art. Diagnostic agents need only be able to allow the user to identify the presence of a given target at a particular locale or concentration. Simply the ability to form binding pairs with the target may be sufficient to trigger a positive signal for diagnostic puφoses. Those skilled in the art would also be able to adapt any nucleic acid ligand by procedures known in the art to incoφorate a labeling tag in order to track the presence of such ligand. Such a tag could be used in a number of diagnostic procedures. The nucleic acid ligands to cytokines described herein may specifically be used for identification of the cytokine proteins. SELEX provides high affinity ligands of a target molecule. This represents a singular achievement that is unprecedented in the field of nucleic acids research. The present invention applies the SELEX procedure to the specific target. In the Example section below, the experimental parameters used to isolate and identify the nucleic acid ligands to cytokines are described. In order to produce nucleic acids desirable for use as a pharmaceutical, it is preferred that the nucleic acid ligand ( 1 ) binds to the target in a manner capable of achieving the desired effect on the target; (2) be as small as possible to obtain the desired effect; (3) be as stable as possible; and (4) be a specific ligand to the chosen target. In most situations, it is preferred that the nucleic acid ligand have the highest possible affinity to the target. In co-pending and commonly assigned U.S. Patent Application Serial No. 07/964,624, filed October 21 , 1992 ('624), methods are described for obtaining improved nucleic acid ligands after SELEX has been performed. The '624 application, entitled Methods of Producing Nucleic Acid Ligands, is specifically incoφorated herein by reference. This invention includes the SELEX process for identification of nucleic acid ligands of cytokines. Cytokines are a diverse group of small proteins that mediate cell signaling/communication. Cytokines include immune/ hematopoietins (e.g.,EPO, GM-CSF, G-CSF, LIF, OSM, CNTF, GH, PRL, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12), interferons (e.g.,IFNα, IFNβ, IFN-gamma), TNF-related molecules (e.g.,TNFα, IFNβ, gp 39 (CD40-L), CD27-L, CD30-L,NGF), and chemokines (e.g, PF4, PBP, groα, MIG, ENA-78, MlPlα, MIPl β, MCP-1, 1-309, HC14, CIO, RANTES, IL-8, MIP-1). In one embodiment, cytokines are derived from T-lymphocytes. . In the present invention, SELEX experiments were performed in order to identify RNA with specific high affinity for the cytokines IFN-gamma, IL-4, IL-10, hTNFα, and RANTES from degenerate libraries containing 30 or 40 random positions (40N for IFN-gamma, IL-4, IL-10 and RANTES; 30N for hTNFα) (Tables 1 , 5, 9, 11 , and 16). This invention includes the specific RNA ligands to IFN-gamma, IL-4, IL-10, and TNFα shown in Tables 3, 4, 7, 8, 10, and 12 (SEQ ID NOS:7-73; 79-185; 189-205; 209-255), identified by the methods described in Examples 1, 3, 5, 7, and 12. This invention further includes RNA ligands to IFN-gamma, IL-4, IL-10, and TNFα which inhibit the function of IFN-gamma, IL-4, IL-10, and TNFα. This invention further includes DNA ligands to RANTES which inhibit the function of RANTES. The scope of the ligands covered by this invention extends to all nucleic acid ligands of IFN-gamma, IL-4, IL-10, TNF a, and RANTES modified and unmodified, identified according to the SELEX procedure. More specifically, this invention includes nucleic acid sequences that are substantially homologous to the ligands shown in Tables 3, 4, 7, 8, 10, and 12 (SEQ ID NOS:7-73; 79-185; 189-205; 209-255). By substantially homologous it is meant a degree of primary sequence homology in excess of 70%, most preferably in excess of 80%. A review of the sequence homologies of the ligands of IFN-gamma, IL-4, IL-10, and TNFα shown in Tables 3, 4, 7, 8, 10, and 12 (SEQ ID NOS:7-73; 79-185; 189-205; 209-255) shows that sequences with little or no primary homology may have substantially the same ability to bind IFN-gamma, IL-4, IL-10, and TNFα. For these reasons, this invention also includes nucleic acid ligands that have substantially the same structure and ability to bind IFN-gamma, IL-4, IL-10, and TNFα as the nucleic acid ligands shown in Tables 3, 4, 7, 8, 10, and 12 (SEQ ID NOS:7-73; 79-185; 189-205; 209-255). Substantially the same ability to bind IFN-gamma, IL-4, IL-10, and TNFα means that the affinity is within one or two orders of magnitude of the affinity of the ligands described herein. It is well within the skill of those of ordinary skill in the art to determine whether a given sequence — substantially homologous to those specifically described herein — has substantially the same ability to bind IFN-gamma, IL-4, IL-10, and TNFα. This invention also includes the ligands as described above, wherein certain chemical modifications are made in order to increase the in vivo stability of the ligand or to enhance or mediate the delivery of the ligand. Examples of such modifications include chemical substitutions at the sugar and/ or phosphate and/or base positions of a given nucleic acid sequence. See, e.g., U.S. Patent Application Serial No. 08/117,991, filed September 9, 1993, entitled High Affinity Nucleic Acid Ligands Containing Modified Nucleotides which is specifically incoφorated herein by reference. Other modifications are known to one of ordinary skill in the art. Such modifications may be made post-SELEX (modification of previously identified unmodified ligands) or by incoφoration into the SELEX process. As described above, because of their ability to selectively bind IFN-gamma, IL-4, IL-10, hTNFα, and RANTES, the nucleic acid ligands to IFN-gamma, IL-4, IL-10,TNFα, and RANTES described herein are useful as pharmaceuticals. This invention, therefore, also includes a method of inhibiting cytokine function by administration of a nucleic acid ligand capable of binding to a cytokine. Therapeutic compositions of the nucleic acid ligands may be administered parenterally by injection, although other effective administration forms, such as intraarticular injection, inhalant mists, orally active formulations, transdermal iontophoresis or suppositories, are also envisioned. One preferred carrier is physiological saline solution, but it is contemplated that other pharmaceutically acceptable carriers may also be used. In one preferred embodiment, it is envisioned that the carrier and the ligand constitute a physiologically-compatible, slow release formulation. The primary solvent in such a carrier may be either aqueous or non-aqueous in nature. In addition, the carrier may contain other pharmacologically-acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, or odor of the formulation. Similarly, the carrier may contain still other pharmacologically-acceptable excipients for modifying or maintaining the stability, rate of dissolution, release, or absoφtion of the ligand. Such excipients are those substances usually and customarily employed to formulate dosages for parental administration in either unit dose or multi-dose form. Once the therapeutic composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready to use form or requiring reconstitution immediately prior to administration. The manner of administering formulations containing nucleic acid ligands for systemic delivery may be via subcutaneous, intramuscular, intravenous, intranasal or vaginal or rectal suppository. The following Examples are provided to explain and illustrate the present invention and are not intended to be limiting of the invention. EXAMPLE 1. EXPERIMENTAL PROCEDURES FOR 2 -NH 2 AND 2'- F-MODIFIED LIGANDS TO IFN-GAMMA This example provides general procedures followed and incoφorated in Example 2 for the evolution of nucleic acid ligands to IFN-gamma. A. Oligonucleotides 2'F modified CTP and UTP were prepared according to the method of Pieken et al, 1991. 2*NH 2 modified CTP and UTP were prepared according to the method of McGee et al, U.S. Patent Application No. 08/264,029, filed June 22, 1994, which is incoφorated herein by reference (see also McGee et al. 1995). DNA oligonucleotides were synthesized by Operon Technologies (Alameda CA). B. SELEX The SELEX procedure has been described in detail in U.S. Patent No. 5,270, 163 (see also Tuerk and Gold, 1990; Gold et al, 1993). Three SELEX procedures were performed to evolve high affinity ligands to IFN-gamma. Each SELEX procedure utilized RNA pools containing pyrimidines modified at the 2' position as follows, 1) 2'F-CTP and 2'F-UTP referred to as 2T, 2) 2T-CTP and 2-NH 2 -UTP referred to as 2T/NH 2 , and 3) 2TSTH 2 -CTP and 2*NH 2 -UTP referred to as 2*NH 2 . For each SELEX, the DNA template 40N7 was designed to contain 40 random nucleotides, flanked by 5' and 3' regions of fixed sequence (Table 1; SEQ ID NO:l). The fixed regions include DNA primer annealing sites for PCR and cDNA synthesis as well as the consensus T7 promoter region to allow in vitro transcription. Single-stranded DNA primers and templates were synthesized and amplified into double-stranded transcribable templates by PCR. Preparation of the initial pool of RNA molecules involved PCR amplification of 1000 pmoles of single-stranded template (Table 1; SEQ ID NO:l) and 2500 pmoles of both the 5*- (5P7; SEQ ID NO:2) and 3'- (3P7; SEQ ID NO:3) primers. These were incubated in a reaction mixture containing 50 mM KC1, 10 mM Tris-Cl (pH 8.3), 3 mM MgCl 2 , 0.5 mM of each dATP, dCTP, dGTP, and dTTP. Taq DNA Polymerase (Perkin-Elmer, Foster City CA) at 0.1 U/μl was added and the reaction incubated at 97°C for 3 min to denature the template and primers. Following the initial denaturing step, the reaction was cycled 10 times at 93°C for 30 sec, 53oC for 30 sec, and 72°C for 1 min to denature, anneal, and extend, respectively, the primers and template. To get an accurate concentration of double-stranded PCR product for the initial round of SELEX, the PCR product was purified using QIAquick-spin PCR purification columns (QIAGEN Inc., Chatsworth CA) as specified by the manufacturer. For in vitro transcription using modified nucleotides 200 pmoles (final concentration of 1 μM) of double-stranded DNA template was incubated in a reaction mixture containing 40 mM Tris-Cl (pH 8.0), 12 mM MgCl 2 , 5 mM DTT, 1 mM spermidine, 0.002% Triton X-100, 4% PEG 8000, 0.5 μ M α-"P-ATP, 5 U/μl T7 RNA Polymerase (Davanloo et al, 1984), and concentrations of other nucleotides as follows, 1 ) for the 2 SELEX: 1 mM ATP and GTP, 3 mM 2T-CTP and 2T-UTP, 2) for the 2T NH, SELEX: 1 mM ATP, GTP, and 2"NH,-UTP and 3 mM 2T-CTP, and 3) for the 2"NH 2 SELEX: 1 mM ATP, GTP, 2"NH 2 -CTP, and 2"NH 2 -UTP. These incubations were performed in a 37°C incubator for between 6 hrs and overnight. Typically the RNA was purified by gel purification and elution. To expedite the process, for rounds 11, 12, and 14-17 the RNA was purified using Bio-Spin 6 chromatography columns (Bio-Rad Laboratories, Hercules CA) according to manufacturer's specifications. To reduce background, the RNA was pre-filtered prior to all rounds of SELEX except rounds 1, 2, 4, 6, 14, and 16. The pre-filtration step involved bringing the RNA up to 200 μl in phosphate buffered saline (PBS), modified to contain ImM Mg 2+ ions, (138 mM NaCl, 2.7 mM KC1, 8.1 mM Na 2 HPO 4 , 1.1 mM KH 2 PO 4, ImM MgCl 2 , pH 7.4), (mPBS), and passing this RNA solution through three filter discs (0.45 μm, nitrocellulose/ cellulose acetate, Millipore Coφoration, Bedford MA) pre- wetted with mPBS. For initial binding, 1000 pmoles of RNA were incubated with human IFN-gamma protein in binding buffer, (mPBS plus 0.01% human serum albumin (HSA)), for 5-10 min at 37°C to allow binding to occur. Human recombinant IFN-gamma used in this SELEX procedure was purchased from two different sources. The first three rounds of both the 2'F and 2T/NH 2 SELEX were performed with protein obtained from Upstate Biotechnology, Lake Placid NY. The subsequent rounds of these two SELEX procedures as well as the entire 2TSTH 2 SELEX were performed with protein obtained from Genzyme Inc., Cambridge MA. For each round of SELEX the concentration of RNA and protein was carefully chosen to provide optimum stringency. Increased stringency was obtained during rounds 8-13 of SELEX by adding NaCl to the binding buffer to bring the final chloride ion concentration up to 250 mM. Preliminary experiments had shown that IFN-gamma had a tendency to aggregate at high protein concentrations. To prevent the evolution of RNA species having an affinity for this aggregated IFN-gamma, beginning with round 4 of SELEX and for all subsequent rounds of the SELEX procedure, the binding mix was centrifuged at 16,000 x g for 3 min in an eppendorf centrifuge before nitrocellulose filter partitioning. IFN-gamma/RNA complexes were separated from unbound RNA by nitrocellulose filter partitioning described below. For nitrocellulose partitioning, the 2'F and 2'F/NH 2 SELEX procedures used 0.2 μm pore size pure nitrocellulose filters (Scleicher & Schuell, Keene NH) for the first two rounds of SELEX. All subsequent rounds of these two SELEX procedures and the entire 2"NH 2 SELEX were performed with 0.45 μm pore size nitrocellulose/cellulose acetate mixed matrix filters (Millipore Coφoration, Bedford MA). Filter discs were placed into a vacuum manifold and wetted with 5 ml of mPBS buffer. The IFN-gamma/RNA binding mix was aspirated through the filter discs which were immediately washed with 5 ml of mPBS buffer. To fiirther increase stringency and reduce background for rounds 8-13, and 15, this washing step was modified to include washing of the filter discs with 15 ml 0.5 M urea followed by 20 ml mPBS buffer. Bound RNA was isolated from filters by extraction in a solution of 400 m 1 phenol (equilibrated in Tris-Cl, pH 8.0)/300 m 1 7 M urea (freshly prepared). The filters were bathed in the phenol/urea solution at room temperature for 30 min and at 95°C for 2 min. The RNA was phenol/chloroform extracted and ethanol precipitated with 20 mg tRNA. The RNA was reverse transcribed into cDNA by addition of 50 pmoles DNA primer, 0.4 mM each of dNTPs, and 1 U/μl AMV reverse transcriptase (AMV RT) (Life Sciences, Inc., St. Petersburg FL) in buffer containing 50 mM Tris-Cl (pH 8.3), 60 mM NaCl, 6 mM Mg(OAc) 2 , 10 mM DTT. The reaction was incubated at 37°C for 30 min then 48°C for 30 min then 70°C for 10 min, to ensure the melting of secondary structure present in the isolated RNA. To begin a new round of SELEX, the cDNA was PCR amplified by addition of 250 pmoles of both the 5* (5P7; SEQ ID NO:2) and 3' (3P7; SEQ ID NO:3) primer in reaction conditions identical to those detailed above. The number of cycles of PCR required to amplify the cDNA was carefully calculated for each round of SELEX so that 250 pmoles double-stranded DNA template would be used to initiate the next round of SELEX. C. Equilibrium Dissociation Constants (Kds) The determination of equilibrium dissociation constants (Kds) for RNA pools was made subsequent to rounds 5, 8, 12, and 17 to monitor the progress of each SELEX . The Kds of RNA pools for mouse IFN-gamma (Genzyme Inc., Cambridge MA) were also determined after rounds 8 and 17. Kds were determined for individual ligands after cloning and sequencing of RNA pools and truncations (described below). Nitrocellulose filter binding was used to determine Kds as follows: filter discs were placed into a vacuum manifold and wetted with 5 ml of mPBS buffer. "P-labeled-RNA was incubated with serial dilutions of IFN-gamma in binding buffer for 5-10 min at 37°C to allow binding to occur. Binding mixes were centrifuged as described above to remove aggregates, aspirated through the filter discs, and then immediately washed with 5 ml mPBS buffer. The filter discs were dried and counted in a liquid .scintillation counter (Beckmann Instruments, Palo Alto CA). Equilibrium dissociation constants were determined by least square fitting of the data points using the Kaleidagraph™ graphics program (Synergy Software, Reading PA). Many ligands and evolved RNA pools yield biphasic binding curves. Biphasic binding can be described as the binding of two affinity species that are not in equilibrium. Biphasic binding constants were calculated according to standard procedures. Kds were determined by least square fitting of the data points using the Kaleidagraph™ graphics program. D. Cloning and Sequencing After the 17th round of SELEX, RNA molecules were reverse transcribed to cDNA and made double-stranded by PCR amplification with primers containing recognition sites for the restriction endonucleases Hind III (Table 1 ; 5' primer 5P7H; SEQ ID NO:4) and Bam HI (Table 1; 3' primer 3P7B; SEQ ID NO:5). Using these restriction sites the DNA sequences were inserted directionally into the pUC19 vector. These recombinant plasmids were transformed into Epicurian coli JM109 competent cells (Stratagene, La Jolla CA). Plasmid DNA was prepared with the PERFECTprep™ plasmid DNA kit (5 ρrime~>3 prime, Boulder CO). Plasmid clones were sequenced using a PCR sequencing protocol (Adams et al, 1991) using PCR sequencing primer pUC19F30 (SEQ ID NO:6). E. Ligand Truncation Boundary experiments were carried out to determine the minimal sequence necessary for high affinity binding of the RNA ligands to IFN-gamma using end-labeled RNA. Prior to end-labeling, RNA transcribed with T7 RNA polymerase was gel purified by UV shadowing. The 5'-end of 20 pmoles of each RNA was dephosphorylated in a reaction mixture containing 20 mM Tris-Cl (pH 8.0), 10 mM MgCl 2 and 0.1 U/μl shrimp alkaline phosphatase (SAP), (United States Biochemical, Cleveland OH) by incubating for 30 min at 37°C. Alkaline phosphatase activity was destroyed by incubating for 30 min at 70°C. RNA was subsequently 5'-end labeled in a reaction mixture containing 50 mM Tris-Cl (pH 7.5), 10 mM MgCl 2 , 5 mM DTT, 0.1 mM EDTA, 0.1 mM spermidine, 0.75 m M g - 32 P-ATP and 1 U/μl T4 polynucleotide kinase (New England Biolabs, Beverly MA) by incubating for 30 min at 37°C. 3'-end-labeling of 20 pmoles of each RNA was performed in a reaction mixture containing 50 mM Tris-Cl (pH 7.8), 10 mM MgCl 2!l 10 mM b -mercaptoethanol, 1 mM ATP, 0.9 m M (5'- 32 P)pCρ and 1 U/μl T4 RNA ligase (New England Biolabs, Beverly MA) by incubating for 18 hrs at 4°C. 5'- and 3'- end-labeled RNAs were gel band purified on a 12%, 8M urea, polyacrylamide gel. After partial alkaline hydrolysis of the end-labeled RNA by addition of NajCOj to a final concentration of 50 mM and incubation in a boiling water bath for 3 min, radiolabeled RNA ligands were incubated with IFN-gamma at three different protein concentrations, 1) 5-fold below the approximate Kd, 2) at the approximate Kd, and 3) 5-fold above the approximate Kd. Protein-bound RNA was separated by nitrocellulose partitioning. RNA truncates were analyzed on a high-resolution denaturing 12% polyacrylamide gel. To orient the sequences, a ladder of radioactively labeled ligands terminating with G-residues was generated by RNase Tl digestion of end-labeled RNA. The Tl digest was carried out in a reaction mixture containing 7 M urea, 20 mM sodium citrate (pH 5.0), 1 mM EDTA and 5 units RNase Tl (Boehringer Mannheim, Indianapolis IN) by incubating for 5 min at 50°C. Complementary single-stranded DNA oligonucleotides containing the sequence of the T7 promoter (5'-TAATACGACTCACTATAG-3*; fragment of SEQ ID NO:2) and the sequence of the truncated ligand were annealed to form a double-stranded template for transcription of each truncated ligand. F. Receptor Binding Competitions Human lung carcinoma cells (A549; ATCC) were plated in 24-well plates at a density of 5 X 10' cells/well in RPMI 1640 plus 10% fetal bovine serum (FBS) and incubated overnight or until confluent. The cells were washed 3 times with PBS. Growth media was replaced with 200 μl RPMI 1640 plus 0.2% human serum albumin/0.02% sodium azide/20 mM Hepes, pH 7.4 together with increasing amounts (20 pg/ml- 100 ng/ml) of ,25 I-IFN-gamma (New England Nuclear) with or without an excess (200 fold) of unlabeled IFN-gamma. Incubations were carried out at 4°C with shaking for 2 hrs. The cells were washed 2 times with cold PBS to remove free IFN and detached with 0.5% SDS. Cell-associated 125 I-IFN-gamma was determined by measuring the radioactivity of the detached cells in a gamma counter. The data was corrected for nonspecific binding and the affinity of 125 I-IFN-gamma was determined by Scatchard analysis of the binding data. Scatchard analysis suggests that there are high-affinity binding sites (Kd = 20pM) and low-affinity binding sites (Kd = 0.5nM). For competition with oligonucleotide, the cells were incubated for 2 hr at 4°C as above with 30 pM 125 I-IFN-gamma and increasing concentrations (1.01-500 nM) of competitor oligonucleotide. Cell-associated 125 I-IFN-gamma was determined as above. EXAMPLE 2. 2 -NH 2 AND 2 -F-MODIFIED RNA LIGANDS TO IFN-GAMMA A. SELEX Three libraries of RNAs modified at the 2' position of pyrimidines, 1) 2'F incoφorating 2'F-CTP and 2'F-UTP, 2) 2'F/NH 2 incoφorating 2'F-CTP and 2"NH 2 -UTP and 3) 2 * NH 2 incoφorating 2'NH 2 -CTP and 2 * NH 2 -UTP were used in simultaneous SELEX protocols to generate a diverse set of high-affinity modified RNA ligands to human IFN-gamma. Each of these libraries contained between 10 n -10 14 molecules with a variable region of 40 nucleotides The template and primers used for the SELEX and the conditions of the SELEX, as described in Example 1, are summarized in Tables 1 and 2, respectively. B. RNA Sequences and Dissociation Constants The random modified RNA pools bound human IFN-gamma with approximate Kds of greater than 0.7 μM. After 17 rounds of SELEX, the approximate Kds of the evolving pools had improved to, 1) 70 nM for the 2'F SELEX, 2) 115 nM for the 2'F/NH 2 SELEX, and 3) 20 nM for the 2"NH 2 SELEX. For mouse IFN-gamma, the approximate Kds of the RNA pools after 17 rounds of SELEX were 1) 410 nM for the 2'F SELEX, 2) 175 nM for the 2'F/NH 2 SELEX, and 3) 85 nM for the 2"NH 2 SELEX. These Kds did not shift further in subsequent rounds. In order to determine to what extent the evolving pool was still random, PCR product from the final round of SELEX was sequenced as detailed above and found to be non-random. RNA from the 17th round was reverse transcribed, amplified and cloned. The sequences of 32 of the 2"F, 40 of the 2*NH 2 , and 11 of the 2'F/NH 2 individual clones were determined (Table 3; SEQ ID NOS:7-65). The sequences were analyzed for conserved sequences and aligned by this criterion (Table 3). The 2'F sequences fell in to 2 groups with 9 oφhan sequences. Group 1 2'F RNAs were the most abundant, representing 18 of 32 sequences, while group 22'F RNAs represented 5 of 32 sequences. The 2'NH 2 sequences fell into 2 groups with 25 of 402*NH 2 RNAs in group 1 and 15 of 402"NH 2 RNAs in group 2. The 2'F/NH 2 sequences were of a single group. The Kds of individual RNAs within each group were determined by nitrocelulose filter binding as described above. The Kds were determined using either a monophasic or biphasic least squares fit of the data. Minimal sequence requirements for high-affinity binding of the best clones were determined by 5' and 3' boundary experiments as described. The truncated RNAs were transcribed from double-stranded templates containing the T7 promoter and the truncated sequence. For those successful transcriptions, the Kd of the truncated ligand was determined. The sequence of the truncated ligands and their Kds, both for full-length and for the truncate (if determined) are shown in Table 4 (SEQ ID NOS:66-73). C. Receptor Competition Both full-length 2'NH 2 (2'NH 2 raπdom> 2'NH 2-17, 2'NH 2 . 30) and2'F (2'F random, 2'F-l, and 2 -28) oligonucleotides were tested for their ability to inhibit receptor binding. This competition was targeted primarily to the high-affinity binding component using a concentration of ,25 I-IFN-gamma of 30pM. At this concentration, neither the 2 'NH 2 nor the 2'F random oligos showed inhibition, while varying degrees of inhibition were seen with the 4 clones tested. The 2'NH 2 ligand #30 (SEQ ID NO:72) was the best inhibitor and showed 50% inhibition at 10 nM. EXAMPLE 3. EXPERIMENTAL PROCEDURES FOR 2'-NH 2 AND 2 -F-MODIFIED LIGANDS TO IL-4 This Example provides general procedures followed and incoφorated in Example 4 for the evolution of nucleic acid ligands to IL-4. A. Oligonucleotides 2'F modified CTP and UTP were prepared according to the method of Pieken et al, 1991. 2"NH 2 modified CTP and UTP were prepared according to the method of McGee et al, U.S. Patent Application No. 08/264,029, filed June 22, 1994, which is incoφorated herein by reference (see also McGee et al. 1995). DNA oligonucleotides were synthesized by Operon Technologies (Alameda CA). B. SELEX The SELEX procedure has been described in detail in U.S. Patent No. 5,270, 163 (see also Tuerk and Gold, 1990; Gold et al, 1993). Three SELEX procedures were performed to evolve high affinity ligands to IL-4. Each SELEX procedure utilized RNA pools containing pyrimidines modified at the 2' position as follows, 1) 2'F-CTP and 2T-UTP referred to as 2'F, 2) 2'F-CTP and 2TSfH 2 -UTP referred to as 2T/NH 2 , and 3) 2'NH 2 -CTP and 2Ts[H 2 -UTP referred to as 2*NH 2 . For each SELEX, the DNA template 40N8 was designed to contain 40 random nucleotides, flanked by 5' and 3' regions of fixed sequence (Table 5; SEQ ID NO: 74). The fixed regions include DNA primer annealing sites for PCR and cDNA synthesis as well as the consensus T7 promoter region to allow in vitro transcription. Single-stranded DNA primers and templates were synthesized and amplified into double-stranded transcribable templates by PCR. Preparation of the initial pool of RNA molecules involved PCR amplification of 1000 pmoles of single-stranded template (Table 5; SEQ ID NO:74) and 2500 pmoles of both the 5' (5P8; SEQ ID NO:75) and 3' (3P8; SEQ ID NO:76) primers. These were incubated in a reaction mixture containing 50 mM KC1, 10 mM Tris-Cl (pH 8.3), 3 mM MgCl 2 , 0.5 mM of each dATP, dCTP, dGTP, and dTTP. Taq DNA Polymerase (Perkin-Elmer, Foster City CA) at 0.1 U/μl was added and the reaction incubated at 97°C for 3 min to denature the template and primers. Following the initial denaturing step, the reaction was cycled 7 times at 93 °C for 30 sec, 53 °C for 30 sec, and 72°C for 1 min to denature, anneal, and extend, respectively, the primers and template. To get an accurate concentration of double-stranded PCR product for the initial round of SELEX, the PCR product was purified using QIAquick-spin PCR purification columns (QIAGEN Inc., Chatsworth CA) as specified by the manufacturer. For in vitro transcription using modified nucleotides 200 pmoles (final concentration of 1 μM) of double-stranded DNA template was incubated in a reaction mixture containing 40 mM Tris-Cl (pH 8.0), 12 mM MgCl 2 , 5 mM DTT, 1 mM spermidine, 0.002% Triton X-100, 4% PEG 8000, 0.5 μ M α- 32 P 2'OH ATP, 5 U/μl T7 RNA Polymerase (Davanloo et al, 1984), and concentrations of other nucleotides as follows, 1) for the 2'F SELEX: 1 mM ATP and GTP, 3 mM 2'F-CTP and 2'F-UTP, 2) for the 2*F/NH 2 SELEX: 1 mM ATP, GTP, and 2"NH 2 -UTP and 3 mM 2'F-CTP, and 3) for the 2-NH 2 SELEX: 1 mM ATP, GTP, 2*NH 2 -CTP, and 2TSTH 2 -UTP. These incubations were performed in a 37°C incubator for between 6 hrs and overnight. Typically the RNA was ptirified by gel purification and elution. To expedite the process for rounds 11, 12, and 14-17 the RNA was purified using Bio-Spin 6 chromatography columns (Bio-Rad Laboratories, Hercules CA) according to manufacturer's specifications. To reduce background, the RNA was pre-filtered prior to all rounds of SELEX except rounds 1, 2, 4, 6, 14, and 16. The pre-filtration step involved bringing the RNA up to 200 μl in phosphate buffered saline (PBS), modified to contain 1 mM Mg 2+ ions, (138 mM NaCl, 2.7 mM KCl, 8.1 mM Na^PO,, 1.1 mM KH 2 PO 4, ImM MgCl 2 , pH 7.4), (mPBS), and passing this RNA solution through three filter discs (0.45 μm, nitrocellulose/ cellulose acetate, Millipore Coφoration, Bedford MA) pre-wetted with mPBS. For initial binding, 1000 pmoles of RNA were incubated with human IL-4 protein in binding buffer, (mPBS plus 0.01% human serum albumin (HSA)), for 5-10 min at 37 °C to allow binding to occur. Human recombinant IL-4 used in this SELEX procedure was purchased from R & D Systems, Minneapolis MN. For each round of SELEX the concentration of RNA and protein was carefully chosen to provide optimum stringency. Preliminary experiments had shown that IL-4 had a tendency to aggregate at high protein concentrations. To prevent the evolution of RNA species having an affinity for this aggregated IL-4, beginning with round 4 of SELEX and for all subsequent rounds of the SELEX procedure, the binding mix was centrifuged at 16,000 X g for 3 min in an eppendorf centrifuge before nitrocellulose filter partitioning. IL-4/ RNA complexes were separated from unbound RNA by nitrocellulose filter partitioning described below. For nitrocellulose partitioning, the 2'F and 2'F/NH 2 SELEX procedures used 0.2 μm pore size pure nitrocellulose filters (Scleicher & Schuell, Keene NH) for the first two rounds of SELEX. All subsequent rounds of these two SELEX procedures and the entire 21^ 2 SELEX were performed with 0.45 μm pore size nitrocellulose/cellulose acetate mixed matrix filters (Millipore Coφoration, Bedford MA). Filter discs were placed into a vacuum manifold and wetted with 5 ml of mPBS buffer. The IL-4/RNA binding mix was aspirated through the filter discs which were immediately washed with 5 ml of mPBS buffer. To further increase stringency and reduce background for rounds 8-13, and 15, this washing step was modified to include washing of the filter discs with 15 ml 0.5 M urea followed by 20 ml mPBS buffer. Bound RNA was isolated from filters by extraction in a solution of 400 μl phenol (equilibrated in Tris-Cl, pH 8.0)/ 300 μl 7 M urea (freshly prepared). The filters were bathed in the phenol/urea solution at room temperature for 30 min and at 95°C for 2 min. The RNA was phenol/chloroform extracted and ethanol precipitated with 20 μg tRNA. The R A was reverse transcribed into cDNA by addition of 50 pmoles DNA primer, 0.4 mM each of dNTPs, and 1 U/μl AMV reverse transcriptase (AMV RT) (Life Sciences, Inc., St. Petersburg FL) in buffer containing 50 mM Tris-Cl (pH 8.3), 60 mM NaCl, 6 mM Mg(OAc) 2 , 10 mM DTT. The reaction was incubated at 37°C for 30 min then 48°C for 30 min then 70°C for 10 min, to ensure the melting of secondary structure present in the isolated RNA. To begin a new round of SELEX, the cDNA was PCR amplified by addition of 250 pmoles of both the 5' (5P8; SEQ ID NO:75) and 3' (3P8; SEQ ID NO:76) primer in reaction conditions identical to those detailed above. The number of cycles of PCR required to amplify the cDNA was carefully calculated for each round of SELEX so that 250 pmoles double-stranded DNA template would be used to initiate the next round of SELEX. C. Equilibrium Dissociation Constants (Kds) The determination of equilibrium dissociation constants (Kds) for RNA pools was made subsequent to rounds 5, 8, 12, and 17 to monitor the progress of each SELEX. The Kds of RNA pools for mouse IL-4 (R & D Systems, Minneapolis MN) were also determined after round 8. Kds were determined for individual ligands after cloning and sequencing of RNA pools and truncations (described below). Nitrocellulose filter binding was used to determine Kds as follows: filter discs were placed into a vacuum manifold and wetted with 5 ml of mPBS buffer. 32 P-labeled-RNA was incubated with serial dilutions of IL-4 in binding buffer for 5-10 min at 37°C to allow binding to occur. Binding mixes were centrifuged as described above to remove aggregates, aspirated through the filter discs, and then immediately washed with 5 ml mPBS buffer. The filter discs were dried and counted in a liquid scintillation counter (Beckmann Instruments, Palo Alto CA). Equilibrium dissociation constants were determined by least square fitting of the data points using the Kaleidagraph™ graphics program (Synergy Software, Reading PA). Many ligands and evolved RNA pools yield biphasic binding curves. Biphasic binding can be described as the binding of two affinity species that are not in equilibrium. Biphasic binding constants were calculated according to standard procedures. Kds were determined by least square fitting of the data points using the Kaleidagraph™ graphics program. D. Cloning and Sequencing After the 17th round of SELEX, RNA molecules were reverse transcribed to cDNA and made double-stranded by PCR amplification with primers containing recognition sites for the restriction endonucleases Hindlll (Table 5; 5' primer 5P8H; SEQ ID NO:77) and Bam HI (Table 5; 3' primer 3P8B; SEQ ID NO:78). Using these restriction sites the DNA sequences were inserted directionally into the pUC19 vector. These recombinant plasmids were transformed into Epicurian coli JM109 competent cells (Stratagene, La Jolla CA). Plasmid DNA was prepared with the PERFECTprep™ plasmid DNA kit (5 prime — >3 prime, Boulder CO). Plasmid clones were sequenced using a PCR sequencing protocol (Adams et al, 1991) using PCR sequencing primer pUC19F30 (SEQ ID NO:6). E. Ligand Truncation Boundary experiments were carried out to determine the minimal sequence necessary for high affinity binding of the RNA ligands to IL-4 using end-labeled RNA. Prior to end-labeling, RNA transcribed with T7 RNA polymerase was gel purified by UV shadowing. The 5'-end of 20 pmoles of each RNA was dephosphorylated in a reaction mixture containing 20 mM Tris-Cl (pH 8.0), 10 mM MgCl 2 and 0.1 U/μl shrimp alkaline phosphatase (SAP), (United States Biochemical, Cleveland OH) by incubating for 30 min at 37°C. Alkaline phosphatase activity was destroyed by incubating for 30 min at 70°C. RNA was subsequently 5 '-end labeled in a reaction mixture containing 50 mM Tris-Cl (pH 7.5), 10 mM MgCl 2 , 5 mM DTT, 0.1 mM EDTA, 0.1 mM spermidine, 0.75 m M g - 32 P-ATP and 1 U/μl T4 polynucleotide kinase (New England Biolabs, Beverly MA) by incubating for -30 min at 37°C. 3 '-end-labeling of 20 pmoles of each RNA was performed in a reaction mixture containing 50 mM Tris-Cl (pH 7.8), 10 mM MgCl 2 , 10 mM b -mercaptoethanol, 1 mM ATP, 0.9 μM (5'- 32 P)pCp and 1 U/μl T4 RNA ligase (New England Biolabs, Beverly MA) by incubating for 18 hrs at 4°C. 5'- and 3'- end-labeled RNAs were gel band purified on a 12%, 8M urea, polyacrylamide gel. After partial alkaline hydrolysis of the end-labeled RNA by addition of Na 2 CO 3 to a final concentration of 50 mM and incubation in a boiling water bath for 3 min, radiolabeled RNA ligands were incubated with IL-4 at three different protein concentrations, 1) 5-fold below the approximate Kd, 2) at the approximate Kd, and 3) 5-fold above the approximate Kd. Protein-bound RNA was separated by nitrocellulose partitioning. RNA truncates were analyzed on a high-resolution denaturing 12% polyacrylamide gel. To orient the sequences, a ladder of radioactively labeled ligands terminating with G-residues was generated by RNase Tl digestion of end-labeled RNA. The Tl digest was carried out in a reaction mixture containing 7 M urea, 20 mM sodium citrate (pH 5.0), 1 mM EDTA and 5 units RNase Tl (Boehringer Mannheim, Indianapolis IN) by incubating for 5 min at 50°C. Complementary single-stranded DNA oligonucleotides containing the sequence of the T7 promoter (5'-TAATACGACTCACTATAG-3'; fragment of SEQ ID NO:75) and the sequence of the truncated ligand were annealed to form a double-stranded template for transcription of each truncated ligand. F. Receptor Competition Human T-cell lymphoma cells (H-9; ATCC) were cultured in suspension in RPMI 1640 + 10% FCS. Cells were washed two times with PBS and resuspended (5.0 x 10 5 cells) in 200 μl media containing RPMI 1640 + 0.02% human serum albumin/0.2% Na azide/20 mM HEPES, pH 7.4 for 2 hr at 4°C in 1.5 ml polypropylene tubes (Eppendorf, W. Germany) with various amounts of 125 I-rIL-4 in the presence or absence of a 200-fold excess of unlabeled cytokine. Following incubation, the tubes were spun (150 x g, 5 min, 4°C) and the supernatant was aspirated. The cell pellet was resuspended in 200 μl RPMI-HS A. 100 μl aliquots were centrifuged through a cushion of an equal volume of phthalate oils (dibutyl dioctyl, 1:1 v/v). The tube was rapidly frozen in dry ice/ethanol and the tip containing the cell pellet was cut off and placed in a vial for gamma counting. The data was corrected for nonspecific binding and the affinity of ,25 I-IL-4 was determined by Scatchard analysis. For competition with oligonucleotide, or neutralizing antibody (R & D Systems), the cells were incubated for 2 hr at 4° as above with 0.7 nM 125 I-IL-4 and increasing concentrations (0.01-500 nM) of competitor oligonucleotide. Cell-associated 125 I-IL-4 was determined as above. EXAMPLE 4. 2 -NH 2 AND 2 -F-MODIFIED RNA LIGANDS TO IL-4 A. SELEX Three libraries of RNAs modified at the 2' position of pyrimidines, 1) 2'F incoφorating 2'F-CTP and 2'F-UTP, 2) 2'F/NH 2 incoφorating 2T-CTP and 2"NH 2 -UTP and 3) 2TSTH, incoφorating 2'NH 2 -CTP and 2"NH 2 -UTP were used in simultaneous SELEX protocols to generate a diverse set of high-affinity modified RNA ligands to human IL-4. Each of these libraries contained between 10 13 - 10 14 molecules with a variable region of 40 nucleotides. The template and primers used for the SELEX and the conditions of the SELEX, as described in Example 3 are summarized in Tables 5 and 6, respectively. B. RNA Sequences and Dissociation Constants The random modified RNA pools bound human IL-4 with approximate Kds of greater than 20 μM. After 17 rounds of SELEX, the approximate Kds of the evolving pools had improved to, 1) 30 nM for the 2'F SELEX, and 2) 55 nM for the 2'F/NH 2 SELEX. Binding curves performed on 2"NH 2 RNA from an earlier round had shown an approximate Kd of 100 nM, however, difficulties with background reduction in this SELEX led to an apparent Kd after round 17 of 1 μM. It was felt that despite this "masking" due to background, the high affinity unique sequence 2*NH 2 RNAs were still in the pool after round 17. These Kds did not shift further in subsequent rounds. The RNA pools after 8 rounds of SELEX did not bind mouse IL-4, while there was a significant improvement in binding after 8 rounds for the human protein (data not shown). In order to determine to what extent the evolving pool was still random, PCR product from the final round of SELEX was sequenced as detailed above and found to be non-random. RNA from the 17th round was reverse transcribed, amplified, and cloned. The sequences of 41 of the 2'F, 57 of the 2"NH 2 , and 30 of the 2T/NH 2 individual clones were determined (Table 7; SEQ ID NOS:79-177). The sequences were analyzed for conserved sequences and aligned by this criterion (Table 7). The 2'F sequences fell into a single group representing 29 of 41 sequences. The remaining 12 clones were categorized as oφhans due to their lack of sequence homology with the primary group or to each other. The 2*NH 2 sequences fell into 2 distinct groups of sequences. Group 1 which represented 21 of 57 sequences were shown to bind to IL-4. The other group, representing 35 of 57 sequences were shown to bind to nitrocellulose filters. The presence of such a large number of nitrocellulose filter binding RNAs was not a suφrise as these sequences were cloned from a pool with high background binding. These nitrocellulose binding RNAs are identified by the presence of a direct repeat of the sequence GGAGG. A single oφhan 2"NH 2 sequence was also found. The 2'F/NH 2 sequences were more heterogeneous with sequences falling into 3 groups. RNAs in group 1 and 2 bound to IL-4, while the 3rd group bound to nitrocellulose filters. The clones in the nitrocellulose filter binding group also contained a single or repeat of the sequence GGAGG. It should be noted that this sequence is also found in the 3'-fixed region (underlined in Table 7). The Kds of individual RNAs within each group were determined by nitrocelulose filter binding as described in Example 3 above. The Kds were determined using a monophasic least squares fit of the data. Minimal sequence requirements for high-affinity binding ofthe best clones were determined by 5' and 3' boundary experiments as described in Example 3. The truncated RNAs were transcribed from double-stranded templates containing the T7 promoter and the truncated sequence. For those successful transcriptions, the Kd ofthe truncated ligand was determined. The sequence ofthe truncated ligands and their Kds, both for full-length and for the truncate (if determined) are shown in Table 8 (SEQ ID NOS:178-185). C. Receptor Competition Full-length 2*NH 2 C'NH-, random, 2'NH 2 -29), 2'F (2T random, 2T-9) and 2'F/NH, (2'F/NH 2 random, 2*F/NH 2 -9 and 2T/NH 2 -28) oligonucleotides were tested for their ability to inhibit receptor binding. Neither the 2TSIΗ 2 , 2'F, or 2'F/NH 2 random oligos showed inhibition, while varying degrees of inhibition was seen with the clones tested. At an IL-4 concentration of 0.7 nM the 2'F/NH 2 ligand-9 was the best competitor for receptor binding and showed 50% inhibition at approximately 40 nM. The competition by this oligonucleotide was similar to that seen by a neutralizing antibody to IL-4. EXAMPLE 5. EXPERIMENTAL PROCEDURES FOR 2 -F MODIFIED LIGANDS TO IL-10 This Example provides general procedures followed and incoφorated in Example 6 for the evolution of nucleic acid ligands to IL- 10. A. Materials DNA sequences were synthesized by using cyanoethyl phosphoramidite under standard solid phase chemistry. 2'-F CTP and 2'-F UTP were purchased from United States Biochemicals. Human IL-10 was bought from either Bachem or R&D Systems. Neutralizing anti-human IL-10 monoclonal antibody, murine IL-10 and ELISA detection kit for human IL-10 were purchased from R &D Systems. B. SELEX Five nmoles of synthetic DNA template, that was purified on an 8% polyacrylamide gel under denaturing conditions were amplified by four cycles of polymerase chain reaction (PCR). The PCR products were transcribed in vitro by T7 RNA polymerase (1000 U) in 1 mL reaction consisting of 2 mM each of ATP and GTP, 3 mM each of 2'-F CTP and 2*-F UTP, 40 mM Tris-HCl (pH 8.0), 12 mM MgCl 2 , 1 mM Spermidine, 5 mM DTT, 0.002% Triton X-100 and 4% polyethelene glycol (w/v) for 10 - 12 hr. The full-length transcription products (SEQ ID NO: 186) were purified on 8% denaturing polyacrylamide gels, suspended in TBS buffer [100 mM Tris-HCl, (pH 7.5) 150 mM NaCl) (binding buffer), heated to 70 °C, chilled on ice, then incubated with IL-10 at 37 °C for 10 min. The RNA-protein mixture was filtered through a pre- wet nitrocellulose filter then washed with 5 mL ofthe binding buffer. Bound RNAs were eluted from the filter and recovered by ethanol precipitation. The RNA was reverse transcribed by avian myeloblastosis virus reverse transcriptase (Life Sciences) at 48 °C for 45 min with 5*-GCCTGTTGTGAGCCTCCTGTCGAA-3' primer (Table 9; SEQ ID NO:188). The cDNA was amplified by PCR (with 5' and 3' primers (SEQ ID NOS: 187-188)) and the resulting DNA template was transcribed to obtain RNA for the next round of selection. During the course of SELEX, the concentration of IL- 10 was decreased gradually from 5 μM to 500 nM to progressively increase selective pressure. The selection process was repeated until the affinity ofthe enriched RNA pool for IL-10 was substantially increased. At that point, cDNA was amplified by PCR with primers that introduced BamHI and Hind III restriction sites at 5' and 3' ends, respectively. PCR products were digested with BamHI and Hind III and cloned into pUC 18 that was digested with the same enzymes. Individual clones were screened and sequenced by standard techniques. C. Determination of equilibrium dissociation constants K d ). Internally-labeled RNA transcripts were prepared by including [α- 32 P]ATP in T7 RNA polymerase transcription reactions. Full-length transcripts were purified on 8% denaturing polyacrylamide gels to ensure size homogeneity. Gel-purified RNA was diluted to a concentration of ~ 5 nM in TEM buffer, heated to 80 °C then chilled on ice to facilitate secondary structure formation. RNA concentrations were kept lower than 100 pM in binding reactions. Briefly, equal amounts of RNA were incubated with varying amounts of IL-10 in 50 μL of TEM buffer for 10 min at 37 °C. RNA-protein mixtures were passed through pre-wet nitrocellulose filters (0.2 μ) and the filters were immediately washed with 5 mL of binding buffer. Radioactivity retained on filters was determined by liquid scintillation counting. The quantities of RNA bound to filters in the absence of protein was determined and used for background correction. The percentage of input RNA retained on each filter was plotted against the corresponding log protein concentration. The nonlinear least square method to obtain the dissociation constant (K d ). D. Sandwich ELISA Sandwich ELISA was carried out by using commercially available ELISA kit for quantitative determination of hIL- 10 (from R&D systems) according to manufacturer's instructions. Varying amounts of RNA 43, random pool RNA and anti-hIL- 10 monoclonal antibody (from R&D Systems) were incubated with 125 pg/mL hIL-10 at room temperature for 10 min before added to microtiter wells. EXAMPLE 6. 2 -F-MODIFIED RNA LIGANDS TO IL-10 Under nitrocellulose filter binding conditions the random sequence pool that was used to initiate the SELEX experiment did not show detectable binding to IL-10 as high as 5 μM concentration. However, after twelve rounds of affinity selection the enriched pool exhibited improved affinity, and further selection beyond the 12th round had no effect on increasing the affinity for IL- 10. Table 10 (SEQ ID NOS : 189-205) shows the sequences identified from the 12th round pool. Sequences are grouped into three classes based on the sequence similarity. The 5' part in the variable 40 nucleotide region of most sequences in class I has sequence complementarity to the 3* part, suggesting that such sequences can fold into a stemloop structure. Individual clones were initially screened for their ability to bind IL-10 at 250 nM concentration. The results show that 20-40% of input individual RNAs was bound to IL-10 at 250 nM. Based on preliminary screening, sequence 43 (SEQ ID NO: 189) was chosen as a representative ligand to carry out in section B below. The Kd of sequence 43 for binding to IL- 10 is 213 nM. The ligand 43 , on the other hand does not bind to other cytokines such as interferon g and IL-4, indicating the specificity of SELEX-derived RNA sequence. Human IL-10 (hIL-10) and mouse IL-10 (mIL-10) have high degree of sequence homology at the cDNA and amino acid level (73% amino acid homology) and hIL-10 has been shown to active on mouse cells. However, ligand 43 does not bind to mIL-10 with high affinity. B. RNA in IL-10 ELISA An anti-ILlO monoclonal antibody that neutralizes the receptor binding is commercially available. The R&D systems' Quantikine Immunoassay kit is based on 96 well microtiter plates coated with the neutralizing antibody to capture hIL-10. The ELISA was used to investigate whether RNA binds at or near the neutralizing antibody binding site on IL-10. RNA 43, similar to the random pool RNA (used as a control) did not show any inhibition of IL-10 binding to anti-IL-10 antibody on the plate (data not shown). These data suggest that the evolved RNA ligand does not bind to the site at or near that recognized by the neutralizing antibody. The soluble anti-ILlO that was used in the assay as a control behaved as expected, competing for binding with the same antibody on the solid phase. EXAMPLE 7. EXPERIMENTAL PROCEDURES FOR LIGANDS TO hTNFα This Example provides general procedures followed and incoφorated in Examples 8-11 for the evolution of nucleic acid ligands to hTNFα. A. Materials Recombinant human TNFα (hTNFα ) was purchased from Genzyme (Cambridge, MA) or R&D Systems (Minneapolis, MN), recombinant murine TNFα (mTNFα), recombinant human TNFβ (hTNFβ), and soluble human TNF receptor 2 (sTNF-R2) were purchased from R&D Systems. Acetylated, and nuclease free bovine serum albumin (BSA), ligase and restriction enzymes were from new England Biolabs (Beverly, MA). AMV resverse transcriptased were from Life Sciences (St. Petersburg, FL). RNasin ribonuclease inhibitor, and Taq DNA polymerase was from Promega (Madison, WI). Ultrapure nucleotide triphosphates were from Pharmacia (Piscataway, NJ). 125 -I-TNFα, α- 32 P-ATP, and γ- 32 P-ATP were from DuPont NEN Research Products (Boston, MA). U937 cells were from ATCC (catalog number CRL1593). Oligonucleotides were obtained from Operon, Inc. (Alameda, CA). Nitrocellulose/cellulose acetate mixed matrix (HA), 0.45 μm filters were from Millipore (Bedford, MA). Chemicals were at least reagent grade and purchased from commercial sources. B) SELEX The SELEX procedure has been described in the SELEX Patent Application (see also Tuerk and Gold, 1990; Gold et al, 1993). The starting RNA contained 30 random nucleotides, flanked by 5' and 3' constant regions for primer anealing sites for cDNA synthesis and PCR amplification (Table 11; SEQ ID NO:206). The single stranded DNA molecules were converted to double stranded by PCR amplification. PCR conditions were 50 mM KCl, 10 mM Tris-HCl, pH9, 0.1% Triton X-100, 3 mM MgCl 2 , 0.5 mM of each dATP, dCTP, dGTP, and dTTP, 0.1 units/μl Taq DNA polymerase and 1 nM each ofthe 5' and 3' primers. Transcription reactions were done with about 5μM DNA template, 5 units/μl T7 RNA polymerase, 40 mM Tris-HCl (pH8), 12 mM MgCl 2 , 5 mM DTT, 1 mM spermidine, 0.002% Triton X-100, 4% PEG 8000, 2-4 mM each 2'OH NTP, and 0.25 μM a- 32 P-ATP (800 Ci/mmole). For 2'F modified transcripts, 2'F-CTP and 2'F-UTP were used instead of 2'OH-CTP and 2'OH-UTP. Two different SELEX experiments were done. In the first SELEX experiment, SELEX- A, the protein was immobilized onto nitrocellulose filters and the RNA ligands were partitioned by capture to the immobilized protein. Briefly, hTNFα was spotted on a nitrocellulose filter (Millipore, HA 0.45 μm) and following 5 min air drying over filter paper, the nitrocellulose filter was incubated in a 24- well microtiter plate with 1-2X10" 6 M radiolabeled RNA for 30 min at room temperature in 500 μl binding buffer (BB=10 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 0.02% acetylated BSA, 0.02% ficol, and 0.02% PVP). The filter was then washed three times for 10 minutes each in 1.5 ml BB without BSA. Binding and washing was done under rigorous agitation. The RNA bound to the immobilized protein was recovered by phenol/urea extraction and was then reverse transcribed into cDNA by AMV reverse transcriptase at 48°C for 60 min in 50 mM Tris-HCl pH8.3, 60 mM NaCl, 6 mM Mg(OAc) 2 , 10 mM DTT, 50 pmol DNA primer-1 (Table 11; SEQ ID NOS:206-208), 0.4 mM each of dATP, dCTP, dGTP, and dTTP, and 1 unit/μl AMV RT. The cDNA was then PCR amplified and used to initiate the next SELEX cycle as described above. In the second SELEX experiment, SELEX-B, the binding buffer was Dulbecco's Phosphate-Buffered Saline (DPBS) with calcium and magnesium (Life Technologies, Gaithersburg, MD, Cat. No 21300-025) and the protein-RNA complexes were partitioned by filtering through nitrocellulose/cellulose acetated mixed matiix, 0.45 μm pore size filter disks (Millipore, Co., Bedford, MA). Nitrocellulose filter bound RNA was recovered by phenol/urea extraction. The partitioned RNA was then reverse transcribed and PCR amplified as above and used to initiate the next SELEX cycle. C. Determination of Equilibrium Dissociation Constants To partition the protein-RNA complexes, the binding reactions were filtered through nitrocellulose/cellulose acetated mixed matrix, 0.45 μm pore size filter disks (Millipore, Co., Bedford, MA). For filtration, the filters were placed onto a vacuum manifold and wetted by aspirating 5 ml of DPBS. The binding reactions were aspirated throught the filters and following a 5 ml wash, the filters were counted in a scintilation counter (Beckmann). Nitrocellulose partitionsing was used for SELEX and for determining the equilibrium dissociation constants of RNA ligands to TNFα. RNA ligands to TNFα bind monophasically. To obtain the equilibrium dissociation constants of RNA ligands to TNFα the binding reaction: K R : ? Ξ Ξr - J -? R=RNA P=Protein K D =dissociation constant is converted into an equation for the fraction of RNA bound at equilibrium: q=(f72R τ )(P τ +R τ +K D -((P τ +R τ +K D ) -4P τ R τ ) 1/2 ) q=fraction of RNA bound P τ =total protein concentration R τ =total RNA concentration f=retention efficiency of RNA-protein complexes The average retention efficiency for RNA-TNFα complexes on nitrocellulose filters is 0.1-0.2. The K D s were determined by least square fitting ofthe data points using the software Kaleidagraph (Synergy Software, Reading, PA). D. Cloning and Sequencing RT-PCR amplified cDNA from the last round of SELEX was cloned between BamHI and Hindlll restriction sites of pUC18 plasmid (Vieira et αl, 1982, Gene 19: 259-268) in MC1061 E. coli (Casadaban et αl., 1980, JMo Biol 138: 179-207). Sequencing was done using PCR products as templates with a commerically available kit (Promega, Madison WI). E. Receptor Binding Competition Assay A receptor binding competition assay was used to determine the bioactivity ofthe RNA ligands. 125 I labelled hTNFα at 0.1 nM was incubated in 50 μl of binding medium (PBS with 0.5 mM Mg^ , 0.2% BSA, 0.02% sodium azide, lU/μl RNasin) for 15 min at 4°C with serially diluted competitors at 10" 4 to 10' 11 M, and lxlOVμl U937 cells. Duplicate aliquots were subsequently removed, centrifuged through 2:1 dibutyl-phthalate:dinonyl-phthalate mixture to separate free and bound 125 I labelled hTNFα, and the radioactivity in the pellet was measured on a gamma counter. Nonspecific binding was determined by inclusion of a 200-fold molar excess of unlabeled TNF. The inhibition constants (Ki) ofthe RNA ligands were determined by a nonlinear regression analysis ofthe data using standard techniques. To obtain Ki values the concentration of TNF receptor was assumed to be 3.4x10"" M and the K D ofthe TNFα-TNFR interaction of 0.1 nM. F. Boundary determination For 3' boundary determination, the 6A RNA ligand was 5' end labeled with γ - 32 P-ATP using T4 polynucleotide kinase. 5' boundaries were established using 3' end labeled ligand with α- 32 P-pCp and T4 RNA ligase. After partial alkaline hydrolysis, the radiolabeled RNA ligand was incubated with hTNFα at 5, 25, and 125 nM, and the protein bound RNA was isolated by nitrocellulose partitioning. The RNA truncates were analyzed on a high resolution denaturing polyacrylamide gel. An alkaline hydrolysis ladder and a ladder of radioactively labeled ligands terminated with G-residues, generated by partial RNase Tl digestion, were used as markers. EXAMPLE 8. RNA LIGANDS TO hTNFα A. pre-SELEX characterization Nitrocellulose filter binding could not detect any interaction of hTNFα with random RNA even at high protein concentrations. The binding curves were completely flat even up to 10μM hTNFα and RNA up to lμM and the estimated dissociation constant (K D ) is greater than 10 "3 M. No buffer conditions were found that improved the interaction of hTNFα and random RNA. To determine whether hTNFα was binding any RNA at all we used a more sensitive technique similar to northwestern probing (Bowen et al, 1980). This technique was used in various studies of protein nucleic acid interaction and aided in the cloning of various DNA binding proteins (Singh et al, 1988). This experiment showed clearly that some random RNA can bind to hTNFα. RNA binding occurred only when the filter was previously spotted with hTNFα and and then dried, but not if the filter was spotted with hTNFα and then placed wet in the incubation chamber. The RNA was binding only on the filters carrying hTNFα but not on filters carrying BSA possibly because, either not enough BSA was immobilized on the filter or the BSA present in the incubation mix was competing for available BSA-specific RNA ligands. B. SELEX. Two independent SELEX experiments (A and B) were initiated with pools of randomized RNA containing about 10 14 unique molecules. The starting RNA and the PCR primer sequences are shown in Table 11. In the A-SELEX, the protein was immobilized on a nitrocellulose filter by drying. The protein containing filter was incubated in BB (see Example 7) with labeled RNA, then washed, autoradiographed and the bound RNA was recovered by phenol-urea extraction. For the first round of A-SELEX about 1,000 pmoles of hTNFα monomer was used and the RNA concentration was at 2xlO "6 M. For the subsequent 14 rounds, two different filters containing about 500 and 100 pmoles of hTNFα monomer were incubated in the same chamber containing amplified RNA from the previous round at about 2xlO"°M. Only the RNA from the high protein filter was carried to the next round. A steady increase in the signal to noise ratio was observed and at round 15 the signal retained on the 500- and 100-pmole protein filters was 170- and 35-fold above background respectively. For comparison, in the first round the signal was only about 3-fold above background. RNA from round 15 had a higher affinity for hTNFα with an estimated Kd of 5x10 5 M, representing a possible 100 fold improvement over the random RNA. To increase the stringency ofthe selection, we carried 8 more rounds using filters with about 10 and 1 pmole of hTNFα. For all these subsequent rounds, except for round 20, the RNA from the 1 pmole hTNFα filters was carried to the next round. Because of high background, at round 20 we used the RNA from the 10 pmoles hTNFα filter of round 19. The signal to noise ratio for these subsequent rounds became worse at each round but nevertheless the affinity ofthe evolved RNA continued to improve with estimated final Kd of 7x10 "7 M, which represents two additional orders of magnitude improvement. In the final round, we could detect signal with 10-fold shorter exposure time was detected, and with 100 - fold less hTNFα on the filter. In parallel with the stringent phase of A-SELEX, RNA from round 15 of the A-SELEX was evolved using B-SELEX conditions (see below) for 6 more rounds. We designated this as C-SELEX. The affinity ofthe evolved population at the end of C-SELEX was similar to the round 23 population of A-SELEX with approximate Kd=4xl0" 7 M. The evolved RNA from round 23 had not only improved affinity for hTNFα but it was also specific (Table 13). Binding could be detected only with hTNFα. In the B- SELEX experiment, binding reactions were set in 25-50μl and after 10 min incubation at 37°C it was filtered through a 0.45 μm HA nitrocellulose filter. For the first round of the B-SELEX, the RNA and protein were at about 4x10 "5 M each. Under these conditions only 0.1% ofthe input RNA was retained on the filter. This was not suφrising since the hTNFα-random-RNA interaction is very weak with a Kd too high to measure and probably in the 10 '3 M range. Subsequent rounds were set similar to the first round. By round 8, the background binding ofthe RNA to the nitrocellulose filters was very high. C. RNA sequences and Affinitites RT-PCR amplified cDNA from round 23 of A-SELEX and round 6 of C-SELEX were cloned and sequenced as described in Example 7. 37 clones were sequenced from A-SELEX and 36 cloned from C-SELEX. From the total of 73 sequences, 48 were unique (Table 12; SEQ ID NOS:209-255). A unique sequence is defined as one that differs from all others by three or more nucleotides. Ofthe 47 unique clones, 18 clones could bind to hTNFα with Kd better than 1 μM (Table 12). The best ligand, 25A, (SEQ ID NO:233) binds with affinity dissociation constant at about 40 nM. If it is assumed that the random RNA binds with a dissociation constant of greater than 10" 3 M, then the affinity of 25 A is at least four to five orders of magnitude better than the starting pool. Using sequence alignment and conserved predicted secondary structure, 17 out of 18 clones that bind hTNFα could be assigned into two classes. The members ofthe class II can be folded in stem-loop structures with internal bulges and asymmetric loops. Linear sequence alignment did not reveal any significant conserved sequences. D. Specificity of RNA Ligands to TNF We tested the specificity ofthe evolved pool of round 23 of A-SELEX against human TNFα, human TNFβ and murine TNFα. The evolved pool is highly specific for human TNFα and specificity ratios are shown in Table 13. EXAMPLE 9. Inhibition of hTNFα Binding to Cell Surface receptors To test the ability ofthe TNFα ligands to competitively inhibit the binding of hTNFα to its cell surface receptor, the U937 cells were used to screen several hTNFα ligands. The observed Kis are listed in Table 14. The data show that several ligands can competitively inhibit binding of hTNFα to its cell surface receptors while random RNA cannot. Ligand 25 A has the highest potency with a Ki of 21 nM. This Ki value is only 6 fold worse than the Ki observed with the sTNF-R2 under the same experimental conditions. EXAMPLE 10. Effect of 2'F Pyrimidine Modification on the Binding and Inhibitory Activities ofthe hTNFα Ligands Transcripts containing 2'F modified pyrimidines are resistant to RNase degradation. To obtain ligands with improved stability we tested the effect of 2'F pyrimidine modification on the binding and inhibitory activity of several hTNFα ligands. The results summarized in Table 15 show that some ofthe ligands retained binding activity when are modified with 2'F pyrimidines but in general the modified ligands bind worse than the unmodified counteφarts. Class II ligands are in general more tolerant of the 2'F pyrimidine modification. Most ofthe ligands that retained binding after the 2'F pyrimidine modification lose their inhibitory activity. Only the 2'F pyrimidine modification ofthe most abundant ligand, 6 A, did not affect its binding and inhibitory activities. EXAMPLE 11: Experimental Procedures for DNA Ligands to RANTES This example provides general procedures followed and incoφorated in Example 12 for the evolution of nucleic acid ligands to RANTES. A. Materials Recombinant human RANTES was purchased from Genzyme (Cambridge, MA). Taq DNA polymerase was Perkin Elmer (Norwalk, CT). T4 polynucleotide kinase was purchased from New England Biolabs (Beverly, MA). Ultrapure nucleotide triphosphates were purchased form Pharmacia (Piscataway, NJ). Affinity purified streptavidin (Cat. No 21122) was from Pierce (Rockford, IL). Oligonucleotides were obtained from Operon, Inc. (Alameda, CA). Nitrocellulose/cellulose acetate mixed matrix (HA), 0.45 μm filters were purchased form Millipore (Bedford, MA). Chemicals were.at least reagent grade and purchased from commercial sources. B. SELEX The SELEX procedure has been described in detail in the SELEX Patent Applications. The DNA template contained 40 random nucleotides, flanked by 5' and 3' constant regions for primer anealing sites for PCR (Table 16; SEQ ID NOS :256-258). Primer 3G7 (SEQ ID NO:258) has 4 biotin residues in its 5' end to aid in the purification of single stranded DNA (ssDNA). For the first round, 105 pmoles of synthetic 40N7 ssDNA were 5' end labelled using T4 polynucleotide kinase in a 25 μl reaction containing 70 mM Tris-HCl pH 7.6, 10 mM MgCl 2 , 5 mM DTT, 39.5 pmoles of g - 32 P-ATP (3000 Ci/mmol), and 16 units kinase, for 1 h at 37°C. The kinased DNA was then purified on an 8% polyacrilamide, 7M urea, denaturing gel and then mixed with gel purified unlabeled 40N7 to achieve about 5,000 cpm/pmol specific activity. To prepare binding reactions, the DNA molecules were incubated with recombinant RANTES in Hanks' Balanced Salt Solution (HBSS) without calcium and magnesium (Life Technologies, Gaithersburg, MD, Cat. No 14175) containing 0.01% human serum albumin. Two SELEX experiments were performed, one with normal salt concentration and the other with 300 mM NaCl. The high salt concentration was achieved by adding additional NaCl to the HBSS. Following incubation at room temperature for 30 minutes the protein-DNA complexes were partitioned from unbound DNA by filtering through HA nitrocellulose 0.45 μm. Nitrocellulose filter bound DNA was recovered by phenol/urea extraction. The partitioned DNA was PCR amplified in 50 mM KCl, lOmM Tris-HCl, pH9, 0.1% Triton X-100, 3mM MgCl 2 , 1 mM of each dATP, dCTP, dGTP, and dTTP, with 0.1 units/μl Taq DNA polymerase. The 3G7 and 5G7 primers were present at 2 μM. The 5G7 primer was 5'-end labeled before use described above. To purify ssDNA, the PCR product was ethanol precipitated and then reacted with affinity purified streptavidin at a molar ratio 1 :10 DNA to streptavidin in 10 mM Tris-HCl pH 7.5, 50 mM NaCl, 1 mM EDTA, 0.05% sodium azide. Following 30 incubation at room temperature, equal volume of 100% formamide tracking dye was added and the strands were denatured by incubating at 85 °C for 1.5 min. The denatured strands were then electophoresed in an 8% polyacrylamide, 7M urea gel and the nonshifted band was excised and purified from the crushed gel. The purified ssDNA was then used for the next SELEX cycle. EXAMPLE 12: DNA LIGANDS TO RANTES A. SELEX To generate DNA ligands for RANTES, two SELEX experiments were performed, one with 150 mM and the other with 300 mM NaCl. The high salt was used in order to avoid precipitation ofthe RANTES-DNA complexes that occurs at the lower salt concentration. The SELEX at 300 mM salt was prematurely terminated because of high background. The SELEX conditions and results for each round ofthe 150 mM salt SELEX are summarized in Table 17. The starting pool contained 1.8xl0 15 (2,940 pmoles) of DNA for the 150 mM salt SELEX. The starting KD values ofthe random DNA were 3xlO" 6 M. After 19 rounds of SELEX the evolved pools bound with a K D of 20 nM. This represents about 150 fold improvement. Table 1 40N7 TEMPLATES AND PRIMERS SEQ ID NO. 40N7 ssDNA Template: 5' GGGAGGACGAUGCGG [-40N-] CAGACGACUCGCCCGA 3' 1 SELEX PCR Primers: 5P7: 5' TAATACGACTCACTATAGGGAGGACGATGCGG 3* 2 3P7: 5' TCGGGCGAGTCGTCTG 3' 3 Cloning PCR Primers: 5P7H: Hind III 5' CCGAAQCTIAATACGACTCACTATAGGGAGGACGATGCGG 3' 4 3P7B: Bam HI 5* GCCGGATCCTCGGGCGAGTCGTCTG 3' 5 PCR Sequencing Primer: pUC19F30: 5' AGTCACGACGTTGTAAAACGACGGCCAGTG 3 ' 6 Table 2 SELEX STRATEGY Stringent NaCl Bio-spin Wash 250mM purified 3NA8 X X X X X X X X X X X X X X X X X X X Table 3 SEQ N a) IFN-gamma 2'F Sequences 5 ' -GGGAGGACGAUGCGG(4ON) CAGACGACUCGCCCGA-3 4ON GROUP 1 (18 clones) #1,2,5,11,12,15,18,21,26,32,35 ACACCGUUAAUCUGAGGCCCUGUCCUAUUCCUUCACGCCU 7 #3 ACACCGUUAGUCUGAGGCCUUGUCCUAUUCCUUCACGCCU 8 #10 ACACCUUUAAUCUGAGGCCCUGUCCUAUUCCUUCACGCCU 9 #22 ACACCUUGAAUCUGAGGCCCUGUCCUAUUCCUUCACGCCU 10 #29 ACACCGUUAAUCUGAGGCCCUGUCCUAUUCCUCCACGCCU 11 #31 ACACCGUAGAUCUGAGGCCCUGUCCUAUUCCUCCACGCCU 12 #19 ACACCGUUAAUCUGAGGCCCUGUCC AUUCCUUCACGCCU 13 #13 ACACCGUUAAACUGAGGCCCUGUCCUAUUCCUUCACGCCU 14 GROUP 2 (5 clones) #27 AACACCCCCGGUCUGACGCUUGUUCCGAAUUCCUCCACCGU 15 #8 GAACACCCCCGGUCUGACGCUUGUUCCGAAUUCCUCCACCGU 16 #33 AACACC CCGGUCUGACGCUUGUUCCGAAUUCCUCCACCGU 17 #34 AACACCCCCGGUUUGACGCUUGUUCCGAAAUCCUCCACCGU 18 #36 AACACCCCCGGUCUGACGCUUGUUCCG AAUCCUCCACCGU 19 Table 3 (Page 2 ) SE 3QQ ORPHANS ( 9 clones) #4 GGUUCCUGUUCUACUUUCUAAUUAUCCGCACCUCCUCCU 20 #6 UGGAGUUUUAAUCUUACUUCCUACUCUUGCUCCACUGGGU 21 #7 GAUUCAUUUUGAUCUUUCUUUCUCUUAUCCCGCUGUGCCU 22 #23 AUUCCUUUUUCCUUUCUCUUUUCUGACCGACUGAUCCGCCU 23 #25 UAAUCUACACUUAUAUUUUUUUUCUUUUUCUUUCCACCCAUCGU 24 #28 AGGGUUGGGAGGGGUCCUUCUUUUCGUCUGCGUGGACCGU 25 #16 CAUCCCUAGAGCAGCCAGCCGGAAAGAAGUCACGCCUGCU 26 #17 UAGUGACCGUCAGGUAGGUGGGUUAGGCCAUUACGUACGU 27 #30 GUGCCAACAAUGGAGGUCGGGUUAGGUAAGCCAACGGGU 28 b) IFN-gamma 2'NH, Sequences 5' -GGGAGGACGAUGCGG(40N) CAGACGACUCGCCCGA-3 ' 1 4ON GROUP 1 (25 clones) #7 UAGUAGCGCGAUAUAGCG CUGGUAGGGUUGCCGGUGGAU 29 #B4,B5,B6 UAGUAGCGCGAUAUAGCG CUGGUAGGGUAGCCGGUG AU 30 #8 UUGUAGCGCGAUAUAGCG CUGGUAGGGUUGCCGGUGGAU 31 Table 3 (Page 3) SEQ #B23 UGGUAGCGCGAUAUAGCG CUGGUAGGGUAGCCGGUG AU #17,24,B3,BIO UGGUAGCGCGAUAUAGCG CUGGUAGGGUUGCCGGUG AU 33 #33 UUGUAGCGCGAUAUAGCG CUGGUAGGGUUGCCGGUG AU 34 #31 UGGUAGCGCGAUAUAGCG CUGGUAGGGUUGCCGGUGGGU 35 #B7 UUGUAGCGCGAUAUAGCG CUGGCAGGGUUGCCGGUGGGU 36 #11 UGGCAGCGCGAGAUAGCG CUGGUAGGGUUGCCGGUGGAU 37 #B13 UGGUAGCGCGACAUAGCG CUGGUAGGGUUGCCGGUG AU 38 #6,14 AAGUGGUGAUCCCAUCUAGGGGUCGGUUGGGUCGACGGUG 39 #23 UGUGUGGGGUGCCAUAUAACC CCGGUUGGGUUGACGGUGU 40 #13,15,18,22,B8 UAGUGCUCACAGAGC GGUUGGGUAGCCGGUGGAUGCGGU 41 #25 UGUGGUGCAAUCUAAGCACCGGUUGGGUAGUUCGGUGGCU 42 #12 AGGCUCAAAAGGC C GGUUGGGUUAGGUAACUGUGUGCGGU 43 GROUP 2 (15 clones) #16 UAUGGUGGGUUUACGCGAGAGUAAGGGUCGCGUGGU 44 #29 ACGUAUGGUGGGUUCGUAGUAUUGGGCUCGUAGCGUGGGU 45 #30 CAGGUAAUUACAUGAAGGUGGGUUAGGUACUUUCAGGGU 46 #B9,B22 UAGGUAAUUACAUGAAGGUGGGUUAGGUACUUUCAGGGU 47 #B12 CAGUAAAUUCGGUAGGUGGGUUAGGUAGGAUCGUGAGGGU 48 #35 UAUGGUGGGUUGCACGUAUUAAGGGACGUACAUCUGUGCU 49 #B14 UAUAGGUAACUAUCAGGUGGGUAGUCGGUGGAAACGGGCUGUUGGU 50 #32 UACAGGUGGGUCGUGGAUAAUUGGGCACGCUCUAUCUCCU 51 #B16 CACUAGGUGGGUCGUGGUUGUUGGGCACGUAACUUCGCGU 52 Table 3 (Page 4) SEQ N #B24 UACUAGGUGGGUCGUGGUUGUUGGGCACGUAACUUCGCGU 53 #34 ACGUGGCCUUAGAUAGGCAGGUGGGUUAGGCAUAUUCAGU 54 #10 UUCGCGGCCUAAUUAAAGGCAGGAGGGUUAGGCAUUGCU 55 #B2 UGACUACGCCUGUAGUAGGUCGGGUUAGG CAUUGGGCGU 56 #B11 UGCGCAAUUGCGCAGGUCGGGUUAGGUAUCUGGGUAGCU 57 c) IFN-gamma 2'F/NH- Sequences 5' -GGGAGGACGAUGCGG(4O )CAGACGACUCGCCCGA-3' 1 4ON GROUP 1 (11 clones) #3 UUCAGAGGGUAGGUAAGUGGGAGGAAAAAUGCCGUAUCGCCU 58 #4 AGGUAAGAGGGAGGGACCUUCCAGUGAAUGUGCGCGUGGU 59 #14 AGGCCUGUGGUGAGGAUUGUGGGUGGUUGGCCACGCGCGU 60 #32 UCCAAAGAGGGUGGUUGUGGGUGGCACUAAGGUACCGCGU 61 #2 UAUUCGUAAGGCCAGAGCUGCGGGUGGGACCUCCGGCCU 62 #3,A8,13 CCAUAGUGGGUGGGUUUGGAGUGGAAUAGUGCCGAGCGU 63 #15,23,33 UGCACAUGAGGGUGGUGUGGGAGGAAACGUGACGCAUGGU 64 #1 UUCCGUCCGUGGGAUAGGUUUGUGGGAUGUACCGGCUGGU 65 Table 4 SEQ I NO. Truncated IFN-σa ma Liσands #1 (Kd=6.8/320 nM full-length; Kd=4.4/716 nM truncate) 5• -gggaggacgaugcggACACCGUUAADCUGAGGCCCUGUCCUAUUCCUUCACGCCUcaga-3 ' 66 #6 (Kd=3.2/314 nM full-length) 5• -GUUUUAAUCUUACUUCCUACUCUUGCϋCCACUGGGUcagacgacuc-3 ' (orphan) 67 #16 (Kd=9.3/232 nM full-length) 5• -gggaggacgaugcggCAUCCCUAGAGCAGCCAGCCGGAAAGAAGUCACGCCUGCUca-3 ■ (orphan) 68 #27 (Kd=8.8/384 nM full-length) 5 ' -gggaggacgaugcggAACACCCCCGGUCUGACGCUUGUϋCCGAAUUCCUCCACCGUcagacgac-3 ' 69 #28 (Kd=35 nM full-length; Kd=53 nM truncate) 5 ' -gggaggacgaugcggAGGGUUGGGAGGGGUCCUUCUU-3 ' (orphan) 70 2'WH-, #17 (Kd=l.8/750 nM full-length; Kd=12.4 nM truncate) 5' -gggaggacgaugcggUGGUAGCGCGAUAUAGCGCUGGUAGGGUUGCCGGUG-3 ' 71 #30 (Kd=2.7/103 nM full-length; Kd=ll nM truncate) 5' -gggaggacgaugcggCAGGUAAUUACAUGAAGGUGGGUTJAGGUA-3 ' 72 2'F/NH, #3 (Kd=106 nM full-length; Kd=119 nM truncate) 5 ' - (g)ggacgaugcggUUCAGAGGGUAGGUAAGUGGGAGGAAAAAUGCCGUAUCG-3 ' 73 73 Table 5 0N8 TEMPLATES AND PRIMERS 40N8 ssDNA Template 5' GGGAGACAAGAATAAACGCTCAA[-4ON-]TTCGACAGGAGGCTCACAACAGGC 3' 74 SELEX PCR Primers: 5P8: 5' TAATACGACTCACTATAGGGAGACAAGAATAAACGCTCAA 3' 75 3P8: 5' GCCTGTTGTGAGCCTCCTGTCGAA 3' 76 Cloning PCR Primers: 5P8H: Hind I II 5 ' CCG QCI1TAATACGACTCACTATAGGGAGACAAGAATAAACGCTCAA 3 ' 77 3P8B : Bam HI 5 ' GCCQGΔXCCGCCTGTTGTGAGCCTCCTGTCGAA 3 ' 78 PCR Sequencing Primer : Table 6 SELEX STRATEGY Interleukin-4 (IL-4) Stringent Bio-spin Wash purified RNAs X X X X X X X X X X X X X Table 7 SEQ I NO . a) IL-4 2 ' F Sequences 5 ' -GGGAGACAAGAAUAAACGCUCAA (40N) UUCGACAGGAGGCUCACAACAGGC- 3 ' 74 4ON GROUP 1 (29 clones) #2 CUAUGGGGAGCCACAUU AACGGCAAUAAAUCAUUACGAC 79 #3 CUAUGGGGAGCCACAUUU AACGGCUAUAAAAAACAUUACGAC 80 #6 CUCGGGAGCCAGAGUAAC AACGGCAUUAUAUAAUUUACU 81 #7,8,11,16 UCCCACCGGGGUGCCACGGUUUA AACGGCUUAAUAUGAAU 82 #12 GUCUGACUAUUGGGGCGCCACAAUAUC AACGGCUGUAC 83 #17 UCCCACCGGGGUGCCACGGUUUA AACGGCUUAAUAUUUACU 84 #19 GUCUUCCAUGGGGAGCCACAUU AACGGCGCAAUACUGAAC 85 #22,27,34,40 CUCGGGAGCCAGAGUAAC AACGGCACUAUAUAAUUUUACU 86 #26 CUAUGGGGAGCCACAUUU AACGGCAAUAAAUCAUUACGAC 87 #28 AGUGGGGAGCCACACUAA AACGGCAUAUUGACAUCGUCCC 88 #31 UCUCCUCAUGGGGCGCCACAUGGUUUUAACGGCAUAUCACU 89 #32 CUAUGGGGAGCCACAUUU AACGGCUAUAAAUCAUUACGAC 90 #35 ACUGGGGAGCCACAGAUUU AACGGCGCAUAUGAGUUGAGC 91 #39 CUCUCACUGGGGAGCCACAGUUUUA AACGGCAAGGGAGA 92 #41 CAUCAGAUGGGGUGCCACAUCAUCA AACGGCUAUAUA 93 #44 ACUGGGGAGCCACAGAUUU AACGGCACAUAUGAUUGAGC 94 #42 AACGGCUGUAACAAACAAGGUGGGGGGCCACACCAG AGCGGC 95 #9,15,1,33,46 ACGGCUGUAACAAACAAGGUGGGGGGCCACACAGAGCGGGUUCGAC 96 #25 ACGGCUGUGACAAACAAGGUGGGGGGCCACACAGAGCGGG 97 Table 7 (Page 2) SEQ I NO, ORPHANS (12 clones) #4 AUAGCAGAGCCCAUGGCGGGAGGGAGGAUUGUGGUGGAA 98 #13 CAUCGACGGACCAGAGGUAGUGGGGGGGAUGGGAUGCCCG 99 #14 ACCUAACAUCUUACCAUAUUCAAUUUACAUUACACACUAU 100 #18 GCUGCCCAAGGAAUUUAACUUGGACCGCGAUCUGGAGUC 101 #21 AGGAGCGCCAUGAAGCAAAGGGAGGAUUGUGGUGGAAGGC 102 #23 CCGUAUUAACACUUAUUUUACAAUUUUUUCAUA 103 #24 GGUACGACCAAGGAAUGUGGGUGGAAGAGGGUGCCGUACC 104 #30 GACGAACGACCACGGGAUGGGUGGGCAAAUAGGGAUGCCG 105 #38 GCUAACCCGUACAAAUUUUCUUUUUCAUUUUCAUCACUA 106 #43 CUCGGGAGCCAGAGUAACAACGGCACUAUAUAAUUUUACC 107 #47 CGACCCGACCAAGGGUAGGCAUGUGGGGGGGUGCCGGG 108 #48 UCCGAACAUGGGGUGCCACAAAAACGGCUAUUAUCACUAU 109 b) IL-4 2'NHj Sequences 5 ' -GGGAGACAAGAAUAAACGCUCAA(40 )UUCGACAGGAGGCUCACAACAGGC-3 • 74 4ON GROUP 1 (21 clones) #12 GGACUGG UGAGCCACG UAUA CGGUCUUAGGGGCUUGGGCG 110 #27 CCUUGUGG GGAGCCACG UAUA CGGCCAUAGCAUACCGCAA 111 #29 GAGCUGG UGAGCCACG UAUA CGGCCUUAGGGGCUUGGGCG 112 Table 7 (Page 3) SEQ ID NO. #B31 GAGCUGG UGAGCCACG UAUA CGGUCUUAGGGGCUUGGGCG 113 #17 GUAUUGG GGAGCCACAU UACAACGGCACAGGCAACCAGGG 114 #31 GUGCUGG UGAGCCACGC AUA CGGUCUUAGGGGCUUGAGCG 115 #B14,B19 UAAAUGG AGAGCCACAC UA A CGGCGUAUGAAAACACUCA 116 #B16,B17 UCACAAGCACCCUUGG GGAGCCACA UUAA CGGCCUAGGC 117 #B26 AUGG AGAGCCACA UUAA CGGCAGCAUAUCACAGUAGGAA 118 #B8 UGUGG GGAGCCACAG UUAA CGGCUUCAACUGAUUAGAA 119 #B24 AGAUUUAAAGUAUUUGG GGAGCCACA UCAA CGGCAUUGUG 120 #B29 UGACUGAACGAUGGUAUUGG AGAGCCACA UCAA CGGCAAU 121 #22 CAGAUGGUAUCUAGUGG AGAGCCACA UCAA CGGCGCAGA 122 #B5 CGAUAGUAUACACAUGAUGAUGG GGAGCCACG UGUA CGGC 123 #B18,B20 CGAUGG AGCGCCACAUCGCUAUAACGGCAUUUAACAAAAU 124 #B33,B34 GCGGUCUGAUUGAGCCACCG UGGA GGGUACGUGGAGGGA 125 #6 * ACAAUUUCACACAGAAACAGCUAUGACCAUGAUUACGCCA 126 AGCUUUGG GGAGCCACA UAUAACGGCAUGAUCAAAUAUAG 127 ORPHAN (1 clone) #32 AUACAAUGUGGUUGAAGCUACCUCCCACUCGUAGUGGGCC 128 NITROCELLULOSE FILTER BINDERS (35 clones) #1,B4 CCGUAGCCUCCAGCGGAACGCGGAGGGUACGUGGAGGGG 129 #2,3,24,25,26,36,B9,B15,B22 CCGUAGCCUCCAGCGGAAUGCGGAGGGCACGUGGAGGGG 130 #5 GAGCCUCCGUGAAUGACGUGGAGGCACGC GGAGGGGAA 131 #8 UCGAUACUACUCCUGGAGAAAAGGGAGGACCGU GGAGGA 132 #10 UCGAUACUACUCCUGGAGAAAAGGGAGGAUCGU GGAGGA 133 Table 7 (Page 4) SEQ I #11,B6 GCGGUCUGAUUGAGCCUCCGUGGAGGGUACGUGGAGGGA #18 AGGGUGGAUUGU GGAGGAAUGAGUUGUCUAUGGACUCCA 135 #19 UCGAUACUACUCCUGGAGAAAAGGGAGGAUCGU GGAGGAA 136 #28 CCGAUACUACUCCUGGAGAAAAGGGAGGAUCGU GGAGGAA 137 #30 GGGAGGAUAGU GGAGGAAGAGCGUGUAAUAAUGUUACGA 138 #34 UCGUAGCCUCCAGCGGAAUGCGGAGGGCACGUGGAGGGG 139 #35 UCGAUACUACUCCUGGAGAAAAGGGAGGAUCGU GGAGGAA 140 #B3 CCGCAGCCUCCAGCAAUGCGGAGGGCACGUGGAGGGG 141 #B7 GAGCCUCCGAGAAUGACGUGGAGGGUACGUGGAGGGGUA 142 #B11 CCGUAGCCUCCAGCGGAACGCGGAGGGCACGUGGAGGGG 143 #B12 UGCCGAGAGGAGGGCUGA GGAGGACGCGGCAUUAAGUGA 144 #B13 UCGAUACUACUCCUGGAGAAAAGGGAGGAUCGU GGAGGAU 145 #B23 GAGCCUCCGAGAAUGACGUGGAGGGCACGUGGAGGGGAA 146 #B25 UGCUGAGAGGAGGGCUGA GGAGGACACGGCAGUAUGAGA 147 #B27 ACGUAGCCUCCAGCGGAAUGCGGAGGGCACGUGGAGGGG 148 #B28 GCGGUCUGAUCGAGCCUCCGUGGAGGGUACGUGGAGGGA 149 #B30 GCGGUCUGAUUGAGCCUCCGUGGAGGGCACGUGGAGGGA 150 #B32 UGCCGAGAGGAGGGCUGA GGAGGACACGGCAGUAUGUAA 151 #B36 CCGUAGCCUCCAGCGGAAUGUGGAGGGCACGUGGAGGGG 152 #9 AAGGUGGGUCGU GGAGGAAUGAGCUCGCUCCCAGCUAA 153 c) IL-4 2'F/NHj Sequences 5 ' -GGGAGACAAGAAUAAACGCUCAA(4ON)UUCGACAQGAQGCUCACAACAGGC-3 • 74 Table 7 (Page 5) SEQ ID NO. 4ON GROUP 1 (7 clones) #9 AGAGUGCAGGUCUGGGGCGCCACA AUUACA ACGG CAAUAA 154 #19 GUCUUCCAUGGGGAGCCACAUUA ACGGCGCAAUACUGAAC 155 #13 CUCGGGAGCCAG AGUAACAACGGCACUAUAUAAUUUUAC 156 #25 AGAGCCGUUUUGGGGACCCAC AGUA ACGGGUUUAUGGUA 157 #8,10 GUCGGAGCGAUGGAGAGCCACG AUAU ACGGUCUGUGCGC 158 #41 AGUAACGUGGGGAGCCACACGU AAU ACGGCACUAA 159 GROUP 2 (11 clones) #16 GGUACGA CCAAG GAAUGUGGGUGGAAG AGGGCGCCGUACC 160 #28 GAUCCUGCGACGCCA GGGGUGGAU AGGGGGAAGGGAGCGG 161 #2 GACGAACGA CCAAG GGACGGGUGGGCAAAU AGGGAUGCCG 162 #11,22,29,30,44,45 GGUACGA CCAAG GAAUGUGGGUGGAAG AGGGUGCCGUACC 163 #43 CAACGCUGA CCA UGGGAGGAAUGUGGGAAGGGCGCCAGCG 164 #14 CAGCCA AGGGUUGGAUAGGGGGUAGGGAGCCGUAGCAGCG 165 ORPHAN (1 clone) #18 CCGCCUGCGAUAGUUAGACCGUUGAGCUGAGAGCAACACU 166 NITROCELLULOSE FILTER BINDERS (11 clones) Table 7 (Page 6) #1 AAGGUGGGUUGAQQAQGAAAGUAGCGUGAGUCAGUACCA 167 #4 AGGGAGGAUUGUGQ&GSAAGGGAGUGGAAGUGUCCCAGCC . 168 #5 GGAUGACCAAGCGUCGAACGAGGQ SQAUUGUGGUSQ QS 169 #12 GGGUGGAUUGUG£A£QAAGUAGCGCAGGGUUCCGUAAGCC 170 #21 AGGAGCGCCAUGAAGCAAAGGGAGGAUUGUGGUGGAAGG 171 #24 ACUGGAGCCAUACAGACGAGAGGAUGGGUGUGUSSΔQSA 172 #31 AGGGAGGAUUGUSSΔSSAAGGGAGUGGAAGUGUCUCAGCC 173 #32 UCGGGUGAGGACUGGUAGAAAAAGi2Ai2SGUUGUQQΔQSAG 174 #34 ACCUGAUAACCGCGGAGQQΔQQAUAGAQQ SSAAGUGCGG 175 #35 AGGCAGCCCCUCGACGAGAAAGGUGGGUAGUGGAGGAAC 176 #42 CUUACGACACCAAAGSQA≤SAUUGUGGUGGAAUGGGGUCG 177 Table 8 Truncated IL-4 Ligands 2'F #9 (Kd=14.7 nM full-length; Kd=18 nM truncate) 5' - (ggg)aaACGGCUGUAACAAACAAGGUGGGGGGCCACACA-3 ' 178 #12 (Kd=30 nM full-length) 5' -gggagacaagaauaaacgcucaaGUCUGACUAUUGGGGCGCC-ACAAUAUCAACGGC-3 ' 179 #18 (Kd=43 nM full-length) 5' -aagaauaaacgcucaaGCUGCCCAAGGAAUUUAACUUGGACCGCGAUCU-3 ' (orphan) 180 #21 (Kd=ll nM full-length) 5'-AAGCAAAGGGAGGAUUGUGGUGGAAGGCUUC-3' (orphan) 181 2'NH-t #29 (Kd=8.3 nM full-length; Kd=10 nM truncate) 5 • - (ggg)acgcucaaGAGCUGGUGAGCCACGUAUACGGCCUUAGGGGCUUGGGCG-3 ' 182 •2T/NH, #9 (Kd=3.3 nM full-length) 5' -gggagacaagaauaaacgcucaaAGAGUGCAGGUCUGGGGCGCCACAAUUAGAACGGCA-3 ' 183 #18 (Kd=30 nM full-length) 5'-gcucaaCCGCCUGCGAUAGUUAGACCG-3' (orphan) 184 #28 (Kd=8.7 nM full-length) 5' -CCUGCGACGCCAGGGGUGGAUAGGGGGAAGGGAGCGGuucgacagga-3 • 185 Table 9 SEQ ID NO . Initial random sequence RNA pool: 5 '-GGGAGACAAGAAUAAACGCUCAA- (N) 40 -UUCGACAGGAGGCUCACAACAGGC-3' 186 5'-Primer: 5'-TAATACGACTCACTATAGGGAGACAAGAATAAACGCTCAA-3' 187 3'-Primer: 5' -GCCTGTTGTGAGCCTCCTGTCGAA-3 ' 188 Table 10 SEQ ID (10) : ACAUCGUAUAA CUCUA-AGGGCCUGGAUAUACGAUGAA 189 ACAUCGUAUAA CUCUA-AGCGCCUGGAUAUACGAUGAA 190 ACAUCGUAUAA CUCUA-AGAGCCUGGAUAUACGAUGAA 191 ACAUCGUAUAA---CUCUA-AGUGCCUGGAUAUACGAUGAA 192 ACAUCGUAUAAU--CUCUA-AGAGCCUGGAUAUACGAUGAA 193 ACAUCGUAUAAUCUCUCUA-AGAGCCUGGA-AUACGAUGAA 194 AUCCCA-AU CUCUA-AGAGCCUGGA-U---AAGAAUGCGCAUUGGGC 195 AUCCCA-AU---CUCUA-AGAGCCUGGA-U---GACAAU-CGCAUUGGGC 196 AUCCCA-AU---CUCUA-AGAGCCUGGA-U---GAGAAUGCGCAUUGGGC 197 CUGAGAU CUCUA-AGAGCCUGGACU-CAG-CUCCGACUGACC 198 CUGAGAU CUCUA-AGAGCCUGGACU-CAG-CUCCGAUUGAUCC 199 CUGAGAU CUCUA-AGAGCCUGGACU-CAG-CUCCGAUUGAACC 200 UCUCUA-UGAGCCUGGA-U-CGACGAACUCUCUACGGGCUGUG 201 UCUCUA-AGAGCCUGGA-U-GUCGAGGGGCCAUUUCGCACGC 202 AUCUCUACUGAGCCUGGA-U-UCGCCAGAAGUUUUAUCACAGU 203 CGUAAAAGUUAUCGAAU--CUCUG-UGAGCCUGGA-U-CGAUUAC 204 CUGAGAU---CUCUA-AGAGCCUGGACUCAGCUACGAUUGAGCGUUUAUUCUUG 205 Table 11 SEQ ID NO. STARTING RNA: 5 ■ -GGGAGCUCAGAAUAAACGCUCAA (N 30 ) UUCGACAUGAGGCCCGGAUCCGGC 206 PCR PRIMER 1: PemH I 5'-GCCGGATCCGGGCCTCATGTCGAA 207 PCR PRIMER 2: His≤L EII 5 ' - CCGAAGCTTAATACGACTCACTATAGGGAGCTCAGAATAAACGCTCAA 208 T7 promoter TABLE 12 Sequences of the hTNFα ligands 8 SEQ ID Clone. 5' constant random 3 1 constant K ^ .nM d Class NO lA b (2) < = gggagctcagaataaacgctcaaACGGCTGACAACGGCTGGACTTGCGTATTG ttcgacatgaggcccggatccggc 209 2A (3 gggagctcagaataaacgctcaaGCGCTTGACCATTTCGTAGGGTCGCCCTTG ttcgacatgaggcccggatccggc 210 3A (2) gggagctcagaataaacgctcaaGATCGACGCATCGAGTCGCCTCATCGCTCC ttcgacatgaggcccggatccggc 135 I 211 4A gggagctcagaataaacgctcaaCGCACTCGGACGGAATCTCCGTAGGACACG ttcgacatgaggcccggatccggc 320 II 212 5A gggagctcagaataaacgctcaaTGTCATGCATGTGTGTCGCCTCATCACGCA ttcgacatgaggcccggatccggc 213 6A(7) gggagctcagaataaacgctcaaCCACTGGCTAGGAACTCGAGTACTGGGTGG ttcgacatgaggcccggatccggc 120 II 214 7A(2) gggagctcagaataaacgctcaaTTCGAAGCCACGTTTCATGTCCGTCGCTGC ttcgacatgaggcccggatccggc 215 8A gggagctcagaataaacgctcaaCAGTGGAGGCTGTCCAAACCCACCCACCCC ttcgacatgaggcccggatccggc 785 216 9A(4) gggagctcagaataaacgctcaaGTGGAGGGTACGTGGAGGGGAGAGCGATA ttcgacatgaggcccggatccggc 217 10A gggagctcagaataaacgctcaaTCTCATGCTCGCGTGCGTCGCCTCAACCA ttcgacatgaggcccggatccggc 218 11A gggagctcagaataaacgctcaaTCCCTCAGTGTCAAGTGCGTCGCCTCAGCA ttcgacatgaggcccggatccggc 219 12A gggagctcagaataaacgctcaaCTTCTTGGCCCCGTCTCAATGTCCGTACTTCttcgacatgaggcccggatccggc 220 13A(2) gggagctcagaataaacgctcaaCGTGATTTGGCCACGGGAAAGAGCCATACC ttcgacatgaggcccggatccggc 221 14A(4 gggagctcagaataaacgctcaaCGTTGAACGCTTGGTTTCATGTCCCTCGCC ttcgacatgaggcccggatccggc 222 15A gggagctcagaataaacgctcaaCGTCGATCGCGTGCTGTAGCCTCAGGCACC ttcgacatgaggcccggatccggc 223 16A gggagctcagaataaacgctcaaGGTGGAAGGCCTTTGAAGCCCGTACATCTCCttcgacatgaggcccggatccggc 224 17A gggagctcagaataaacgctcaaGGTCGAACTAGCGCTGGAGCGTGCGTTGGT ttcgacatgaggcccggatccggc 225 18A(2) gggagctcagaataaacgctcaaGTCGCTCGATCGTTTCATGCCCGTCCGACC ttcgacatgaggcccggatccggc 226 19A gggagctcagaataaacgctcaaGTCGATGCGCAGTCCGCCTCAGCTGCACTG ttcgacatgaggcccggatccggc 227 20A(3) gggagctcagaataaacgctcaaGGTGTGCCCAAGGCCCTTGAGAGAGGCGTG ttcgacatgaggcccggatccggc 228 21A gggagctcagaataaacgctcaaCGTCTAGGAACTGCGTCGCCTCAACAGCGC ttcgacatgaggcccggatccggc 229 22A gggagctcagaataaacgctcaaGTCGGATGGTTTTGCGCGTTTCCCG ttcgacatgaggcccggatccggc 230 23A gggagctcagaataaacgctcaaCCTCATCCTCGCACGCCATCGCCTGAACCG ttcgacatgaggcccggatccggc 52 231 24A gggagctcagaataaacgctcaaGGTGTGCCAAAGGCCCTTGAGAGAGGCGTA ttcgacatgaggcccggatccggc 232 25A(2) gggagctcagaataaacgctcaaGGCCGCATGCCCCTCCTAACAGCATGCAAC ttcgacatgaggcccggatccggc 40 233 26A gggagctcagaataaacgctcaaCCCTCGTGCGTGCGCTTGGAGCGTGGCGCA ttcgacatgaggcccggatccggc 234 27A gggagctcagaataaacgctcaaGTCGCTCGATCGTTTCATGTCCGTTCGACC ttcgacatgaggcccggatccggc 235 28A gggagctcagaataaacgctcaaGTCCACACTTTGCCGAGCGTCCTAGTG ttcgacatgaggcccggatccggc 236 TABLE 12 (Page 2) Sequences of the hTNFα ligands 3 SEQ I Clone 5' constant random 3' constant Kp.nM" Class NO IC gggagctcagaataaacgctcaaCGGGTGAATCACGGCTGGTGCGTTGCCCC ttcgacatgaggcccggatccggc 23 2C(2) gggagctcagaataaacgctcaaCGTCGACGCACTGTGCCGCCTCACACACGC ttcgacatgaggcccggatccggc 23 3C(2) gggagctcagaataaacgctcaaGCGAACGTCATGCCGCCTCATCATGCCACG ttcgacatgaggcccggatccggc 23 4C gggagctcagaataaacgctcaaCTAGGCCCACCGTCCCTTCTAACAACGTC ttcgacatgaggcccggatccggc 92 24 5C gggagctcagaataaacgctcaaCAGTCACGAACGTGCGCCGGAAGAACGCTC ttcgacatgaggcccggatccggc 24 6C gggagctcagaataaacgctcaaTGTCGCACGTGTCCCGGCCCGCCCTACCCC ttcgacatgaggcccggatccggc 24 7C (2) gggagctcagaataaacgctcaaCAGGTGGCACCGCCCTTCCAACACGGTGCG ttcgacatgaggcccggatccggc I 24 8C (2) gggagctcagaataaacgctcaaGTCCACACTTTGCCGAGCGTCCTAGTG ttcgacatgaggcccggatccggc II 24 9C gggagctcagaataaacgctcaaATGGTGGAGGCCATCTCAAACCCACGACAC ttcgacatgaggcccggatccggc I 24 10C gggagctcagaataaacgctcaaCGCCGAGACCCACCTCATAACACCGCTACC ttcgacatgaggcccggatccggc I 24 11C gggagctcagaataaacgctcaaTGAGGCGCGCCACAGGATGGCCCTCAACCC ttcgacatgaggcccggatccggc I 24 12C gggagctcagaataaacgctcaaGTCCGCATGATGCTTCGAACAGCATACAAC ttcgacatgaggcccggatccggc I 24 13C gggagctcagaataaacgctcaaGGTGTGCCCCTACGTGCGGCCCTTCGTTTA ttcgacatgaggcccggatccggc 24 14C gggagctcagaataaacgctcaaCGGCTTGCAGGTCGCCGAAATGACCGCACA ttcgacatgaggcccggatccggc II 25 15C gggagctcagaataaacgctcaaCTAGTTCAACCGTCCCTTCTAACAACCGTC ttcgacatgaggcccggatccggc I 25 16C gggagctcagaataaacgctcaaCCTGGTGGTCGTGCGGCTGTCGCCTCAAGG ttcgacatgaggcccggatccggc I 25 17C gggagctcagaataaacgctcaaGATCGAAGTTGTCGTCCGCCTCAGCGACTC ttcgacatgaggcccggatccggc 25 18C gggagctcagaataaacgctcaaTGTCGAGTGCGATGGAGGAGTAGGGATGCA ttcgacatgaggcccggatccggc o 25 12£ gqqaqctcagaataaacqctcaaTGTCGATCGTGTCAAGGTCCGTCCTACTTC ttcgacatgaggcccggatccggc I 25 • Only unique sequences are shown. A unique sequence is defined as one that differs from all others by three o more nucleotides. "Clone numbers followed by "A" were obtained from the round 23A or the round 6C pool. Clone numbers followed by "C" were obtained only from the round 6C pool. c The number in parentheses indicates the occurrence of the clone in the sequenced pool. d No value is shown for ligands that have Kd greater than lμM. TABLE 13 Binding specificity of the evolved pool of ligands from round 23A TABLE 14 Ki values of hTNFα competitors on the U937 cell competition assay Competitior Ki, nM •Fit correlation coefficient TABLE 15 Effect of 2'F-pyrimidine modification in the affinities and inhibitory activities of the hTNFα ligands a Ki values were obtained based on 5-8 point curves except for 16C and 23A 2'OH ligands where only 3 points were used. *No binding. 'Not determined. Table 16 SEQ ID NO. Starting DNA: 40N7: 5 'GGGAGGACGATGCGG[-4ON-] CAGACGACTCGCCCGA 3 • 256 SELEX PCR Primers: 5G7: 5 ' GGGAGGACGATGCGG 3 ' 257 3G7 : 5 ' XXXXTCGGGCGAGTCGTCTG 3 ' 258 X=biotin TABLE 17 Conditions and progress of the SELEX Process against RANTES Round [DNA] , M [RANTES],M net % Signal/ PF » PS b B- ash c U- ash d SPKD e , nM bound noise (ml) (ml) M KD f 35.0 25 1.24E-03 3000 7.8 25 1.01E-03 1.4 25 1.85E-03 1.5 25 50 20E-40 100 09E-05 100 89E-06 100 91E-06 890 o 100 89E-06 100 85E-07 100 90E-07 1.2 100 44E-06 2.0 100 60E-06 159 96E-06 39E-06 96E-06 48E-06 49E-06 49 1.48E-06 18 "Prefiltered DNA through nitrocellulose to counter select for nitocellulose binding molecules "Preadsorption of the DNA under binding conditions Volu e of buffer used to wash the captured complexes ■ Volume of 0.5M urea wash following the buffer wash "Calculated single point K D from the binding data at each round f K„ values obtained from binding curves References References Adams, D. O., and T. A. 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DeFrance, D. Blanchard, J. E. DeVries, F. Lee, K.-I. Arai (1986) Proc. Natl. Acad. Sci. USA 83:5894-5898. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: NEXSTAR PHARMACEUTICALS, INC. DIANE TASSET NIKOS PAGRATIS SUMEDHA JAYASENA LARRY GOLD OF CYTOKINES #200 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Diskette, 3.50 inch, 1.44 Mb storage (B) COMPUTER: IBM compatible (C) OPERATING SYSTEM: MS-DOS (D) SOFTWARE: WordPerfect 6.0 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: Unassigned (B) FILING DATE: (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: 08/477,829 (B) FILING DATE: 07-JUNE-1995 (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: 08/481,710 (B) FILING DATE: 07-JUNE-1995 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Barry J. Swanson (B) REGISTRATION NUMBER: 33,215 (C) REFERENCE/DOCKET NUMBER: NEX41/PCT (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (303) 793-3333 (B) TELEFAX: (303) 793-3433 (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: GGGAGGACGA UGCGGNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN 50 NNNNNCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 32 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: TAATACGACT CACTATAGGG AGGACGATGC GG 32 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 16 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: TCGGGCGAGT CGTCTG 16 (2) INFORMATION FOR SEQ ID NO: 4: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: CCGAAGCTTA ATACGACTCA CTATAGGGAG GACGATGCGG 40 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: GCCGGATCCT CGGGCGAGTC GTCTG 25 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 30 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: AGTCACGACG TTGTAAAACG ACGGCCAGTG 30 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: GGGAGGACGA UGCGGACACC GUUAAUCUGA GGCCCUGUCC UAUUCCUUCA 50 CGCCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: GGGAGGACGA UGCGGACACC GUUAGUCUGA GGCCUUGUCC UAUUCCUUCA 50 CGCCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 9: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9: GGGAGGACGA UGCGGACACC UUUAAUCUGA GGCCCUGUCC UAUUCCUUCA 50 CGCCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 10: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: GGGAGGACGA UGCGGACACC UUGAAUCUGA GGCCCUGUCC UAUUCCUUCA 50 CGCCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 11: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: GGGAGGACGA UGCGGACACC GUUAAUCUGA GGCCCUGUCC UAUUCCUCCA 50 CGCCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 12: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12: GGGAGGACGA UGCGGACACC GUAGAUCUGA GGCCCUGUCC UAUUCCUCCA 50 CGCCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: GGGAGGACGA UGCGGACACC GUUAAUCUGA GGCCCUGUCC AUUCCUUCAC 50 GCCUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: GGGAGGACGA UGCGGACACC GUUAAACUGA GGCCCUGUCC UAUUCCUUCA 50 CGCCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 15: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 72 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15: GGGAGGACGA UGCGGAACAC CCCCGGUCUG ACGCUUGUUC CGAAUUCCUC 50 CACCGUCAGA CGACUCGCCC GA 72 (2) INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 73 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: GGGAGGACGA UGCGGGAACA CCCCCGGUCU GACGCUUGUU CCGAAUUCCU 50 CCACCGUCAG ACGACUCGCC CGA 73 (2) INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: GGGAGGACGA UGCGGAACAC CCCGGUCUGA CGCUUGUUCC GAAUUCCUCC 50 ACCGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 18: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 72 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: GGGAGGACGA UGCGGAACAC CCCCGGUUUG ACGCUUGUUC CGAAAUCCUC 50 CACCGUCAGA CGACUCGCCC GA 72 (2) INFORMATION FOR SEQ ID NO: 19: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: GGGAGGACGA UGCGGAACAC CCCCGGUCUG ACGCUUGUUC CGAAUCCUCC 50 ACCGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 20: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20: GGGAGGACGA UGCGGGGUUC CUGUUCUACU UUCUAAUUAU CCGCACCUCC 50 UCCUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 21: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21: GGGAGGACGA UGCGGUGGAG UUUUAAUCUU ACUUCCUACU CUUGCUCCAC 50 UGGGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 22: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22: GGGAGGACGA UGCGGGAUUC AUUUUGAUCU UUCUUUCUCU UAUCCCGCUG 50 UGCCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 23: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 72 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23: GGGAGGACGA UGCGGAUUCC UUUUUCCUUU CUCUUUUCUG ACCGACUGAU 50 CCGCCUCAGA CGACUCGCCC GA 72 (2) INFORMATION FOR SEQ ID NO: 24: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 75 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24: GGGAGGACGA UGCGGUAAUC UACACUUAUA UUUUUUUUCU UUUUCUUUCC 50 ACCCAUCGUC AGACGACUCG CCCGA 75 (2) INFORMATION FOR.SEQ ID NO:25: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25: GGGAGGACGA UGCGGAGGGU UGGGAGGGGU CCUUCUUUUC GUCUGCGUGG 50 ACCGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 26: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26: GGGAGGACGA UGCGGCAUCC CUAGAGCAGC CAGCCGGAAA GAAGUCACGC 50 CUGCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 27: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27: GGGAGGACGA UGCGGUAGUG ACCGUCAGGU AGGUGGGUUA GGCCAUUACG 50 UACGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 28: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28: GGGAGGACGA UGCGGGUGCC AACAAUGGAG GUCGGGUUAG GUAAGCCAAC 50 GGGUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 29: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified ( i) SEQUENCE DESCRIPTION: SEQ ID NO: 29: GGGAGGACGA UGCGGUAGUA GCGCGAUAUA GCGCUGGUAG GGUUGCCGGU 50 GGAUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 30: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 69 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30: GGGAGGACGA UGCGGUAGUA GCGCGAUAUA GCGCUGGUAG GGUAGCCGGU 50 GAUCAGACGA CUCGCCCGA 69 (2) INFORMATION FOR SEQ ID NO: 31: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31: GGGAGGACGA UGCGGUUGUA GCGCGAUAUA GCGCUGGUAG GGUUGCCGGU 50 GGAUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 32: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 69 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32: GGGAGGACGA UGCGGUGGUA GCGCGAUAUA GCGCUGGUAG GGUAGCCGGU 50 GAUCAGACGA CUCGCCCGA 69 (2) INFORMATION FOR SEQ ID NO: 33: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 69 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33: GGGAGGACGA UGCGGUGGUA GCGCGAUAUA GCGCUGGUAG GGUUGCCGGU 50 GAUCAGACGA CUCGCCCGA 69 (2) INFORMATION FOR SEQ ID NO: 34: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 69 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34: GGGAGGACGA UGCGGUUGUA GCGCGAUAUA GCGCUGGUAG GGUUGCCGGU 50 GAUCAGACGA CUCGCCCGA 69 (2) INFORMATION FOR SEQ ID NO: 35: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35: GGGAGGACGA UGCGGUGGUA GCGCGAUAUA GCGCUGGUAG GGUUGCCGGU 50 GGGUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 36: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36: GGGAGGACGA UGCGGUUGUA GCGCGAUAUA GCGCUGGCAG GGUUGCCGGU 50 GGGUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 37: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37: GGGAGGACGA UGCGGUGGCA GCGCGAGAUA GCGCUGGUAG GGUUGCCGGU 50 GGAUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 38: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 69 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38: GGGAGGACGA UGCGGUGGUA GCGCGACAUA GCGCUGGUAG GGUUGCCGGU 50 GAUCAGACGA CUCGCCCGA 69 (2) INFORMATION FOR SEQ ID NO: 39: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39: GGGAGGACGA UGCGGAAGUG GUGAUCCCAU CUAGGGGUCG GUUGGGUCGA 50 CGGUGCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 40: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 72 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40: GGGAGGACGA UGCGGUGUGU GGGGUGCCAU AUAACCCCGG UUGGGUUGAC 50 GGUGUCAGAG CGACUCGCCC GA 72 (2) INFORMATION FOR SEQ ID NO: 41: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41: GGGAGGACGA UGCGGUAGUG CUCACAGAGC GGUUGGGUAG CCGGUGGAUG 50 CGGUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 42: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42: GGGAGGACGA UGCGGUGUGG UGCAAUCUAA GCACCGGUUG GGUAGUUCGG 50 UGGCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO:43: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43: GGGAGGACGA UGCGGAGGCU CAAAAGGCCG GUUGGGUUAG GUAACUGUGU 50 GCGGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 44: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 67 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44: GGGAGGACGA UGCGGUAUGG UGGGUUUACG CGAGAGUAAG GGUCGCGUGG 50 UCAGACGACU CGCCCGA 67 (2) INFORMATION FOR SEQ ID NO: 45: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45: GGGAGGACGA UGCGGACGUA UGGUGGGUUC GUAGUAUUGG GCUCGUAGCG 50 UGGGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 46: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46: GGGAGGACGA UGCGGCAGGU AAUUACAUGA AGGUGGGUUA GGUACUUUCA 50 GGGUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 47: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single . (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47: GGGAGGACGA UGCGGUAGGU AAUUACAUGA AGGUGGGUUA GGUACUUUCA 50 GGGUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 48: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48: GGGAGGACGA UGCGGCAGUA AAUUCGGUAG GUGGGUUAGG UAGGAUCGUG 50 AGGGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 49: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: GGGAGGACGA UGCGGUAUGG UGGGUUGCAC GUAUUAAGGG ACGUACAUCU 50 GUGCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR ' SEQ ID NO: 50: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50: GGGAGGACGA UGCGGUAUAG GUAACUAUCA GGUGGGUAGU CGGUGGAAAC 50 GGGCUGUUGG UCAGACGACU CGCCCGA 77 (2) INFORMATION FOR SEQ ID NO: 51: (i) SEQUENCE CHARACTERIZATION: " (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51: GGGAGGACGA UGCGGUACAG GUGGGUCGUG GAUAAUUGGG CACGCUCUAU 50 CUCCUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 52: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52: GGGAGGACGA UGCGGCACUA GGUGGGUCGU GGUUGUUGGG CACGUAACUU 50 CGCGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 53: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 53: GGGAGGACGA UGCGGUACUA GGUGGGUCGU GGUUGUUGGG CACGUAACUU 50 CGCGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 54: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54: GGGAGGACGA UGCGGACGUG GCCUUAGAUA GGCAGGUGGG UUAGGCAUAU 50 UCAGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 55: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 55: GGGAGGACGA UGCGGUUCGC GGCCUAAUUA AAGGCAGGAG GGUUAGGCAU 50 UGCUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 56: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56: GGGAGGACGA UGCGGUGACU ACGCCUGUAG UAGGUCGGGU UAGGCAUUGG 50 GCGUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 57: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57: GGGAGGACGA UGCGGUGCGC AAUUGCGCAG GUCGGGUUAG GUAUCUGGGU 50 AGCUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 58: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 73 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 • -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58: GGGAGGACGA UGCGGUUCAG AGGGUAGGUA AGUGGGAGGA AAAAUGCCGU 50 AUCGCCUCAG ACGACUCGCC CGA 73 (2) INFORMATION FOR SEQ ID NO: 59: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59: GGGAGGACGA UGCGGAGGUA AGAGGGAGGG ACCUUCCAGU GAAUGUGCGC 50 GUGGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 60: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60: GGGAGGACGA UGCGGAGGCC UGUGGUGAGG AUUGUGGGUG GUUGGCCACG 50 CGCGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 61: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 • -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61: GGGAGGACGA UGCGGUCCAA AGAGGGUGGU UGUGGGUGGC ACUAAGGUAC 50 CGCGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 62: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ■ -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 62: GGGAGGACGA UGCGGUAUUC GUAAGGCCAG AGCUGCGGGU GGGACCUCCG 50 GCCUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 63: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 70 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63: GGGAGGACGA UGCGGCCAUA GUGGGUGGGU UUGGAGUGGA AUAGUGCCGA 50 GCGUCAGACG ACUCGCCCGA 70 (2) INFORMATION FOR SEQ ID NO: 64: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 • -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64: GGGAGGACGA UGCGGUGCAC AUGAGGGUGG UGUGGGAGGA AACGUGACGC 50 AUGGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 65: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65: GGGAGGACGA UGCGGUUCCG UCCGUGGGAU AGGUUUGUGG GAUGUACCGG 50 CUGGUCAGAC GACUCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 66: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 59 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66: GGGAGGACGA UGCGGACACC GUUAAUCUGA GGCCCUGUCC UAUUCCUUCA 50 CGCCUCAGA 59 (2) INFORMATION FOR SEQ ID NO: 67: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 46 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67: GUUUUAAUCU UACUUCCUAC UCUUGCUCCA CUGGGUCAGA CGACUC 46 (2) INFORMATION FOR SEQ ID NO: 68: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 57 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68: GGGAGGACGA UGCGGCAUCC CUAGAGCAGC CAGCCGGAAA GAAGUCACGC 50 CUGCUCA 57 (2) INFORMATION FOR SEQ ID NO: 69: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 64 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69: GGGAGGACGA UGCGGAACAC CCCCGGUCUG ACGCUUGUUC CGAAUUCCUC 50 CACCGUCAGA CGAC 64 (2) INFORMATION FOR SEQ ID NO: 70: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 37 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 70: GGGAGGACGA UGCGGAGGGU UGGGAGGGGU CCUUCUU 37 (2) INFORMATION FOR SEQ ID NO: 71: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 51 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71: GGGAGGACGA UGCGGUGGUA GCGCGAUAUA GCGCUGGUAG GGUUGCCGGU 50 G 51 (2) INFORMATION FOR SEQ ID NO: 72: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 44 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 72: GGGAGGACGA UGCGGCAGGU AAUUACAUGA AGGUGGGUUA GGUA 44 (2) INFORMATION FOR SEQ ID NO: 73: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 50 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73: GGACGAUGCG GUUCAGAGGG UAGGUAAGUG GGAGGAAAAA UGCCGUAUCG 50 (2) INFORMATION FOR SEQ ID NO: 74: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 74: GGGAGACAAG AATAAACGCT CAANNNNNNN NNNNNNNNNN NNNNNNNNNN 50 NNNNNNNNNN NNNTTCGACA GGAGGCTCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 75: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 75 TAATACGACT CACTATAGGG AGACAAGAAT AAACGCTCAA 40 (2) INFORMATION FOR SEQ ID NO: 76: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 24 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 76: GCCTGTTGTG AGCCTCCTGT CGAA 24 (2) INFORMATION FOR SEQ ID NO: 77: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 49 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77: CCGAAGCTTT AATACGACTC ACTATAGGGA GACAAGAATA AACGCTCAA 49 (2) INFORMATION FOR SEQ ID NO: 78: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 33 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 78: GCCGGATCCG CCTGTTGTGA GCCTCCTGTC GAA 33 (2) INFORMATION FOR SEQ ID NO: 79: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79: GGGAGACAAG AAUAAACGCU CAACUAUGGG GAGCCACAUU AACGGCAAUA 50 AAUCAUUACG ACUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 80: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 89 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 80: GGGAGACAAG AAUAAACGCU CAACUAUGGG GAGCCACAUU UAACGGCUAU 50 AAAAAACAUU ACGACUUCGA CAGGAGGCUC ACAACAGGC 89 (2) INFORMATION FOR SEQ ID NO: 81: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 81: GGGAGACAAG AAUAAACGCU CAACUCGGGA GCCAGAGUAA CAACGGCAUU 50 AUAUAAUUUA CUUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 82: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82: GGGAGACAAG AAUAAACGCU CAAUCCCACC GGGGUGCCAC GGUUUAAACG 50 GCUUAAUAUG AAUUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 83: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 85 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 83: GGGAGACAAG AAUAAACGCU CAAGUCUGAC UAUUGGGGCG CCACAAUAUC 50 AACGGCUGUA CUUCGACAGG AGGCUCACAA CAGGC 85 (2) INFORMATION FOR SEQ ID NO: 84: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 88 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 84: GGGAGACAAG AAUAAACGCU CAAUCCCACC GGGGUGCCAC GGUUUAAACG 50 GCUUAAUAUU UACUUUCGAC AGGAGGCUCA CAACAGGC 88 (2) INFORMATION FOR SEQ ID NO: 85: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 85: GGGAGACAAG AAUAAACGCU CAAGUCUUCC AUGGGGAGCC ACAUUAACGG 50 CGCAAUACUG AACUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 86: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86: GGGAGACAAG AAUAAACGCU CAACUCGGGA GCCAGAGUAA CAACGGCACU 50 AUAUAAUUUU ACUUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 87: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 87: GGGAGACAAG AAUAAACGCU CAACUAUGGG GAGCCACAUU UAACGGCAAU 50 AAAUCAUUAC GACUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 88: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 88: GGGAGACAAG AAUAAACGCU CAAAGUGGGG AGCCACACUA AAACGGCAUA 50 UUGACAUCGU CCCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 89: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 88 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 89: GGGAGACAAG AAUAAACGCU CAAUCUCCUC AUGGGGCGCC ACAUGGUUUU 50 AACGGCAUAU CACUUUCGAC AGGAGGCUCA CAACAGGC 88 (2) INFORMATION FOR SEQ ID NO: 90: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 90: GGGAGACAAG AAUAAACGCU CAACUAUGGG GAGCCACAUU UAACGGCUAU 50 AAAUCAUUAC GACUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 91: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 91: GGGAGACAAG AAUAAACGCU CAAACUGGGG AGCCACAGAU UUAACGGCGC 50 AUAUGAGUUG AGCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 92: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 92: GGGAGACAAG AAUAAACGCU CAACUCUCAC UGGGGAGCCA CAGUUUUAAA 50 CGGCAAGGGA GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 93: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 84 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 93: GGGAGACAAG AAUAAACGCU CAACAUCAGA UGGGGUGCCA CAUCAUCAAA 50 CGGCUAUAUA UUCGACAGGA GGCUCACAAC AGGC 84 (2) INFORMATION FOR SEQ ID NO: 94: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 94: GGGAGACAAG AAUAAACGCU CAAACUGGGG AGCCACAGAU UUAACGGCAC 50 AUAUGAUUGA GCUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 95: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 89 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 95: GGGAGACAAG AAUAAACGCU CAAAACGGCU GUAACAAACA AGGUGGGGGG 50 CCACACCAGA GCGGCUUCGA CAGGAGGCUC ACAACAGGC 89 (2) INFORMATION FOR SEQ ID NO: 96: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 93 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 96: GGGAGACAAG AAUAAACGCU CAAACGGCUG UAACAAACAA GGUGGGGGGC 50 CACACAGAGC GGGUUCGACU UCGACAGGAG GCUCACAACA GGC 93 (2) INFORMATION FOR SEQ ID NO: 97: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 97: GGGAGACAAG AAUAAACGCU CAAACGGCUG UGACAAACAA GGUGGGGGGC 50 CACACAGAGC GGGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 98: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 98: GGGAGACAAG AAUAAACGCU CAAAUAGCAG AGCCCAUGGC GGGAGGGAGG 50 AUUGUGGUGG AAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 99: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 99: GGGAGACAAG AAUAAACGCU CAACAUCGAC GGACCAGAGG UAGUGGGGGG 50 GAUGGGAUGC CCGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 100: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 100: GGGAGACAAG AAUAAACGCU CAAACCUAAC AUCUUACCAU AUUCAAUUUA 50 CAUUACACAC UAUUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 101: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 101: GGGAGACAAG AAUAAACGCU CAAGCUGCCC AAGGAAUUUA ACUUGGACCG 50 CGAUCUGGAG UCUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 102: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 102: GGGAGACAAG AAUAAACGCU CAAAGGAGCG CCAUGAAGCA AAGGGAGGAU 50 UGUGGUGGAA GGCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 103: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 80 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 103: GGGAGACAAG AAUAAACGCU CAACCGUAUU AACACUUAUU UUACAAUUUU 50 UUCAUAUUCG ACAGGAGGCU CACAACAGGC 80 (2) INFORMATION FOR SEQ ID NO: 104: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104: GGGAGACAAG AAUAAACGCU CAAGGUACGA CCAAGGAAUG UGGGUGGAAG 50 AGGGUGCCGU ACCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 105: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 105: GGGAGACAAG AAUAAACGCU CAAGACGAAC GACCACGGGA UGGGUGGGCA 50 AAUAGGGAUG CCGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 106: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106: GGGAGACAAG AAUAAACGCU CAAGCUAACC CGUACAAAUU UUCUUUUUCA 50 UUUUCAUCAC UAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 107: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107: GGGAGACAAG AAUAAACGCU CAACUCGGGA GCCAGAGUAA CAACGGCACU 50 AUAUAAUUUU ACCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 108: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 85 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 108: GGGAGACAAG AAUAAACGCU CAACGACCCG ACCAAGGGUA GGCAUGUGGG 50 GGGGUGCCGG GUUCGACAGG AGGCUCACAA CAGGC 85 (2) INFORMATION FOR SEQ ID NO: 109: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2--F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109: GGGAGACAAG AAUAAACGCU CAAUCCGAAC AUGGGGUGCC ACAAAAACGG 50 CUAUUAUCAC UAUUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 110: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 110: GGGAGACAAG AAUAAACGCU CAAGGACUGG UGAGCCACGU AUACGGUCUU 50 AGGGGCUUGG GCGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 111: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111: GGGAGACAAG AAUAAACGCU CAACCUUGUG GGGAGCCACG UAUACGGCCA 50 UAGCAUACCG CAAUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 112: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 112: GGGAGACAAG AAUAAACGCU CAAGAGCUGG UGAGCCACGU AUACGGCCUU 50 AGGGGCUUGG GCGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 113: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic ,acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 113: GGGAGACAAG AAUAAACGCU CAAGAGCUGG UGAGCCACGU AUACGGUCUU 50 AGGGGCUUGG GCGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 114: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 114: GGGAGACAAG AAUAAACGCU CAAGUAUUGG GGAGCCACAU UACAACGGCA 50 CAGGCAACCA GGGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 115: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 115: GGGAGACAAG AAUAAACGCU CAAGUGCUGG UGAGCCACGC AUACGGUCUU 50 AGGGGCUUGA GCGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 116: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 116: GGGAGACAAG AAUAAACGCU CAAUAAAUGG AGAGCCACAC UAACGGCGUA 50 UGAAAACACU CAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 117: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 117: GGGAGACAAG AAUAAACGCU CAAUCACAAG CACCCUUGGG GAGCCACAUU 50 AACGGCCUAG GCUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 118: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 118: GGGAGACAAG AAUAAACGCU CAAAUGGAGA GCCACAUUAA CGGCAGCAUA 50 UCACAGUAGG AAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 119: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 85 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 119: GGGAGACAAG AAUAAACGCU CAAUGUGGGG AGCCACAGUU AACGGCUUCA 50 ACUGAUUAGA AUUCGACAGG AGGCUCACAA CAGGC 85 (2) INFORMATION FOR SEQ ID NO: 120: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 120: GGGAGACAAG AAUAAACGCU CAAAGAUUUA AAGUAUUUGG GGAGCCACAU 50 CAACGGCAUU GUGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 121: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 121: GGGAGACAAG AAUAAACGCU CAAUGACUGA ACGAUGGUAU UGGAGAGCCA 50 CAUCAACGGC AAUUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 122: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 122: GGGAGACAAG AAUAAACGCU CAACAGAUGG UAUCUAGUGG AGAGCCACAU 50 CAACGGCGCA GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 123: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 123: GGGAGACAAG AAUAAACGCU CAACGAUAGU AUACACAUGA UGAUGGGGAG 50 CCACGUGUAC GGCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 124: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 124: GGGAGACAAG AAUAAACGCU CAACGAUGGA GCGCCACAUC GCUAUAACGG 50 CAUUUAACAA AAUUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 125: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 125: GGGAGACAAG AAUAAACGCU CAAGCGGUCU GAUUGAGCCA CCGUGGAGGG 50 UACGUGGAGG GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 126: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 126: GGGAGACAAG AAUAAACGCU CAAACAAUUU CACACAGAAA CAGCUAUGAC 50 CAUGAUUACG CCAUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 127: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 127: GGGAGACAAG AAUAAACGCU CAAAGCUUUG GGGAGCCACA UAUAACGGCA 50 UGAUCAAAUA UAGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 128: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 128: GGGAGACAAG AAUAAACGCU CAAAUACAAU GUGGUUGAAG CUACCUCCCA 50 CUCGUAGUGG GCCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 129: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 129: GGGAGACAAG AAUAAACGCU CAACCGUAGC CUCCAGCGGA ACGCGGAGGG 50 UACGUGGAGG GGUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 130: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 130: GGGAGACAAG AAUAAACGCU CAACCGUAGC CUCCAGCGGA AUGCGGAGGG 50 CACGUGGAGG GGUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 131: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 85 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 131: GGGAGACAAG AAUAAACGCU CAAGAGCCUC CGUGAAUGAC GUGGAGGCAC 50 GCGGAGGGGA AUUCGACAGG AGGCUCACAA CAGGC 85 (2) INFORMATION FOR SEQ ID NO: 132: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 132: GGGAGACAAG AAUAAACGCU CAAUCGAUAC UACUCCUGGA GAAAAGGGAG 50 GACCGUGGAG GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 133: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 133: GGGAGACAAG AAUAAACGCU CAAUCGAUAC UACUCCUGGA GAAAAGGGAG 50 GAUCGUGGAG GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 134: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 134: GGGAGACAAG AAUAAACGCU CAAGCGGUCU GAUUGAGCCU CCGUGGAGGG 50 UACGUGGAGG GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 135: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 135: GGGAGACAAG AAUAAACGCU CAAAGGGUGG AUUGUGGAGG AAUGAGUUGU 50 CUAUGGACUC CAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 136: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 136: GGGAGACAAG AAUAAACGCU CAAUCGAUAC UACUCCUGGA GAAAAGGGAG 50 GAUCGUGGAG GAAUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 137: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 137: GGGAGACAAG AAUAAACGCU CAACCGAUAC UACUCCUGGA GAAAAGGGAG 50 GAUCGUGGAG GAAUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 138: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO : 138: GGGAGACAAG AAUAAACGCU CAAGGGAGGA UAGUGGAGGA AGAGCGUGUA 50 AUAAUGUUAC GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 139: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 139: GGGAGACAAG AAUAAACGCU CAAUCGUAGC CUCCAGCGGA AUGCGGAGGG 50 CACGUGGAGG GGUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 140: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 140: GGGAGACAAG AAUAAACGCU CAAUCGAUAC UACUCCUGGA GAAAAGGGAG 50 GAUCGUGGAG GAAUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 141: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 84 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 141: GGGAGACAAG AAUAAACGCU CAACCGCAGC CUCCAGCAAU GCGGAGGGCA 50 CGUGGAGGGG UUCGACAGGA GGCUCACAAC AGGC 84 (2) INFORMATION FOR SEQ ID NO: 142: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 142: GGGAGACAAG AAUAAACGCU CAAGAGCCUC CGAGAAUGAC GUGGAGGGUA 50 CGUGGAGGGG UAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 143: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 • -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 143: GGGAGACAAG AAUAAACGCU CAACCGUAGC CUCCAGCGGA ACGCGGAGGG 50 CACGUGGAGG GGUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 144: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 144: GGGAGACAAG AAUAAACGCU CAAUGCCGAG AGGAGGGCUG AGGAGGACGC 50 GGCAUUAAGU GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 145: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 145: GGGAGACAAG AAUAAACGCU CAAUCGAUAC UACUCCUGGA GAAAAGGGAG 50 GAUCGUGGAG GAUUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 146: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 146: GGGAGACAAG AAUAAACGCU CAAGAGCCUC CGAGAAUGAC GUGGAGGGCA 50 CGUGGAGGGG AAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 147: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 147: GGGAGACAAG AAUAAACGCU CAAUGCUGAG AGGAGGGCUG AGGAGGACAC 50 GGCAGUAUGA GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 148: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 148: GGGAGACAAG AAUAAACGCU CAAACGUAGC CUCCAGCGGA AUGCGGAGGG 50 CACGUGGAGG GGUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 149: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 149: GGGAGACAAG AAUAAACGCU CAAGCGGUCU GAUCGAGCCU CCGUGGAGGG 50 UACGUGGAGG GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 150: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 150: GGGAGACAAG AAUAAACGCU CCAGCGGUCU GAUUGAGCCU CCGUGGAGGG 50 CACGUGGAGG GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 151: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 151: GGGAGACAAG AAUAAACGCU CAAUGCCGAG AGGAGGGCUG AGGAGGACAC 50 GGCAGUAUGU AAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 152: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 152: GGGAGACAAG AAUAAACGCU CAACCGUAGC CUCCAGCGGA AUGUGGAGGG 50 CACGUGGAGG GGUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 153: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 85 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 153: GGGAGACAAG AAUAAACGCU CAAAAGGUGG GUCGUGGAGG AAUGAGCUCG 50 CUCCCAGCUA AUUCGACAGG AGGCUCACAA CAGGC 85 (2) INFORMATION FOR SEQ ID NO: 154: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 154: GGGAGACAAG AAUAAACGCU CAAAGAGUGC AGGUCUGGGG CGCCACAAUU 50 ACAACGGCAA UAAUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 155: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 • -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 • -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 155: GGGAGACAAG AAUAAACGCU CAAGUCUUCC AUGGGGAGCC ACAUUAACGG 50 CGCAAUACUG AACUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 156: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 • -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 156: GGGAGACAAG AAUAAACGCU CAACUCGGGA GCCAGAGUAA CAACGGCACU 50 AUAUAAUUUU ACUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 157: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH, modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 157: GGGAGACAAG AAUAAACGCU CAAAGAGCCG UUUUGGGGAC CCACAGUAAC 50 GGGUUUAUGG UAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 158: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 158: GGGAGACAAG AAUAAACGCU CAAGUCGGAG CGAUGGAGAG CCACGAUAUA 50 CGGUCUGUGC GCUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 159: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 82 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 159: GGGAGACAAG AAUAAACGCU CAAAGUAACG UGGGGAGCCA CACGUAAUAC 50 GGCACUAAUU CGACAGGAGG CUCACAACAG GC 82 (2) INFORMATION FOR SEQ ID NO: 160: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ■ -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ■ -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 160: GGGAGACAAG AAUAAACGCU CAAGGUACGA CCAAGGAAUG UGGGUGGAAG 50 AGGGCGCCGU ACCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 161: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 161: GGGAGACAAG AAUAAACGCU CAAGAUCCUG CGACGCCAGG GGUGGAUAGG 50 GGGAAGGGAG CGGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 162: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U'S are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 162: GGGAGACAAG AAUAAACGCU CAAGACGAAC GACCAAGGGA CGGGUGGGCA 50 AAUAGGGAUG CCGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 163: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 163: GGGAGACAAG AAUAAACGCU CAAGGUACGA CCAAGGAAUG UGGGUGGAAG 50 AGGGUGCCGU ACCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 164 (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH, modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 164: GGGAGACAAG AAUAAACGCU CAACAACGCU GACCAUGGGA GGAAUGUGGG 50 AAGGGCGCCA GCGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 165: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH, modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 165: GGGAGACAAG AAUAAACGCU CAACAGCCAA GGGUUGGAUA GGGGGUAGGG 50 AGCCGUAGCA GCGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 166 (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 .modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 •-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 166: GGGAGACAAG AAUAAACGCU CAACCGCCUG CGAUAGUUAG ACCGUUGAGC 50 UGAGAGCAAC ACUUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 167: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D)- TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 167: GGGAGACAAG AAUAAACGCU CAAAAGGUGG GUUGAGGAGG AAAGUAGCGU 50 GAGUCAGUAC CAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 168: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 168: GGGAGACAAG AAUAAACGCU CAAAGGGAGG AUUGUGGAGG AAGGGAGUGG 50 AAGUGUCCCA GCCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 169: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 169: GGGAGACAAG AAUAAACGCU CAAGGAUGAC CAAGCGUCGA ACGAGGGAGG 50 AUUGUGGUGG AGGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 170: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH, modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 170: GGGAGACAAG AAUAAACGCU CAAGGGUGGA UUGUGGAGGA AGUAGCGCAG 50 GGUUCCGUAA GCCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 171: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 • -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 171: GGGAGACAAG AAUAAACGCU CAAAGGAGCG CCAUGAAGCA AAGGGAGGAU 50 UGUGGUGGAA GGCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 172: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 172: . GGGAGACAAG AAUAAACGCU CAAACUGGAG CCAUACAGAC GAGAGGAUGG 50 GUGUGUGGAG GAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 173: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 173: GGGAGACAAG AAUAAACGCU CAAAGGGAGG AUUGUGGAGG AAGGGAGUGG 50 AAGUGUCUCA GCCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 174: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 • -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ■ -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 174: GGGAGACAAG AAUAAACGCU CAAUCGGGUG AGGACUGGUA GAAAAAGGAG 50 GGUUGUGGAG GAGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 175: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2' •NH, modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 175: GGGAGACAAG AAUAAACGCU CAAACCUGAU AACCGCGGAG GGAGGAUAGA 50 GGAGGAAGUG CGGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 176: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH, modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 176: GGGAGACAAG AAUAAACGCU CAAAGGCAGC CCCUCGACGA GAAAGGUGGG 50 UAGUGGAGGA ACUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 177: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 177: GGGAGACAAG AAUAAACGCU CAACUUACGA CACCAAAGGG AGGAUUGUGG 50 UGGAAUGGGG UCGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 178: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 38 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 178: GGGAAACGGC UGUAACAAAC AAGGUGGGGG GCCACACA 38 (2) INFORMATION FOR SEQ ID NO: 179: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 56 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 179: GGGAGACAAG AAUAAACGCU CAAGUCUGAC UAUUGGGGCG CCACAAUAUC 50 AACGGC 56 (2) INFORMATION FOR SEQ ID NO: 180: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 49 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 180: AAGAAUAAAC GCUCAAGCUG CCCAAGGAAU UUAACUUGGA CCGCGAUCU 49 (2) INFORMATION FOR SEQ ID NO: 181: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 181: AAGCAAAGGG AGGAUUGUGG UGGAAGGCUU C 31 (2) INFORMATION FOR SEQ ID NO: 182: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 51 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -NH 2 modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 182: GGGACGCUCA AGAGCUGGUG AGCCACGUAU ACGGCCUUAG GGGCUUGGGC 50 G 51 (2) INFORMATION FOR SEQ ID NO: 183 (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 59 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 183: GGGAGACAAG AAUAAACGCU CAAAGAGUGC AGGUCUGGGG CGCCACAAUU 50 AGAACGGCA 59 (2) INFORMATION FOR SEQ ID NO: 184: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 27 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH 2 modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 184: GCUCAACCGC CUGCGAUAGU UAGACCG 27 (2) INFORMATION FOR SEQ ID NO: 185: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 47 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All U's are 2 ' -NH, modified (ix) FEATURE: (D) OTHER INFORMATION: All Cs are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 185: CCUGCGACGC CAGGGGUGGA UAGGGGGAAG GGAGCGGUUC GACAGGA 47 (2) INFORMATION FOR SEQ ID NO: 186: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 186: GGGAGACAAG AAUAAACGCU CAANNNNNNN NNNNNNNNNN NNNNNNNNNN 50 NNNNNNNNNN NNNUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 187: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 187: TAATACGACT CACTATAGGG AGACAAGAAT AAACGCTCAA 40 (2) INFORMATION FOR SEQ ID NO: 188: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 24 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 188: GCCTGTTGTG AGCCTCCTGT CGAA 24 (2) INFORMATION FOR SEQ ID NO: 189: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 84 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 189: GGGAGACAAG AAUAAACGCU CAAACAUCGU AUAACUCUAA GGGCCUGGAU 50 AUACGAUGAA UUCGACAGGA GGCUCACAAC AGGC 84 (2) INFORMATION FOR SEQ ID NO: 190: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 84 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ■ -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 190: GGGAGACAAG AAUAAACGCU CAAACAUCGU AUAACUCUAA GCGCCUGGAU 50 AUACGAUGAA UUCGACAGGA GGCUCACAAC AGGC 84 (2) INFORMATION FOR SEQ ID NO: 191: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 84 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 191: GGGAGACAAG AAUAAACGCU CAAACAUCGU AUAACUCUAA GAGCCUGGAU 50 AUACGAUGAA UUCGACAGGA GGCUCACAAC AGGC 84 (2) INFORMATION FOR SEQ ID NO: 192: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 84 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 192: GGGAGACAAG AAUAAACGCU CAAACAUCGU AUAACUCUAA GUGCCUGGAU 50 AUACGAUGAA UUCGACAGGA GGCUCACAAC AGGC 84 (2) INFORMATION FOR SEQ ID NO: 193: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 85 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 193: GGGAGACAAG AAUAAACGCU CAAACAUCGU AUAAUCUCUA AGAGCCUGGA 50 UAUACGAUGA AUUCGACAGG AGGCUCACAA CAGGC 85 (2) INFORMATION FOR SEQ ID NO: 194: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 194: GGGAGACAAG AAUAAACGCU CAAACAUCGU AUAAUCUCUC UAAGAGCCUG 50 GAAUACGAUG AAUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 195: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 88 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 195: GGGAGACAAG AAUAAACGCU CAAAUCCCAA UCUCUAAGAG CCUGGAUAAG 50 AAUGCGCAUU GGGCUUCGAC AGGAGGCUCA CAACAGGC 88 (2) INFORMATION FOR SEQ ID NO: 196: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 196: GGGAGACAAG AAUAAACGCU CAAAUCCCAA UCUCUAAGAG CCUGGAUGAC 50 AAUCGCAUUG GGCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 197: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 88 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 197: GGGAGACAAG AAUAAACGCU CAAAUCCCAA UCUCUAAGAG CCUGGAUGAG 50 AAUGCGCAUU GGGCUUCGAC AGGAGGCUCA CAACAGGC 88 (2) INFORMATION FOR SEQ ID NO: 198: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 198: GGGAGACAAG AAUAAACGCU CAACUGAGAU CUCUAAGAGC CUGGACUCAG 50 CUCCGACUGA CCUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 199: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 199: GGGAGACAAG AAUAAACGCU CAACUGAGAU CUCUAAGAGC CUGGACUCAG 50 CUCCGAUUGA UCCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 200: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 200: GGGAGACAAG AAUAAACGCU CAACUGAGAU CUCUAAGAGC CUGGACUCAG 50 CUCCGAUUGA. ACCUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 201: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 201: GGGAGACAAG AAUAAACGCU CAAUCUCUAU GAGCCUGGAU CGACGAACUC 50 UCUACGGGCU GUGUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 202: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 86 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 202: GGGAGACAAG AAUAAACGCU CAAUCUCUAA GAGCCUGGAU GUCGAGGGGC 50 CAUUUCGCAC GCUUCGACAG GAGGCUCACA ACAGGC 86 (2) INFORMATION FOR SEQ ID NO: 203: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 88 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 203: GGGAGACAAG AAUAAACGCU CAAAUCUCUA CUGAGCCUGG AUUCGCCAGA 50 AGUUUUAUCA CAGUUUCGAC AGGAGGCUCA CAACAGGC 88 (2) INFORMATION FOR SEQ ID NO: 204: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 87 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2'-F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 204: GGGAGACAAG AAUAAACGCU CAACGUAAAA GUUAUCGAAU CUCUGUGAGC 50 CUGGAUCGAU UACUUCGACA GGAGGCUCAC AACAGGC 87 (2) INFORMATION FOR SEQ ID NO: 205: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 97 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: RNA (ix) FEATURE: (D) OTHER INFORMATION: All pyrimidines are 2 ' -F modified (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 205: GGGAGACAAG AAUAAACGCU CAACUGAGAU CUCUAAGAGC CUGGACUCAG 50 CUACGAUUGA GCGUUUAUUC UUGUUCGACA GGAGGCUCAC AACAGGC 97 (2) INFORMATION FOR SEQ ID NO: 206: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: PNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 206: GGGAGCUCAG AAUAAACGCU CAANNNNNNN NNNNNNNNNN NNNNNNNNNN 50 NNNUUCGACA UGAGGCCCGG AUCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 207: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 24 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 207: GCCGGATCCG GGCCTCATGT CGAA 24 (2) INFORMATION FOR SEQ ID NO: 208: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 48 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 208: CCGAAGCTTA ATACGACTCA CTATAGGGAG CTCAGAATAA ACGCTCAA 48 (2) INFORMATION FOR SEQ ID NO: 209: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 209: GGGAGCTCAG AATAAACGCT CAAACGGCTG ACAACGGCTG GACTTGCGTA 50 TTGTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 210: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 210: GGGAGCTCAG AATAAACGCT CAAGCGCTTG ACCATTTCGT AGGGTCGCCC 50 TTGTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 211: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 211: GGGAGCTCAG AATAAACGCT CAAGATCGAC GCATCGAGTC GCCTCATCGC 50 TCCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 212: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 212: GGGAGCTCAG AATAAACGCT CAACGCACTC GGACGGAATC TCCGTAGGAC 50 ACGTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 213: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 213: GGGAGCTCAG AATAAACGCT CAATGTCATG CATGTGTGTC GCCTCATCAC 50 GCATTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 214: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 214: GGGAGCTCAG AATAAACGCT CAACCACTGG CTAGGAACTC GAGTACTGGG 50 TGGTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 215: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA ( i) SEQUENCE DESCRIPTION: SEQ ID NO: 215: GGGAGCTCAG AATAAACGCT CAATTCGAAG CCACGTTTCA TGTCCGTCGC 50 TGCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 216: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 216: GGGAGCTCAG AATAAACGCT CAACAGTGGA GGCTGTCCAA ACCCACCCAC 50 CCCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 217: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 76 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 217: GGGAGCTCAG AATAAACGCT CAAGTGGAGG GTACGTGGAG GGGAGAGCGA 50 TATTCGACAT GAGGCCCGGA TCCGGC 76 (2) INFORMATION FOR SEQ ID NO: 218: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 76 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 218: GGGAGCTCAG AATAAACGCT CAATCTCATG CTCGCGTGCG TCGCCTCAAC 50 CATTCGACAT GAGGCCCGGA TCCGGC 76 (2) INFORMATION FOR SEQ ID NO: 219: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 219: GGGAGCTCAG AATAAACGCT CAATCCCTCA GTGTCAAGTG CGTCGCCTCA 50 GCATTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 220: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 78 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 220: GGGAGCTCAG AATAAACGCT CAACTTCTTG GCCCCGTCTC AATGTCCGTA 50 CTTCTTCGAC ATGAGGCCCG GATCCGGC 78 (2) INFORMATION FOR SEQ ID NO: 221: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 221: GGGAGCTCAG AATAAACGCT CAACGTGATT TGGCCACGGG AAAGAGCCAT 50 ACCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 222: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 222: GGGAGCTCAG AATAAACGCT CAACGTTGAA CGCTTGGTTT CATGTCCCTC 50 GCCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 223: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS : single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 223: . GGGAGCTCAG AATAAACGCT CAACGTCGAT CGCGTGCTGT AGCCTCAGGC 50 ACCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 224: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 78 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 224: GGGAGCTCAG AATAAACGCT CAAGGTGGAA GGCCTTTGAA GCCCGTACAT 50 CTCCTTCGAC ATGAGGCCCG GATCCGGC 78 (2) INFORMATION FOR SEQ ID NO: 225: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 225: GGGAGCTCAG AATAAACGCT CAAGGTCGAA CTAGCGCTGG AGCGTGCGTT 50 GGTTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 226: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 226: GGGAGCTCAG AATAAACGCT CAAGTCGCTC GATCGTTTCA TGCCCGTCCG 50 ACCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 227: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 227: GGGAGCTCAG AATAAACGCT CAAGTCGATG CGCAGTCCGC CTCAGCTGCA 50 CTGTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 228: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 228: GGGAGCTCAG AATAAACGCT CAAGGTGTGC CCAAGGCCCT TGAGAGAGGC 50 GTGTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 229: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 229: GGGAGCTCAG AATAAACGCT CAACGTCTAG GAACTGCGTC GCCTCAACAG 50 CGCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 230: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 72 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 230: GGGAGCTCAG AATAAACGCT CAAGTCGGAT GGTTTTGCGC GTTTCCCGTT 50 CGACATGAGG CCCGGATCCG GC 72 (2) INFORMATION FOR SEQ ID NO: 231: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 231: GGGAGCTCAG AATAAACGCT CAACCTCATC CTCGCACGCC ATCGCCTGAA 50 CCGTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 232: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 232: GGGAGCTCAG AATAAACGCT CAAGGTGTGC CAAAGGCCCT TGAGAGAGGC 50 GTATTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 233: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 233: GGGAGCTCAG AATAAACGCT CAAGGCCGCA TGCCCCTCCT AACAGCATGC 50 AACTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 234: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 234: GGGAGCTCAG AATAAACGCT CAACCCTCGT GCGTGCGCTT GGAGCGTGGC 50 GCATTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 235: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 235: GGGAGCTCAG AATAAACGCT CAAGTCGCTC GATCGTTTCA TGTCCGTTCG 50 ACCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 236: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 74 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 236: GGGAGCTCAG AATAAACGCT CAAGTCCACA CTTTGCCGAG CGTCCTAGTG 50 TTCGACATGA GGCCCGGATC CGGC 74 (2) INFORMATION FOR SEQ ID NO: 237: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 76 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 237: GGGAGCTCAG AATAAACGCT CAACGGGTGA ATCACGGCTG GTGCGTTGCC 50 CCTTCGACAT GAGGCCCGGA TCCGGC 76 (2) INFORMATION FOR SEQ ID NO: 238: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 238: GGGAGCTCAG AATAAACGCT CAACGTCGAC GCACTGTGCC GCCTCACACA 50 CGCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 239: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 239: GGGAGCTCAG AATAAACGCT CAAGCGAACG TCATGCCGCC TCATCATGCC 50 ACGTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 240: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 76 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single " .- • (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 240: GGGAGCTCAG AATAAACGCT CAACTAGGCC CACCGTCCCT TCTAACAACG 50 TCTTCGACAT GAGGCCCGGA TCCGGC 76 (2) INFORMATION FOR SEQ ID NO: 241: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 241: GGGAGCTCAG AATAAACGCT CAACAGTCAC GAACGTGCGC CGGAAGAACG 50 CTCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 242: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 242: GGGAGCTCAG AATAAACGCT CAATGTCGCA CGTGTCCCGG CCCGCCCTAC 50 CCCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 243: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 243: GGGAGCTCAG AATAAACGCT CAACAGGTGG CACCGCCCTT CCAACACGGT 50 GCGTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 244: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 74 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 244: GGGAGCTCAG AATAAACGCT CAAGTCCACA CTTTGCCGAG CGTCCTAGTG 50 TTCGACATGA GGCCCGGATC CGGC 74 (2) INFORMATION FOR SEQ ID NO: 245: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 245: GGGAGCTCAG AATAAACGCT CAAATGGTGG AGGCCATCTC AAACCCACGA 50 CACTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 246: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 246: GGGAGCTCAG AATAAACGCT CAACGCCGAG ACCCACCTCA TAACACCGCT 50 ACCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 247: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 247: GGGAGCTCAG AATAAACGCT CAATGAGGCG CGCCACAGGA TGGCCCTCAA 50 CCCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 248: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 248: . GGGAGCTCAG AATAAACGCT CAAGTCCGCA TGATGCTTCG AACAGCATAC 50 AACTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 249: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 249: GGGAGCTCAG.AATAAACGCT CAAGGTGTGC CCCTACGTGC GGCCCTTCGT 50 TTATTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 250: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 250: GGGAGCTCAG AATAAACGCT CAACGGCTTG CAGGTCGCCG AAATGACCGC 50 ACATTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 251: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 251: GGGAGCTCAG AATAAACGCT CAACTAGTTC AACCGTCCCT TCTAACAACC 50 GTCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 252: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 252: GGGAGCTCAG AATAAACGCT CAACCTGGTG GTCGTGCGGC TGTCGCCTCA 50 AGGTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 253: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 253: GGGAGCTCAG AATAAACGCT CAAGATCGAA GTTGTCGTCC GCCTCAGCGA 50 CTCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 254: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 254: GGGAGCTCAG AATAAACGCT CAATGTCGAG TGCGATGGAG GAGTAGGGAT 50 GCATTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 255: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 77 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 255: GGGAGCTCAG AATAAACGCT CAATGTCGAT CGTGTCAAGG TCCGTCCTAC 50 TTCTTCGACA TGAGGCCCGG ATCCGGC 77 (2) INFORMATION FOR SEQ ID NO: 256: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 71 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 256: GGGAGGACGA TGCGGNNNNN NNNNNNNNNN NNNNNNNNNN NNNNNNNNNN 50 NNNNNCAGAC GACTCGCCCG A 71 (2) INFORMATION FOR SEQ ID NO: 257: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 15 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 257: GGGAGGACGA TGCGG 15 (2) INFORMATION FOR SEQ ID NO: 258: (i) SEQUENCE CHARACTERIZATION: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULAR TYPE: DNA (ix) FEATURE: (D) OTHER INFORMATION: N at positions 1-4 is biotin (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 258: NNNNTCGGGC GAGTCGTCTG 20

Claims: WE CLAIM: 1. A method of identifying nucleic acid ligands to a cytokine, comprising: a) contacting a candidate mixture of nucleic acids with said cytokine, wherein nucleic acids having an increased affinity to said cytokine relative to the candidate mixture may be partitioned from the remainder ofthe candidate mixture; and b) partitioning the increased affinity nucleic acids from the remainder of the candidate mixture; and c) amplifying the increased affinity nucleic acids to yield a mixture of nucleic acids enriched for nucleic acid sequences with relatively higher affinity and specificity for binding to said cytokine, whereby nucleic acid ligands of said cytokine may be identified. 2. The method of claim 1 further comprising: d) repeating steps a), b), and c). 3. The method of claim 1 wherein said candidate mixture of nucleic acids is comprised of single stranded nucleic acids. 4. The method of claim 3 wherein said single stranded nucleic acids are ribonucleic acids. 5. The method of claim 4 wherein said nucleic acids are modified nucleic acids. 6. The method of claim 5 wherein said nucleic acids are 2'-amino (2'-NH 2 ) modified ribonucleic acids. 7. The method of claim 5 wherein said nucleic acids are 2'-fluoro (2'-F) modified ribonucleic acids. 8. The method of claim 3 wherein said single stranded nucleic acids are deoxyribonucleic acids. 9. The method of claim 1 wherein said cytokine is selected from the group consisting of IFN-gamma, IL-10, IL-4, TNF-alpha, and RANTES. 10. The method of claim 1 wherein said cytokine is IFN-gamma. 11. The method of claim 1 wherein said cytokine is IL-10. 12. The method of claim 1 wherein said cytokine is IL-4. 13. The method of claim 1 wherein said cytokine is TNF-alpha. 14. The method of claim 1 wherein said cytokine is RANTES. 15. A method for treating a cytokine-mediated disease comprising administering a pharmaceutically effective amount of a nucleic acid ligand of a cytokine. 16. The method of claim 15 wherein said nucleic acid ligand of a cytokine is identified according to the method of claim 1. 17. The method of claim 16 wherein said cytokine is IFN-gamma. 18. The method of claim 17 wherein said ligand is selected from one ofthe ligands of Tables 3 and 4 (SEQ ID NOS:7-73). 19. The method of claim 16 wherein said cytokine is IL-4. 20. The method of claim 17 wherein said ligand is selected from one ofthe ligands of Tables 7 and 8 (SEQ ID NOS:100-185). 21. The method of claim 16 wherein said cytokine is IL-10. 22. The method of claim 21 wherein said ligand is selected from one ofthe ligands of Table 10 (SEQ ID NOS:189-205). 23. The method of claim 16 wherein said cytokine is TNF-alpha. 24. The method of claim 23 wherein said ligand is selected from one ofthe ligands of Table 12 (SEQ ID NOS:209-255). 25. A purified and isolated non-naturally occurring nucleic acid ligand to a cytokine. 26. The purified and isolated non-naturally occurring nucleic acid ligand of claim 25 wherein said nucleic acid ligand is single-stranded. 27. The purified and isolated non-naturally occurring nucleic acid ligand of claim 26 wherein said nucleic acid ligand is ribonucleic acid. 28. The purified and isolated non-naturally occurring nucleic acid ligand of claim 26 wherein said nucleic acid ligand is deoxyribonucleic acid. 29. A nucleic acid ligand to a cytokine identified according to the method comprising: a) contacting a candidate mixture of nucleic acids with said cytokine, wherein nucleic acids having an increased affinity to said cytokine relative to the candidate mixture may be partitioned from the remainder ofthe candidate mixture; and b) partitioning the increased affinity nucleic acids from the remainder of the candidate mixture; and c) amplifying the increased affinity nucleic acids to yield a mixture of nucleic acids enriched for nucleic acid sequences with relatively higher affinity and specificity for binding to said cytokine, whereby nucleic acid ligands of said cytokine may be identified. 30. The purified and isolated non-naturally occurring ribonucleic acid ligand of claim 27, wherein said ligand is IFN-gamma. 31. The purified and isolated non-naturally occurring ribonucleic acid ligand to IFN-gamma of claim 30 wherein said ligand is selected from the group consisting ofthe sequences set forth in Tables 3 and 4 (SEQ ID NOS:7-73). 32. The purified and isolated non-naturally occurring ribonucleic acid ligand to IFN-gamma of claim 30 wherein said ligand is substantially homologous to and has substantially the same ability to bind IFN-gamma as a ligand selected from the group consisting ofthe sequences set forth in Tables 3 and 4 (SEQ ID NOS:7-73). 33. The purified and isolated non-naturally occurring ribonucleic acid ligand to IFN-gamma of claim 30 wherein said ligand has substantially the same structure and substantially the same ability to bind IFN-gamma as a ligand selected from the group consisting ofthe sequences set forth in Tables 3 and 4 (SEQ ID NOS: 7-73). 34. The purified and isolated non-naturally occurring ribonucleic acid ligand of claim 27 wherein said ligand is to IL-4. 35. The purified and isolated non-naturally occurring ribonucleic acid ligand to IL- 4 of claim 34 wherein said ligand is selected from the group consisting ofthe sequences set forth in Tables 7 and 8 (SEQ ID NOS:79-l 85). 36. The purified and isolated non-naturally occurring ribonucleic acid ligand to IL- 4 of claim 34 wherein said ligand is substantially homologous to and has substantially the same ability to bind IL-4 as a ligand selected from the group consisting ofthe sequences set forth in Tables 7 and 8 (SEQ ID NOS:79-185). 37. The purified and isolated non-naturally occurring ribonucleic acid ligand to IL- 4 of claim 34 wherein said ligand has substantially the same structure and substantially the same ability to bind IL-4 as a ligand selected from the group consisting ofthe sequences set forth in Tables 7 and 8 (SEQ ID NOS:79-185). 38. The purified and isolated non-naturally occurring ribonucleic acid ligand of claim 27 wherein said ligand is to IL-10. 39. The purified and isolated non-naturally occurring ribonucleic acid ligand to IL- 10 of claim 38 wherein said ligand is selected from the group consisting ofthe sequences set forth in Table 10 (SEQ ID NOS: 189-205). 40. The purified and isolated non-naturally occurring ribonucleic acid ligand to IL- 10 of claim 38 wherein said ligand is substantially homologous to and has substantially the same ability to bind IL-10 as a ligand selected from the group consisting ofthe sequences set foreth in Table 10 (SEQ ID NOS: 189-205). 41. The purified and isolated non-naturally occurring ribonucleic acid ligand to IL- 10 of claim 38 wherein said ligand has substantially the same structure and substantially the same ability to bind IL-10 as a ligand selected from the group consisting ofthe sequences set forth in Table 10 (SEQ ID NOS: 189-205). 42. The purified and isolated non-naturally occurring ribonucleic acid ligand of claim 27 wherein said ligand is to TNF-alpha. 43. The purified and isolated non-naturally occurring ribonucleic acid ligand to TNF-alpha of claim 42 wherein said ligand is selected from the group consisting ofthe sequences set forth in Table 12 (SEQ ID NOS:209-255). 44. The purified and isolated non-naturally occurring ribonucleic acid ligand to TNF-alpha of claim 42 wherein said ligand is substantially homologous to and has substantially the same ability to bind TNF-alpha as a ligand selected from the group consisting ofthe sequences set forth in Table 12 (SEQ ID NOS:209-255). 45. The purified and isolated non-naturally occurring ribonucleic acid ligand to TNF-alpha of claim 42 wherein said ligand has substantially the same structure and substantially the same ability to bind TNF-alpha as a ligand selected from the group consisting ofthe sequences set forth in Table 12 (SEQ ID NOS: 189-205). 46. The purified and isolated non-naturally occurring nucleic acid ligand of claim 25 wherein said ligand is to RANTES.

Inventors: GOLD LARRY, JAYASENA SUMEDHA, PAGRATIS NIKOS, TASSET DIANE, GOLD, LARRY, JAYASENA, SUMEDHA, PAGRATIS, NIKOS, TASSET, DIANE
Applicants: NEXSTAR PHARMACEUTICALS INC, NEXSTAR PHARMACEUTICALS, INC.
Application year: 1996
Main classification: C07H21
IPC codes: A61K31, C07K14, C12N15, C12Q1