Gene Symbol: Tnfrsf9
Description: tumor necrosis factor receptor superfamily, member 9
Alias: 4-1BB, A930040I11Rik, AA408498, AI325004, CDw137, Cd137, ILA, Ly63, tumor necrosis factor receptor superfamily member 9, 4-1BB ligand receptor, CD137 antigen, T-cell antigen 4-1BB, secreted CD137 antigen
Species: mouse
Products:     Tnfrsf9

Top Publications

  1. Pollok K, Kim Y, Zhou Z, Hurtado J, Kim K, Pickard R, et al. Inducible T cell antigen 4-1BB. Analysis of expression and function. J Immunol. 1993;150:771-81 pubmed
    ..Cross-linking of 4-1BB on anti-CD3-stimulated T cells with 53A2 resulted in a dramatic enhancement of T cell proliferation. This suggests that 4-1BB may function as an accessory signaling molecule during T cell activation. ..
  2. Wilcox R, Flies D, Zhu G, Johnson A, Tamada K, Chapoval A, et al. Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. J Clin Invest. 2002;109:651-9 pubmed
    ..previously that established tumors in mice receiving an agonistic mAb to the T cell costimulatory molecule 4-1BB (CD137) regress due to enhanced tumor antigen-specific cytotoxic T lymphocyte responses...
  3. Bertram E, Dawicki W, Sedgmen B, Bramson J, Lynch D, Watts T. A switch in costimulation from CD28 to 4-1BB during primary versus secondary CD8 T cell response to influenza in vivo. J Immunol. 2004;172:981-8 pubmed
    ..The results indicate that anti-4-1BB or 4-1BBL therapy will be most effective during the boost phase of a prime-boost vaccination strategy. ..
  4. Lin G, Sedgmen B, Moraes T, Snell L, Topham D, Watts T. Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease. J Immunol. 2009;182:934-47 pubmed
  5. Wilcox R, Tamada K, Flies D, Zhu G, Chapoval A, Blazar B, et al. Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo. Blood. 2004;103:177-84 pubmed
    ..We show here that administration of an agonistic monoclonal antibody (mAb) to CD137, a member of the tumor necrosis factor receptor superfamily, prevents the induction of CD8+ cytolytic T-lymphocyte ..
  6. Alderson M, Smith C, Tough T, Davis Smith T, Armitage R, Falk B, et al. Molecular and biological characterization of human 4-1BB and its ligand. Eur J Immunol. 1994;24:2219-27 pubmed
    ..In contrast, ligation of 4-1BB on T cell clones enhanced activation-induced cell death when triggered by engagement of the TCR/CD3 complex. ..
  7. Kwon B, Kozak C, Kim K, Pickard R. Genomic organization and chromosomal localization of the T-cell antigen 4-1BB. J Immunol. 1994;152:2256-62 pubmed
    ..A comparison of exon-intron organization among the genes of the nerve growth factor receptor family indicated that most C6 motif is interrupted by an intron. ..
  8. Jeon H, Choi J, Jung I, Park J, Lee M, Lee M, et al. CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice. Circulation. 2010;121:1124-33 pubmed publisher
    ..b>CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human ..
  9. Niu L, Strahotin S, Hewes B, Zhang B, Zhang Y, Archer D, et al. Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice. J Immunol. 2007;178:4194-213 pubmed
    b>CD137-mediated signals costimulate T cells and protect them from activation-induced apoptosis; they induce curative antitumor immunity and enhance antiviral immune responses in mice...

More Information


  1. Foell J, Strahotin S, O Neil S, McCausland M, Suwyn C, Haber M, et al. CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. J Clin Invest. 2003;111:1505-18 pubmed
    ..In this report we show that lupus-prone NZB x NZW F(1) mice given three injections of anti-CD137 (4-1BB) mAb's between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the ..
  2. Zhao Y, Croft M. Dispensable role for 4-1BB and 4-1BBL in development of vaccinia virus-specific CD8 T cells. Immunol Lett. 2012;141:220-6 pubmed publisher
    ..In this study, we examined the role of another member of the TNFR superfamily, 4-1BB (CD137, TNFRSF9), and its ligand (4-1BBL, CD137L, TNFSF9), that have been described to control the generation of memory CD8 T ..
  3. Miller R, Jones J, Le T, Whitmore J, Boiani N, Gliniak B, et al. 4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner. J Immunol. 2002;169:1792-800 pubmed
    4-1BB (CD137) is a member of the TNFR superfamily (TNFRSF9). T cell expression of 4-1BB is restricted to activated cells, and cross-linking has been shown to deliver a costimulatory signal...
  4. Lim H, Kim K, Zhou F, Yoon J, Hill J, Kwon B. 4-1BB-like molecule is expressed in islet-infiltrating mononuclear cells and in the gray matter of the brain. Cell Biol Int. 2002;26:271-8 pubmed
    ..The staining pattern strongly resembled the receptor/nerve terminals in the brain and in the peripheral nervous system. Taken together, BBLP may be associated with the early phase of inflammation and with brain function. ..
  5. Kwon B, Weissman S. cDNA sequences of two inducible T-cell genes. Proc Natl Acad Sci U S A. 1989;86:1963-7 pubmed
    ..Both peptides contain putative leader sequences. The protein encoded by 4-1BB also has a potential membrane anchor segment and other features also seen in known receptor proteins. ..
  6. Sabbagh L, Pulle G, Liu Y, Tsitsikov E, Watts T. ERK-dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo. J Immunol. 2008;180:8093-101 pubmed
    ..Thus, TRAF1 has a prosurvival effect in CD8 T cells via the 4-1BB-mediated up-regulation of Bcl-x(L) and ERK-dependent Bim down-modulation. ..
  7. Shao Z, Sun F, Koh D, Schwarz H. Characterisation of soluble murine CD137 and its association with systemic lupus. Mol Immunol. 2008;45:3990-9 pubmed publisher
    b>CD137 is a member of the tumor necrosis factor receptor family, and is involved in the regulation of activation, proliferation, differentiation and apoptosis of T cells, B cells, monocytes, dendritic cells, natural killer cells and ..
  8. Lee S, Salek Ardakani S, Mittler R, Croft M. Hypercostimulation through 4-1BB distorts homeostasis of immune cells. J Immunol. 2009;182:6753-62 pubmed publisher
  9. Wang J, Zhao W, Cheng L, Guo M, Li D, Li X, et al. CD137-mediated pathogenesis from chronic hepatitis to hepatocellular carcinoma in hepatitis B virus-transgenic mice. J Immunol. 2010;185:7654-62 pubmed publisher
    ..We report in this article that repetitive infusion of anti-CD137 agonist mAb in HBV-transgenic mice closely mimics this process by sequentially inducing hepatitis, fibrosis, ..
  10. Lee S, Park Y, Eun S, Madireddi S, Cheroutre H, Croft M. Cutting edge: 4-1BB controls regulatory activity in dendritic cells through promoting optimal expression of retinal dehydrogenase. J Immunol. 2012;189:2697-701 pubmed publisher
    ..How RALDH expression is regulated is unclear. We found that 4-1BB (CD137), a member of the TNFR family, together with CD103, marked mesenteric lymph node DC with the highest level of ..
  11. Sharma R, Elpek K, Yolcu E, Schabowsky R, Zhao H, Bandura Morgan L, et al. Costimulation as a platform for the development of vaccines: a peptide-based vaccine containing a novel form of 4-1BB ligand eradicates established tumors. Cancer Res. 2009;69:4319-26 pubmed publisher
    ..Potent pleiotropic immunomodulatory activities combined with lack of toxicity highlight the potential of 4-1BBL molecule as an effective component of therapeutic cancer vaccines. ..
  12. Ju S, Park S, Lee S, Kwon B, Kim B. Marked expansion of CD11c+CD8+ T-cells in melanoma-bearing mice induced by anti-4-1BB monoclonal antibody. Mol Cells. 2007;24:132-8 pubmed
    4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily, is expressed on activated T-cells, and 4-1BB signaling due to interaction with 4-1BB ligand or ligation with anti-4-1BB monoclonal antibody (mAb) costimulates T ..
  13. Lee S, Rossi R, Lee S, Croft M, Kwon B, Mittler R, et al. CD134 Costimulation Couples the CD137 Pathway to Induce Production of Supereffector CD8 T Cells That Become IL-7 Dependent. J Immunol. 2007;179:2203-14 pubmed
    The TNFR superfamily members 4-1BB (CD137) and OX40 (CD134) are costimulatory molecules that potently boost CD8 and CD4 T cell responses...
  14. Sharma R, Schabowsky R, Srivastava A, Elpek K, Madireddi S, Zhao H, et al. 4-1BB ligand as an effective multifunctional immunomodulator and antigen delivery vehicle for the development of therapeutic cancer vaccines. Cancer Res. 2010;70:3945-54 pubmed publisher
  15. Curran M, Kim M, Montalvo W, Al Shamkhani A, Allison J. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS ONE. 2011;6:e19499 pubmed publisher
    ..In addition, we identify KLRG1 as a useful marker for monitoring the anti-tumor immune response elicited by this therapy. These findings should aid in the design of future trials for the immunotherapy of melanoma. ..
  16. Schwarz H, Valbracht J, Tuckwell J, von Kempis J, Lotz M. ILA, the human 4-1BB homologue, is inducible in lymphoid and other cell lineages. Blood. 1995;85:1043-52 pubmed
    We recently identified a gene that is induced by lymphocyte activation (ILA). The sequence of the full-length 1...
  17. Maerten P, Kwon B, Shen C, De Hertogh G, Cadot P, Bullens D, et al. Involvement of 4-1BB (CD137)-4-1BBligand interaction in the modulation of CD4 T cell-mediated inflammatory colitis. Clin Exp Immunol. 2006;143:228-36 pubmed
    ..In conclusion, our data provide evidence that 4-1BB-4-1BBL interaction modulates the effector CD4+ T cell-driven immune response and cytokine production in experimental colitis without affecting regulatory T cell function. ..
  18. Cuadros C, Dominguez A, Lollini P, Croft M, Mittler R, Borgstrom P, et al. Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice. Int J Cancer. 2005;116:934-43 pubmed
  19. Halstead E, Mueller Y, Altman J, Katsikis P. In vivo stimulation of CD137 broadens primary antiviral CD8+ T cell responses. Nat Immunol. 2002;3:536-41 pubmed
    ..We found that in vivo CD137 stimulation with an agonistic monoclonal antibody enhanced the primary CD8+ T cell response to influenza type A ..
  20. Zheng G, Wang B, Chen A. The 4-1BB costimulation augments the proliferation of CD4+CD25+ regulatory T cells. J Immunol. 2004;173:2428-34 pubmed
    ..These results support the notion that the peripheral expansion of the CD4(+)CD25(+) T cells is controlled in part by costimulation. ..
  21. Choi B, Bae J, Choi E, Kang W, Sakaguchi S, Vinay D, et al. 4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells. J Leukoc Biol. 2004;75:785-91 pubmed
    4-1BB (CD137) is a costimulatory molecule involved in the activation and survival of CD4, CD8, and natural killer cells...
  22. Lee S, Vella A, Kwon B, Croft M. Enhanced CD4 T cell responsiveness in the absence of 4-1BB. J Immunol. 2005;174:6803-8 pubmed
    The 4-1BB (CD137) is a member of the TNFR superfamily, and is expressed on several cell types, including activated T cells...
  23. Vinay D, Kim J, Kwon B. Amelioration of mercury-induced autoimmunity by 4-1BB. J Immunol. 2006;177:5708-17 pubmed
  24. Nishimoto H, Lee S, Hong H, Potter K, Maeda Yamamoto M, Kinoshita T, et al. Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor. Blood. 2005;106:4241-8 pubmed
    ..Therefore, FcepsilonRI-inducible 4-1BB plays a costimulatory function together with FcepsilonRI stimulation. ..
  25. Chalupny N, Peach R, Hollenbaugh D, Ledbetter J, Farr A, Aruffo A. T-cell activation molecule 4-1BB binds to extracellular matrix proteins. Proc Natl Acad Sci U S A. 1992;89:10360-4 pubmed
    ..These results suggest that carbohydrates may play a role in mediating the 4-1BB-extracellular matrix protein adhesion. ..
  26. Goodwin R, Din W, Davis Smith T, Anderson D, Gimpel S, Sato T, et al. Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Eur J Immunol. 1993;23:2631-41 pubmed
    ..Interaction of 4-1BB with its ligand induces the proliferation of activated thymocytes and splenic T cells, a response which is mimicked on similar cell populations stimulated with an antibody to 4-1BB. ..
  27. Kwon B, Hurtado J, Lee Z, Kwack K, Seo S, Choi B, et al. Immune responses in 4-1BB (CD137)-deficient mice. J Immunol. 2002;168:5483-90 pubmed
    ..The in vitro expression of 4-1BB (CD137) is induced following activation of T cells with various stimuli, including anti-TCR mAbs, lectins, and a ..
  28. Tang Q, Jiang D, Shao Z, Martínez Gómez J, Schwarz H. Species difference of CD137 ligand signaling in human and murine monocytes. PLoS ONE. 2011;6:e16129 pubmed publisher
    Stimulation of CD137 ligand on human monocytes has been shown to induce DC differentiation, and these CD137L-DCs are more potent than classical DCs, in stimulating T cell responses in vitro...
  29. Martínez Gómez J, Croxford J, Yeo K, Angeli V, Schwarz H, Gasser S. Development of experimental autoimmune encephalomyelitis critically depends on CD137 ligand signaling. J Neurosci. 2012;32:18246-52 pubmed publisher
    ..Experimental autoimmune encephalomyelitis (EAE) is a commonly used murine model for MS. Here we report that CD137 ligand (CD137L, 4-1BB ligand, TNFS9), a member of the TNF superfamily, is critical for the development of EAE...
  30. Eckstrum K, Bany B. Tumor necrosis factor receptor subfamily 9 (Tnfrsf9) gene is expressed in distinct cell populations in mouse uterus and conceptus during implantation period of pregnancy. Cell Tissue Res. 2011;344:567-76 pubmed publisher
    Tumor necrosis factor receptor subfamily 9 (TNFRSF9) plays a potentially important general role in immune function. Tnfrsf9 gene expression has previously been characterized in late pregnant mouse uterus and placenta...
  31. Kim Y, Seo S, Choi B, Kang W, Kim C, Lee S, et al. 4-1BB costimulation enhances HSV-1-specific CD8+ T cell responses by the induction of CD11c+CD8+ T cells. Cell Immunol. 2005;238:76-86 pubmed
    ..Our studies demonstrated that 4-1BB stimulation enhanced both primary and memory anti-HSV-1 CD8+ T cell responses, which was mediated by a massive expansion of antigen-specific CD11c+CD8+ T cells. ..
  32. Wilcox R, Chapoval A, Gorski K, Otsuji M, Shin T, Flies D, et al. Cutting edge: Expression of functional CD137 receptor by dendritic cells. J Immunol. 2002;168:4262-7 pubmed
    ..We report in this work that freshly isolated mouse splenic DCs and bone marrow-derived DCs express CD137 on the cell surface and in soluble form. Triggering CD137 increased the secretion of IL-6 and IL-12 from DCs...
  33. Jiang D, Chen Y, Schwarz H. CD137 induces proliferation of murine hematopoietic progenitor cells and differentiation to macrophages. J Immunol. 2008;181:3923-32 pubmed
    b>CD137 is a member of the TNFR family, and reverse signaling through the CD137 ligand, which is expressed as a cell surface transmembrane protein, costimulates or activates APCs...
  34. Lee S, Ju S, Sung B, Heo S, Cho H, Lee E, et al. Stimulation of the molecule 4-1BB enhances host defense against Listeria monocytogenes infection in mice by inducing rapid infiltration and activation of neutrophils and monocytes. Infect Immun. 2009;77:2168-76 pubmed publisher
    The tumor necrosis factor receptor family molecule 4-1BB (CD137) has diverse roles in adaptive and innate immune responses. However, little is known of its role in bacterial infections...
  35. Setareh M, Schwarz H, Lotz M. A mRNA variant encoding a soluble form of 4-1BB, a member of the murine NGF/TNF receptor family. Gene. 1995;164:311-5 pubmed
    ..These results identify a novel form of 4-1BB. This and the previously known membrane-associated form have a broad tissue distribution, suggesting a more diverse role in host defense. ..
  36. Kwajah M M S, Schwarz H. CD137 ligand signaling induces human monocyte to dendritic cell differentiation. Eur J Immunol. 2010;40:1938-49 pubmed publisher
    The ligand for CD137 (4-1BB) is expressed on peripheral human monocytes and delivers a potent activating signal via reverse signaling...
  37. Cooper D, Bansal Pakala P, Croft M. 4-1BB (CD137) controls the clonal expansion and survival of CD8 T cells in vivo but does not contribute to the development of cytotoxicity. Eur J Immunol. 2002;32:521-9 pubmed
    ..These findings demonstrate that 4-1BB contributes to clonal expansion, survival, and development of Tc1 cells when protein antigen is encountered by primary CD8 T cells in an inflammatory environment in vivo. ..
  38. Choi B, Kim Y, Kwon P, Lee S, Kang S, Kim M, et al. 4-1BB functions as a survival factor in dendritic cells. J Immunol. 2009;182:4107-15 pubmed publisher
    4-1BB (CD137) is expressed on dendritic cells (DCs) and its biological function has remained largely unresolved...
  39. Lee S, Myers L, Muralimohan G, Dai J, Qiao Y, Li Z, et al. 4-1BB and OX40 dual costimulation synergistically stimulate primary specific CD8 T cells for robust effector function. J Immunol. 2004;173:3002-12 pubmed
  40. Bandyopadhyay S, Long M, Qui H, Hagymasi A, Slaiby A, Mihalyo M, et al. Self-antigen prevents CD8 T cell effector differentiation by CD134 and CD137 dual costimulation. J Immunol. 2008;181:7728-37 pubmed
  41. Seo S, Park H, Choi J, Kim W, Kim Y, Jung H, et al. Blocking 4-1BB/4-1BB ligand interactions prevents herpetic stromal keratitis. J Immunol. 2003;171:576-83 pubmed
    ..1/5.2, in order of abundance). Analysis of cell surface phenotypes showed that the failure to develop HSK in the 4-1BB(-/-) mice was associated with a reduced expression of CD62L at the time of T cell migration into the corneal stroma. ..
  42. Lee H, Nam K, Park S, Kwon B. 4-1BB enhances CD8+ T cell expansion by regulating cell cycle progression through changes in expression of cyclins D and E and cyclin-dependent kinase inhibitor p27kip1. Eur J Immunol. 2003;33:2133-41 pubmed
    ..Our results suggest a role for cyclin D2, D3, and E, and p27(kip1) proteins in the 4-1BB-mediated cell cycle progression of CD8(+) T cells in vivo. ..
  43. Lee S, Ju S, Pack H, Heo S, Suh J, Park S, et al. 4-1BB (CD137) is required for rapid clearance of Listeria monocytogenes infection. Infect Immun. 2005;73:5144-51 pubmed
    4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily, is a T-cell-costimulatory receptor that is expressed on activated T cells, dendritic cells, and NK cells...
  44. Lee S, Park Y, Song A, Cheroutre H, Kwon B, Croft M. Functional dichotomy between OX40 and 4-1BB in modulating effector CD8 T cell responses. J Immunol. 2006;177:4464-72 pubmed
    ..OX40 can positively regulate effector function and late accumulation/survival, whereas 4-1BB can initially operate in a negative manner to limit primary CD8 responses. ..
  45. Hendriks J, Xiao Y, Rossen J, Van Der Sluijs K, Sugamura K, Ishii N, et al. During viral infection of the respiratory tract, CD27, 4-1BB, and OX40 collectively determine formation of CD8+ memory T cells and their capacity for secondary expansion. J Immunol. 2005;175:1665-76 pubmed
    ..Our data argue that ligand on dendritic cells and/or B cells may be critical for this. ..
  46. Futagawa T, Akiba H, Kodama T, Takeda K, Hosoda Y, Yagita H, et al. Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Int Immunol. 2002;14:275-86 pubmed
    4-1BB (CDw137) and its ligand (4-1BBL) have been implicated in cellular immune responses...
  47. Kang Y, Kim S, Shimada S, Otsuka M, Seit Nebi A, Kwon B, et al. Cell surface 4-1BBL mediates sequential signaling pathways 'downstream' of TLR and is required for sustained TNF production in macrophages. Nat Immunol. 2007;8:601-9 pubmed
    ..Our results indicate that two different TLR4 complexes sequentially form and selectively control early and late TNF production. ..
  48. Kim J, Kim C, Kwon B. Regulation of mouse 4-1BB expression: multiple promoter usages and a splice variant. Mol Cells. 2011;31:141-9 pubmed publisher
    ..The splicing variant was highly induced by TCR stimulation. Our results reveal 4-1BB also has a negative regulation system through soluble 4-1BB produced from a splice variant induced under activation conditions. ..
  49. Cannons J, Chamberlain G, Howson J, Smink L, Todd J, Peterson L, et al. Genetic and functional association of the immune signaling molecule 4-1BB (CD137/TNFRSF9) with type 1 diabetes. J Autoimmun. 2005;25:13-20 pubmed
    ..These data provide evidence in support of Idd9.3 as the locus encoding 4-1BB and suggest that the 4-1BB signaling pathway could have a primary function in the etiology of autoimmune disease. ..
  50. Lyons P, Hancock W, Denny P, Lord C, Hill N, Armitage N, et al. The NOD Idd9 genetic interval influences the pathogenicity of insulitis and contains molecular variants of Cd30, Tnfr2, and Cd137. Immunity. 2000;13:107-15 pubmed
    ..Candidate genes with amino acid differences between the NOD and B10 strains have been localized to the 5.6 cM Idd9.2 interval (Tnfr2, Cd30) and to the 2.0 cM Idd9.3 interval (Cd137).
  51. Loo D, Chalupny N, Bajorath J, Shuford W, Mittler R, Aruffo A. Analysis of 4-1BBL and laminin binding to murine 4-1BB, a member of the tumor necrosis factor receptor superfamily, and comparison with human 4-1BB. J Biol Chem. 1997;272:6448-56 pubmed
    The T cell activation antigen 4-1BB (CDw137) is a distantly related member of the tumor necrosis factor receptor family of cell surface receptors...
  52. Zhu Y, Zhu G, Luo L, Flies A, Chen L. CD137 stimulation delivers an antigen-independent growth signal for T lymphocytes with memory phenotype. Blood. 2007;109:4882-9 pubmed
    b>CD137 has long been recognized as a costimulatory receptor for growth and functional maturation of recently activated T cells in the presence of T-cell receptor signal...
  53. Nguyen Q, Ju S, Park S, Lee S, Yagita H, Lee I, et al. Blockade of CD137 signaling counteracts polymicrobial sepsis induced by cecal ligation and puncture. Infect Immun. 2009;77:3932-8 pubmed publisher
    ..Previously, we have shown that CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, plays critical roles in eradicating infective ..