메뉴 건너뛰기




Volumn 193, Issue 9, 2006, Pages 1323-1331

Both CD4+ and CD8+ T cells can mediate vaccine-induced protection against Coccidioides immitis infection in mice

Author keywords

[No Author keywords available]

Indexed keywords

BETA 2 MICROGLOBULIN; CD4 ANTIGEN; CD8 ANTIGEN; COCCIDIOIDES IMMITIS VACCINE; FUNGUS VACCINE; MESSENGER RNA; T LYMPHOCYTE RECEPTOR ALPHA CHAIN; T LYMPHOCYTE RECEPTOR BETA CHAIN; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR RECEPTOR 1; UNCLASSIFIED DRUG;

EID: 33646018966     PISSN: 00221899     EISSN: None     Source Type: Journal    
DOI: 10.1086/502972     Document Type: Article
Times cited : (55)

References (57)
  • 1
    • 0023688608 scopus 로고
    • Epidemiology of coccidioidomycosis
    • McGinnis MR, ed. New York: Springer-Verlag
    • Pappagianis D. Epidemiology of coccidioidomycosis. In: McGinnis MR, ed. Current topics in Medical Mycology. Vol 2. New York: Springer-Verlag, 1988:199-238.
    • (1988) Current Topics in Medical Mycology , vol.2 , pp. 199-238
    • Pappagianis, D.1
  • 2
    • 0029648655 scopus 로고
    • Coccidioidomycosis
    • Stevens DA. Coccidioidomycosis. N Engl J Med 1995; 332:1077-82.
    • (1995) N Engl J Med , vol.332 , pp. 1077-1082
    • Stevens, D.A.1
  • 3
    • 0344557448 scopus 로고
    • Fungal multiplication and histopathologic changes in vaccinated mice infected with Coccidioides immitis
    • Kong Y-CM, Levine HB, Madin SH, Smith CE. Fungal multiplication and histopathologic changes in vaccinated mice infected with Coccidioides immitis. J Immunol 1964; 92:779-90.
    • (1964) J Immunol , vol.92 , pp. 779-790
    • Kong, Y.-C.M.1    Levine, H.B.2    Madin, S.H.3    Smith, C.E.4
  • 4
    • 0030184730 scopus 로고    scopus 로고
    • Coccidioidomycosis: A reemerging infectious disease
    • Kirkland TN, Fierer J. Coccidioidomycosis: a reemerging infectious disease. Emerg Infect Dis 1996; 2:192-9.
    • (1996) Emerg Infect Dis , vol.2 , pp. 192-199
    • Kirkland, T.N.1    Fierer, J.2
  • 5
    • 0035900719 scopus 로고    scopus 로고
    • Coccidioidomycosis in workers at an archeologic site-Dinosaur National Monument, Utah, June-July 2001
    • Mardo D, Christensen RA, Nielson N, et al. Coccidioidomycosis in workers at an archeologic site-Dinosaur National Monument, Utah, June-July 2001. MMWR Morb Mortal Wkly Rep 2001; 50:1005-8.
    • (2001) MMWR Morb Mortal Wkly Rep , vol.50 , pp. 1005-1008
    • Mardo, D.1    Christensen, R.A.2    Nielson, N.3
  • 7
    • 0031945858 scopus 로고    scopus 로고
    • Risk factors for primary pulmonary coccidioidomycosis hospitalizations among United States Navy and Marine Corps personnel, 1981-1994
    • Gray GC, Fogle EF, Albright KL. Risk factors for primary pulmonary coccidioidomycosis hospitalizations among United States Navy and Marine Corps personnel, 1981-1994. Am J Trop Med Hyg 1998; 58:309-12.
    • (1998) Am J Trop Med Hyg , vol.58 , pp. 309-312
    • Gray, G.C.1    Fogle, E.F.2    Albright, K.L.3
  • 8
    • 0020006967 scopus 로고
    • Racial factors in coccidioidomycosis: Mortality experience in Arizona. A review of the literature
    • Johnson WM. Racial factors in coccidioidomycosis: mortality experience in Arizona. A review of the literature. Ariz Med 1982; 39:18-24.
    • (1982) Ariz Med , vol.39 , pp. 18-24
    • Johnson, W.M.1
  • 9
    • 0027396074 scopus 로고
    • Coccidioidomycosis during human immunodeficiency virus infection: Results of a prospective study in a coccidioidal endemic area
    • Ampel NM, Dois CL, Galgiani JN. Coccidioidomycosis during human immunodeficiency virus infection: results of a prospective study in a coccidioidal endemic area. Am J Med 1993; 94:235-40.
    • (1993) Am J Med , vol.94 , pp. 235-240
    • Ampel, N.M.1    Dois, C.L.2    Galgiani, J.N.3
  • 11
    • 0016685256 scopus 로고
    • Coccidioidomycosis in compromised hosts
    • Deresinski SC, Steven DA. Coccidioidomycosis in compromised hosts. Medicine 1975; 54:377-95.
    • (1975) Medicine , vol.54 , pp. 377-395
    • Deresinski, S.C.1    Steven, D.A.2
  • 12
    • 2642541034 scopus 로고    scopus 로고
    • Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor α antagonists
    • Bergstrom L, Yocum DE, Ampel NM, et al. Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor α antagonists. Arthritis Rheum 2004; 50:1959-66.
    • (2004) Arthritis Rheum , vol.50 , pp. 1959-1966
    • Bergstrom, L.1    Yocum, D.E.2    Ampel, N.M.3
  • 13
    • 0035196374 scopus 로고    scopus 로고
    • Cost-effectiveness of a potential vaccine for Coccidioides immitis
    • Barnato AE, Sanders GD, Owens DK. Cost-effectiveness of a potential vaccine for Coccidioides immitis. Emerg Infect Dis 2001; 7:797-806.
    • (2001) Emerg Infect Dis , vol.7 , pp. 797-806
    • Barnato, A.E.1    Sanders, G.D.2    Owens, D.K.3
  • 14
    • 7944234731 scopus 로고    scopus 로고
    • A vaccine against coccidioidomycosis is justified and attainable
    • Cole GT, Xue M, Okeke CN, et al. A vaccine against coccidioidomycosis is justified and attainable. Med Mycol 2004; 42:189-216.
    • (2004) Med Mycol , vol.42 , pp. 189-216
    • Cole, G.T.1    Xue, M.2    Okeke, C.N.3
  • 15
    • 0016808037 scopus 로고
    • The present status of vaccination against coccidioidomycosis in man
    • Pappagianis D, Levine HB. The present status of vaccination against coccidioidomycosis in man. Am J Epidemiol 1975; 102:30-41.
    • (1975) Am J Epidemiol , vol.102 , pp. 30-41
    • Pappagianis, D.1    Levine, H.B.2
  • 16
    • 0027161961 scopus 로고
    • Evaluation of the protective efficacy of the killed Coccidioides immitis spherule vaccine in humans
    • Pappagianis D, Valley Fever Vaccine Study Group. Evaluation of the protective efficacy of the killed Coccidioides immitis spherule vaccine in humans. Am Rev Respir Dis 1993; 148:656-60.
    • (1993) Am Rev Respir Dis , vol.148 , pp. 656-660
    • Pappagianis, D.1
  • 17
    • 0031824598 scopus 로고    scopus 로고
    • Evaluation of the proline-rich antigen of Coccidioides immitis as a vaccine candidate in mice
    • Kirkland TN, Finley F, Orsborn KI, Galgiani JN. Evaluation of the proline-rich antigen of Coccidioides immitis as a vaccine candidate in mice. Infect Immun 1998; 66:3519-22.
    • (1998) Infect Immun , vol.66 , pp. 3519-3522
    • Kirkland, T.N.1    Finley, F.2    Orsborn, K.I.3    Galgiani, J.N.4
  • 18
    • 0038782007 scopus 로고    scopus 로고
    • A recombinant β-1,3-glucanosyltransferase homolog of Coccidioides posadasii protects mice against coccidioidomycosis
    • Delgado N, Xue J, Yu J-J, Hung C-Y, Cole GT. A recombinant β-1,3-glucanosyltransferase homolog of Coccidioides posadasii protects mice against coccidioidomycosis. Infect Immun 2003; 71:3010-9.
    • (2003) Infect Immun , vol.71 , pp. 3010-3019
    • Delgado, N.1    Xue, J.2    Yu, J.-J.3    Hung, C.-Y.4    Cole, G.T.5
  • 19
    • 0023762241 scopus 로고
    • Active immunization with LD842, a plasmid-cured strain of Salmonella dublin, protects mice against group D and group B Salmonella infection
    • Fierer J, Chikami G, Hatlen L, Heffernan EJ, Guiney D. Active immunization with LD842, a plasmid-cured strain of Salmonella dublin, protects mice against group D and group B Salmonella infection. J Infect Dis 1988; 158:460-3.
    • (1988) J Infect Dis , vol.158 , pp. 460-463
    • Fierer, J.1    Chikami, G.2    Hatlen, L.3    Heffernan, E.J.4    Guiney, D.5
  • 20
    • 0032706265 scopus 로고    scopus 로고
    • Coadministration of interleukin 12 expression vector with antigen 2 cDNA enhances induction of protective immunity against Coccidioides immitis
    • Jiang C, Magee DM, Cox RA. Coadministration of interleukin 12 expression vector with antigen 2 cDNA enhances induction of protective immunity against Coccidioides immitis. Infect Immun 1999; 67:5848-53.
    • (1999) Infect Immun , vol.67 , pp. 5848-5853
    • Jiang, C.1    Magee, D.M.2    Cox, R.A.3
  • 21
    • 0035058922 scopus 로고    scopus 로고
    • Recombinant urease and urease DNA of Coccidioides immitis elicit an immunoprotective response against coccidioidomycosis in mice
    • Li K, Yu J-J, Hung C-Y, Lehmann PF, Cole GT. Recombinant urease and urease DNA of Coccidioides immitis elicit an immunoprotective response against coccidioidomycosis in mice. Infect Immun 2001; 69:2878-87.
    • (2001) Infect Immun , vol.69 , pp. 2878-2887
    • Li, K.1    Yu, J.-J.2    Hung, C.-Y.3    Lehmann, P.F.4    Cole, G.T.5
  • 23
    • 0020130404 scopus 로고
    • Tissue eosinophilia in human coccidioidomycosis
    • Echols RM, Palmer DL, Long GW. Tissue eosinophilia in human coccidioidomycosis. Rev Infect Dis 1982; 4:656-64.
    • (1982) Rev Infect Dis , vol.4 , pp. 656-664
    • Echols, R.M.1    Palmer, D.L.2    Long, G.W.3
  • 24
    • 0021801410 scopus 로고
    • Systemic Coccidioides immitis infection in nude and beige mice
    • Clemons KV, Leathers CR, Lee KW. Systemic Coccidioides immitis infection in nude and beige mice. Infect Immun 1985; 47:814-21.
    • (1985) Infect Immun , vol.47 , pp. 814-821
    • Clemons, K.V.1    Leathers, C.R.2    Lee, K.W.3
  • 25
    • 0017712539 scopus 로고
    • Significance of T cells in resistance to experimental murine coccidioidomycosis
    • Beaman L, Pappagianis D, Benjamini E. Significance of T cells in resistance to experimental murine coccidioidomycosis. Infect Immun 1977; 17:580-5.
    • (1977) Infect Immun , vol.17 , pp. 580-585
    • Beaman, L.1    Pappagianis, D.2    Benjamini, E.3
  • 26
    • 0018375215 scopus 로고
    • Mechanisms of resistance to infection with Coccidioides immitis in mice
    • Beaman L, Pappagianis D, Benjamini E. Mechanisms of resistance to infection with Coccidioides immitis in mice. Infect Immun 1979; 23:681-5.
    • (1979) Infect Immun , vol.23 , pp. 681-685
    • Beaman, L.1    Pappagianis, D.2    Benjamini, E.3
  • 27
    • 0032079195 scopus 로고    scopus 로고
    • Protective immunity in coccidioidomycosis
    • Cox RA, Magee DM. Protective immunity in coccidioidomycosis. Res Immunol 1998; 149:417-28.
    • (1998) Res Immunol , vol.149 , pp. 417-428
    • Cox, R.A.1    Magee, D.M.2
  • 28
    • 0029157103 scopus 로고
    • Roles of γ interferon and interleukin-4 in genetically determined resistance to Coccidioides immitis
    • Magee DM, Cox RA. Roles of γ interferon and interleukin-4 in genetically determined resistance to Coccidioides immitis. Infect Immun 1995; 63:3514-9.
    • (1995) Infect Immun , vol.63 , pp. 3514-3519
    • Magee, D.M.1    Cox, R.A.2
  • 29
    • 0031683522 scopus 로고    scopus 로고
    • Importance of interleukin-10 in genetic susceptibility of mice to Coccidioides immitis
    • Fierer J, Walls L, Eckmann L, Yamamoto T, Kirkland TN. Importance of interleukin-10 in genetic susceptibility of mice to Coccidioides immitis. Infect Immun 1998; 66:4397-402.
    • (1998) Infect Immun , vol.66 , pp. 4397-4402
    • Fierer, J.1    Walls, L.2    Eckmann, L.3    Yamamoto, T.4    Kirkland, T.N.5
  • 30
    • 0029080740 scopus 로고
    • Production of tumor necrosis factor α, interleukin-1 α, and interleukin-6 during murine coccidioidomycosis
    • Cox RA, Magee DM. Production of tumor necrosis factor α, interleukin-1 α, and interleukin-6 during murine coccidioidomycosis. Infect Immun 1995; 63:4178-80.
    • (1995) Infect Immun , vol.63 , pp. 4178-4180
    • Cox, R.A.1    Magee, D.M.2
  • 31
    • 0034125081 scopus 로고    scopus 로고
    • Immunological concepts of vaccine adjuvant activity
    • Schijns VE. Immunological concepts of vaccine adjuvant activity. Curr Opin Immunol 2000; 12:456-63.
    • (2000) Curr Opin Immunol , vol.12 , pp. 456-463
    • Schijns, V.E.1
  • 32
    • 0025852445 scopus 로고
    • A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene
    • Kitamura D, Roes J, Kuhn R, Rajewsky K. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 1991; 350:423-6.
    • (1991) Nature , vol.350 , pp. 423-426
    • Kitamura, D.1    Roes, J.2    Kuhn, R.3    Rajewsky, K.4
  • 33
    • 0025313515 scopus 로고
    • Normal development of mice deficient in β 2M MHC class I proteins, and CD8+ T cells
    • Koller BH, Marrack P, Kappler JW, Smithies O. Normal development of mice deficient in β 2M MHC class I proteins, and CD8+ T cells. Science 1990; 248:1227-30.
    • (1990) Science , vol.248 , pp. 1227-1230
    • Koller, B.H.1    Marrack, P.2    Kappler, J.W.3    Smithies, O.4
  • 34
    • 0028219791 scopus 로고
    • Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-defident mice
    • Kagi D, Ledermann B, Burki K, et al. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-defident mice. Nature 1994; 369:31-7.
    • (1994) Nature , vol.369 , pp. 31-37
    • Kagi, D.1    Ledermann, B.2    Burki, K.3
  • 35
    • 0025817991 scopus 로고
    • + cells but markedly decreased helper cell activity in mice lacking CD4
    • + cells but markedly decreased helper cell activity in mice lacking CD4. Nature 1991; 353:180-4.
    • (1991) Nature , vol.353 , pp. 180-184
    • Rahemtulla, A.1    Fung-Leung, W.P.2    Schilham, M.W.3
  • 36
    • 0028893203 scopus 로고
    • Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production
    • Pollock JS, Williams DA, Gifford MA, et al. Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat Genet 1995; 9:202-9.
    • (1995) Nat Genet , vol.9 , pp. 202-209
    • Pollock, J.S.1    Williams, D.A.2    Gifford, M.A.3
  • 37
    • 0027297663 scopus 로고
    • Mice deficient for the 55 kD tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection
    • Pfeffer K, Matsuyama T, Kundig TM, et al. Mice deficient for the 55 kD tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 1993; 73:457-67.
    • (1993) Cell , vol.73 , pp. 457-467
    • Pfeffer, K.1    Matsuyama, T.2    Kundig, T.M.3
  • 38
  • 39
    • 0026485046 scopus 로고
    • Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages
    • Mombaerts P, Clarke AR, Rudnicki MA, et al. Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature 1992; 360:225-31.
    • (1992) Nature , vol.360 , pp. 225-231
    • Mombaerts, P.1    Clarke, A.R.2    Rudnicki, M.A.3
  • 40
    • 84907130232 scopus 로고
    • Immunization of mice with induced mutants of Coccidioides immitis. I. Characterization of mutants and preliminary studies of their use as viable vaccines
    • Walch HA, Kalvoda A. Immunization of mice with induced mutants of Coccidioides immitis. I. Characterization of mutants and preliminary studies of their use as viable vaccines. Sabouraudia 1971; 9:173-84.
    • (1971) Sabouraudia , vol.9 , pp. 173-184
    • Walch, H.A.1    Kalvoda, A.2
  • 41
    • 0020582321 scopus 로고
    • Inbred mouse strains differ in resistance to lethal Coccidioides immitis infection
    • Kirkland TN, Fierer J. Inbred mouse strains differ in resistance to lethal Coccidioides immitis infection. Infect Immun 1983; 40:912-6.
    • (1983) Infect Immun , vol.40 , pp. 912-916
    • Kirkland, T.N.1    Fierer, J.2
  • 42
    • 0036067301 scopus 로고    scopus 로고
    • Molecular and phenotypic description of Coccidioides posadasii sp. nov., previously recognized as the non-California population of Coccidioides immitis
    • Fisher MC, Koenig GL, White TJ, Taylor JW. Molecular and phenotypic description of Coccidioides posadasii sp. nov., previously recognized as the non-California population of Coccidioides immitis. Mycologia 2002; 94:73-84.
    • (2002) Mycologia , vol.94 , pp. 73-84
    • Fisher, M.C.1    Koenig, G.L.2    White, T.J.3    Taylor, J.W.4
  • 43
    • 0030584708 scopus 로고    scopus 로고
    • S) congenic mouse strains show similar cytokine responses following infection with Salmonella dublin
    • S) congenic mouse strains show similar cytokine responses following infection with Salmonella dublin. J Immunol 1996; 156:2894-900.
    • (1996) J Immunol , vol.156 , pp. 2894-2900
    • Eckmann, L.1    Fierer, J.2    Kagnoff, M.F.3
  • 44
    • 0033783873 scopus 로고    scopus 로고
    • Delayed rejection of fetal pig pancreas in CD4 cell deficient mice was correlated with residual helper activity
    • Zhan Y, Corbett AJ, Brady JL, Sutherland RM, Lew AM. Delayed rejection of fetal pig pancreas in CD4 cell deficient mice was correlated with residual helper activity. Xenotransplantation 2000; 7:267-74.
    • (2000) Xenotransplantation , vol.7 , pp. 267-274
    • Zhan, Y.1    Corbett, A.J.2    Brady, J.L.3    Sutherland, R.M.4    Lew, A.M.5
  • 45
    • 0034541221 scopus 로고    scopus 로고
    • Microbial lipopeptides induce the production of IL-17 in Th cells
    • Infante-Duarte C, Horton HF, Byrne MC, Kamradt T. Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 2000; 165:6107-15.
    • (2000) J Immunol , vol.165 , pp. 6107-6115
    • Infante-Duarte, C.1    Horton, H.F.2    Byrne, M.C.3    Kamradt, T.4
  • 46
    • 0344299221 scopus 로고    scopus 로고
    • Role of innate and adaptive immunity in the outcome of primary infection with Chlamydia pneumoniae, as analyzed in genetically modified mice
    • Rottenberg ME, Gigliotti Rothfuchs AC, Gigliotti D, Svanholm C, Bandholtz L, Wigzell H. Role of innate and adaptive immunity in the outcome of primary infection with Chlamydia pneumoniae, as analyzed in genetically modified mice. J Immunol 1999; 162:2829-36.
    • (1999) J Immunol , vol.162 , pp. 2829-2836
    • Rottenberg, M.E.1    Gigliotti Rothfuchs, A.C.2    Gigliotti, D.3    Svanholm, C.4    Bandholtz, L.5    Wigzell, H.6
  • 47
    • 0036192996 scopus 로고    scopus 로고
    • Requirements for memory maintenance
    • Rocha B. Requirements for memory maintenance. Nat Immunol 2002; 3:209-10.
    • (2002) Nat Immunol , vol.3 , pp. 209-210
    • Rocha, B.1
  • 48
    • 4644309271 scopus 로고    scopus 로고
    • Activation of CD8 T cells by mycobacterial vaccination protects against pulmonary tuberculosis in the absence of CD4 t cells
    • Wang J, Santosuosso M, Ngai P, Zganiacz A, Xing Z. Activation of CD8 T cells by mycobacterial vaccination protects against pulmonary tuberculosis in the absence of CD4 t cells. J Immunol 2004; 173:4590-7.
    • (2004) J Immunol , vol.173 , pp. 4590-4597
    • Wang, J.1    Santosuosso, M.2    Ngai, P.3    Zganiacz, A.4    Xing, Z.5
  • 51
    • 0034644009 scopus 로고    scopus 로고
    • The immune system: Second of two parts
    • Delves PJ, Roitt IM. The immune system: second of two parts. N Engl J Med 2000; 343:108-17.
    • (2000) N Engl J Med , vol.343 , pp. 108-117
    • Delves, P.J.1    Roitt, I.M.2
  • 52
    • 0034675955 scopus 로고    scopus 로고
    • Requirements for bone marrow-derived antigen-presenting cells in priming cytotoxic T cell responses to intracellular pathogens
    • Lenz LL, Butz EA, Bevan MJ. Requirements for bone marrow-derived antigen-presenting cells in priming cytotoxic T cell responses to intracellular pathogens. J Exp Med 2000; 192:1135-42.
    • (2000) J Exp Med , vol.192 , pp. 1135-1142
    • Lenz, L.L.1    Butz, E.A.2    Bevan, M.J.3
  • 54
    • 0037114160 scopus 로고    scopus 로고
    • Requisite elements in vaccine immunity to Blastomyces dermatitidis: Plasticity uncovers vaccine potential in immune-deficient hosts
    • Wüthrich M, Filutowicz HI, Warner T, Klein BS. Requisite elements in vaccine immunity to Blastomyces dermatitidis: plasticity uncovers vaccine potential in immune-deficient hosts. J Immunol 2002; 169:6969-76.
    • (2002) J Immunol , vol.169 , pp. 6969-6976
    • Wüthrich, M.1    Filutowicz, H.I.2    Warner, T.3    Klein, B.S.4
  • 56
    • 29244473093 scopus 로고    scopus 로고
    • Molecular and cellular mechanisms of protective immunity to coccidioidomycosis
    • Kirkland TN, Raz E, Datta SK. Molecular and cellular mechanisms of protective immunity to coccidioidomycosis. Vaccine 2006; 24:495-500.
    • (2006) Vaccine , vol.24 , pp. 495-500
    • Kirkland, T.N.1    Raz, E.2    Datta, S.K.3
  • 57
    • 0033048884 scopus 로고    scopus 로고
    • Resistance to Coccidioides immitis in mice after immunization with recombinant protein or a DNA vaccine of a proline-rich antigen
    • Abuodeh RO, Shubitz LF, Siegel E, et al. Resistance to Coccidioides immitis in mice after immunization with recombinant protein or a DNA vaccine of a proline-rich antigen. Infect Immun 1999; 67:2935-40.
    • (1999) Infect Immun , vol.67 , pp. 2935-2940
    • Abuodeh, R.O.1    Shubitz, L.F.2    Siegel, E.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.