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Volumn 729, Issue 2, 1996, Pages 205-215

Do nitric oxide synthase, NMDA receptor subunit R1 and cytochrome oxidase co-localize in the rat central nervous system?

Author keywords

Double labeling; Excitatory amino acid; Immunogold silver staining; Nitric oxide; Retina

Indexed keywords

CYTOCHROME C OXIDASE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NITRIC OXIDE SYNTHASE;

EID: 0030581279     PISSN: 00068993     EISSN: None     Source Type: Journal    
DOI: 10.1016/0006-8993(96)00370-8     Document Type: Article
Times cited : (32)

References (50)
  • 1
    • 0028580508 scopus 로고
    • Regulation by neuroprotective factors of NMDA receptor mediated nitric oxide synthesis in the brain and retina
    • [1] Akaike, A., Tamura, Y., Terada, K. and Nakata, N., Regulation by neuroprotective factors of NMDA receptor mediated nitric oxide synthesis in the brain and retina, Progress Brain Res., 103 (1994) 391-403.
    • (1994) Progress Brain Res. , vol.103 , pp. 391-403
    • Akaike, A.1    Tamura, Y.2    Terada, K.3    Nakata, N.4
  • 2
    • 0022363222 scopus 로고
    • Excitatory amino acids in the chick retina: Possible involvement of cyclic guanosine monophosphate
    • [2] Anand, H., Roberts, P.J. and Lopez-Colome, A.M., Excitatory amino acids in the chick retina: possible involvement of cyclic guanosine monophosphate, Neurosci. Lett., 58 (1985) 31-36.
    • (1985) Neurosci. Lett. , vol.58 , pp. 31-36
    • Anand, H.1    Roberts, P.J.2    Lopez-Colome, A.M.3
  • 3
    • 0027265895 scopus 로고
    • Nitric oxide synthase in the visual cortex of monocular monkey as revealed by light and electron microscopic immunocytochemistry
    • [3] Aoki, C., Fenstemaker, S., Lubin, M. and Go, C.G., Nitric oxide synthase in the visual cortex of monocular monkey as revealed by light and electron microscopic immunocytochemistry, Brain Res., 62 (1993) 97-113.
    • (1993) Brain Res. , vol.62 , pp. 97-113
    • Aoki, C.1    Fenstemaker, S.2    Lubin, M.3    Go, C.G.4
  • 4
    • 0028111797 scopus 로고
    • Cellular and subsellular localization of NMDA-R1 subunit immunoreactivity in the visual cortex of adult and neonatal rats
    • [4] Aoki, C., Venkatesan, C., Go, C.G., Mong, J.A. and Dawson, T.M., Cellular and subsellular localization of NMDA-R1 subunit immunoreactivity in the visual cortex of adult and neonatal rats, J. Neurosci., 14 (1994) 5202-22.
    • (1994) J. Neurosci. , vol.14 , pp. 5202-5222
    • Aoki, C.1    Venkatesan, C.2    Go, C.G.3    Mong, J.A.4    Dawson, T.M.5
  • 5
    • 0028333991 scopus 로고
    • Synaptic responses of substantia geletinosa neurons to dorsal column stimulation in rat spinal cord in vitro
    • [5] Baba, H., Yoshimura, M., Nishi, S. and Shimoji, K., Synaptic responses of substantia geletinosa neurons to dorsal column stimulation in rat spinal cord in vitro, J. Physiol., 478 (1994) 87-99.
    • (1994) J. Physiol. , vol.478 , pp. 87-99
    • Baba, H.1    Yoshimura, M.2    Nishi, S.3    Shimoji, K.4
  • 7
    • 0027477946 scopus 로고
    • Do defects in mitochondrial energy metabolism underlie the pathology of neurodegeneration diseases?
    • [7] Beal, M.F., Hyman, B.T. and Koroshetz, W., Do defects in mitochondrial energy metabolism underlie the pathology of neurodegeneration diseases? Trends Neurosci., 16 (1993) 125-131.
    • (1993) Trends Neurosci. , vol.16 , pp. 125-131
    • Beal, M.F.1    Hyman, B.T.2    Koroshetz, W.3
  • 8
    • 0028145462 scopus 로고
    • Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes
    • [8] Bolaños, J.P., Peuchen, S., Heales, S.J.R., Land, J.M. and Clark, J.B., Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes, J. Neurochem., 63 (1994) 910-916.
    • (1994) J. Neurochem. , vol.63 , pp. 910-916
    • Bolaños, J.P.1    Peuchen, S.2    Heales, S.J.R.3    Land, J.M.4    Clark, J.B.5
  • 9
    • 0024378999 scopus 로고
    • Nitric oxide mediated glutamate-linked enhancement of cGMP levels in the cerebellum
    • [9] Bredt, D.S. and Synder, S.H., Nitric oxide mediated glutamate-linked enhancement of cGMP levels in the cerebellum, Proc. Natl. Acad. Sci. USA, 86 (1989) 9030-9033.
    • (1989) Proc. Natl. Acad. Sci. USA , vol.86 , pp. 9030-9033
    • Bredt, D.S.1    Synder, S.H.2
  • 10
    • 0025941639 scopus 로고
    • Nitric oxide synthase protein and mRNA are discretely localized in neuronal population of the mammalian CNS together with NADPH diaphorase
    • [10] Bredt, D.S., Glatt, C.E., Hwang, P.M., Fotuhi, M. and Dawson, T.M., Synder, S.H., Nitric oxide synthase protein and mRNA are discretely localized in neuronal population of the mammalian CNS together with NADPH diaphorase, Neuron, 1 (1991) 615-624.
    • (1991) Neuron , vol.1 , pp. 615-624
    • Bredt, D.S.1    Glatt, C.E.2    Hwang, P.M.3    Fotuhi, M.4    Dawson, T.M.5    Synder, S.H.6
  • 11
    • 0025802065 scopus 로고
    • Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase
    • [11] Bredt, D.S., Hwang, P.M., Glatt, C.E., Lowenstein, C., Reed, R.R. and Snyder, S.H., Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase, Nature, 351 (1991) 714-718.
    • (1991) Nature , vol.351 , pp. 714-718
    • Bredt, D.S.1    Hwang, P.M.2    Glatt, C.E.3    Lowenstein, C.4    Reed, R.R.5    Snyder, S.H.6
  • 12
    • 0028178139 scopus 로고
    • 2+ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells
    • 2+ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells, J. Neurosci., 14 (1994) 187-197.
    • (1994) J. Neurosci. , vol.14 , pp. 187-197
    • Brorson, J.R.1    Manzolillo, P.A.2    Miller, R.J.3
  • 13
    • 0024829451 scopus 로고
    • Excitatory amino acid receptors in the vertebrate central nervous system
    • [13] Collingridge, G.L. and Lester, R.A., Excitatory amino acid receptors in the vertebrate central nervous system, Pharmacol. Rev., 40 (1989) 143-210.
    • (1989) Pharmacol. Rev. , vol.40 , pp. 143-210
    • Collingridge, G.L.1    Lester, R.A.2
  • 14
    • 0023232952 scopus 로고
    • Cytochrome oxidase activity in the rat caudate nucleus: Light and electron microscopic observation
    • [14] Difiglia, M., Graveland, G.A. and Schiff, L., Cytochrome oxidase activity in the rat caudate nucleus: light and electron microscopic observation, J. Camp. Neurol., 255 (1987) 137-145.
    • (1987) J. Camp. Neurol. , vol.255 , pp. 137-145
    • Difiglia, M.1    Graveland, G.A.2    Schiff, L.3
  • 15
    • 0028361624 scopus 로고
    • NMDA receptor mRNA expression in NOS-containing neurons in the spinal trigeminal nucleus of the rat
    • [15] Dohrn, C.S. and Beitz, A.J., NMDA receptor mRNA expression in NOS-containing neurons in the spinal trigeminal nucleus of the rat, Neurosci. Lett., 175 (1994) 28-32.
    • (1994) Neurosci. Lett. , vol.175 , pp. 28-32
    • Dohrn, C.S.1    Beitz, A.J.2
  • 16
    • 0028226788 scopus 로고
    • Nitric oxide synthase immunoreactivity in rat pontine medullary neurons
    • [16] Dun, N.J., Dun, S.L. and Forstermann, U., Nitric oxide synthase immunoreactivity in rat pontine medullary neurons, Neuroscience, 59 (1994) 429-445.
    • (1994) Neuroscience , vol.59 , pp. 429-445
    • Dun, N.J.1    Dun, S.L.2    Forstermann, U.3
  • 17
    • 0026034352 scopus 로고
    • NMDA receptor activation in rat hippocampus induces cyclic GMP formation through the L-arginine-nitric oxide pathway
    • [17] East, S.J. and Garthwaite, J., NMDA receptor activation in rat hippocampus induces cyclic GMP formation through the L-arginine-nitric oxide pathway, Neurosci. Lett., 123 (1991) 17-19.
    • (1991) Neurosci. Lett. , vol.123 , pp. 17-19
    • East, S.J.1    Garthwaite, J.2
  • 18
    • 0026077959 scopus 로고
    • Glutamate, nitric oxide and cell-cell signaling in the nervous system
    • [18] Garthwaite, J., Glutamate, nitric oxide and cell-cell signaling in the nervous system. Trend Neurosci., 14 (1991) 60-67.
    • (1991) Trend Neurosci. , vol.14 , pp. 60-67
    • Garthwaite, J.1
  • 19
    • 0024462440 scopus 로고
    • NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices
    • [19] Gaithwait, J., Garthwait, G., Palmer, R.M.J. and Moncade, S., NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices, Eur. J. Pharmacol., 172 (1989) 413-416.
    • (1989) Eur. J. Pharmacol. , vol.172 , pp. 413-416
    • Gaithwait, J.1    Garthwait, G.2    Palmer, R.M.J.3    Moncade, S.4
  • 20
    • 0024296032 scopus 로고
    • Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain
    • [20] Garthwaite, J., Charles, S.L. and Chess-Williams, R., Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain, Nature, 336 (1988) 385-388.
    • (1988) Nature , vol.336 , pp. 385-388
    • Garthwaite, J.1    Charles, S.L.2    Chess-Williams, R.3
  • 22
    • 0017622848 scopus 로고
    • Opiate analgesics inhibit substance P release from rat trigeminal nucleus
    • [22] Jessell, T.M. and Iversen, L.L., Opiate analgesics inhibit substance P release from rat trigeminal nucleus, Nature, 268 (1977) 549-551.
    • (1977) Nature , vol.268 , pp. 549-551
    • Jessell, T.M.1    Iversen, L.L.2
  • 23
    • 0027283430 scopus 로고
    • Localization of NADPH diaphorase activity in monoaminergic neurons of the rat brain
    • [23] Johnson, M.D. and Ma, P.M., Localization of NADPH diaphorase activity in monoaminergic neurons of the rat brain, J. Comp. Neurol., 332 (1993) 391-406.
    • (1993) J. Comp. Neurol. , vol.332 , pp. 391-406
    • Johnson, M.D.1    Ma, P.M.2
  • 24
    • 0019918228 scopus 로고
    • Histochemical localization of cytochrome oxidase in the hippocampus: Correlation with specific neuronal types and different pathways
    • [24] Kageyama, G.H. and Wong-Riley, M.T.T., Histochemical localization of cytochrome oxidase in the hippocampus: correlation with specific neuronal types and different pathways. Neuroscience, 7 (1982) 2337-61.
    • (1982) Neuroscience , vol.7 , pp. 2337-2361
    • Kageyama, G.H.1    Wong-Riley, M.T.T.2
  • 25
    • 0028180156 scopus 로고
    • 2+ /calmodulin-dependent nitric oxide synthase and a soluble guanylyl cyclase in vertebrate photoreceptor cells
    • 2+ /calmodulin-dependent nitric oxide synthase and a soluble guanylyl cyclase in vertebrate photoreceptor cells, EMBO J., 13 (1994) 3312-3320.
    • (1994) EMBO J , vol.13 , pp. 3312-3320
    • Koch, K.W.1    Lambrecht, H.G.2    Haberecht, M.3    Redburn, D.4    Schmidt, H.H.5
  • 26
    • 0027985522 scopus 로고
    • NMDA-dependent nitric oxide release in the hippocampus in vivo interactions with noradrenaline
    • [26] Luo, D. and Vincent, S.R., NMDA-dependent nitric oxide release in the hippocampus in vivo interactions with noradrenaline, Neuropharmacology, 33 (1994) 1345-1350.
    • (1994) Neuropharmacology , vol.33 , pp. 1345-1350
    • Luo, D.1    Vincent, S.R.2
  • 27
    • 0024398179 scopus 로고
    • Double labeling of cytochrome oxidase and gamma-aminobutyric acid in central nervous system neurons of adult cats
    • [27] Luo, X.G., Hevner, R.F. and Wong-Riley, M.T.T., Double labeling of cytochrome oxidase and gamma-aminobutyric acid in central nervous system neurons of adult cats, J. Neurosci. Methods, 30 (1989) 189-195.
    • (1989) J. Neurosci. Methods , vol.30 , pp. 189-195
    • Luo, X.G.1    Hevner, R.F.2    Wong-Riley, M.T.T.3
  • 28
    • 0026624885 scopus 로고
    • Nitroprusside-sensitive and insensitive guanylate cyclases in retinal rod outer segments
    • [28] Margulis, A., Sharma, R.K. and Sitaramayya, A., Nitroprusside-sensitive and insensitive guanylate cyclases in retinal rod outer segments, Biochem. Biophys. Res. Commun., 185 (1992) 909-914.
    • (1992) Biochem. Biophys. Res. Commun. , vol.185 , pp. 909-914
    • Margulis, A.1    Sharma, R.K.2    Sitaramayya, A.3
  • 29
    • 0028305817 scopus 로고
    • Haloperidol-induced morphological changes in striatum are associated with glutamate synapses
    • [29] Meshul, C.K., Stallbaumer, R.K., Tayler, B. and Janowsky, A., Haloperidol-induced morphological changes in striatum are associated with glutamate synapses, Brain Res., 648 (1994) 181-195.
    • (1994) Brain Res. , vol.648 , pp. 181-195
    • Meshul, C.K.1    Stallbaumer, R.K.2    Tayler, B.3    Janowsky, A.4
  • 30
    • 0024215686 scopus 로고
    • Relationship between synaptogenesis and cytochrome oxidase activity in Purkinje cells of the developing rat cerebellum
    • [30] Mjaatvedt, A.E. and Wong-Riley, M.T.T., Relationship between synaptogenesis and cytochrome oxidase activity in Purkinje cells of the developing rat cerebellum, J. Comp. Neurol., 277 (1988) 155-182.
    • (1988) J. Comp. Neurol. , vol.277 , pp. 155-182
    • Mjaatvedt, A.E.1    Wong-Riley, M.T.T.2
  • 31
    • 0026026921 scopus 로고
    • Effects of unilateral climbing fiber deafferentation on cytochrome oxidase activity in the developing rat cerebellum
    • [31] Mjaatvedt, A.E. and Wong-Riley, M.T.T., Effects of unilateral climbing fiber deafferentation on cytochrome oxidase activity in the developing rat cerebellum, J. Neurocytol., 20 (1991) 2-16.
    • (1991) J. Neurocytol. , vol.20 , pp. 2-16
    • Mjaatvedt, A.E.1    Wong-Riley, M.T.T.2
  • 32
    • 0026437728 scopus 로고
    • Molecular diversity of glutamate receptors and implications for brain function
    • [32] Nakanishi, S., Molecular diversity of glutamate receptors and implications for brain function, Science, 258 (1992) 597-603.
    • (1992) Science , vol.258 , pp. 597-603
    • Nakanishi, S.1
  • 33
    • 0029022402 scopus 로고
    • Double labeling of GABA and cytochrome oxidase in the macaque visual cortex: Quantitative EM analysis
    • [33] Nie, F. and Wong-Riley, M.T.T., Double labeling of GABA and cytochrome oxidase in the macaque visual cortex: quantitative EM analysis, J. Comp. Neurol., 356 (1995) 115-131.
    • (1995) J. Comp. Neurol. , vol.356 , pp. 115-131
    • Nie, F.1    Wong-Riley, M.T.T.2
  • 34
    • 0027197061 scopus 로고
    • Nitric oxide synthase neurons in rat brain express more NMDA receptor mRNA than non-NOS neurons
    • [34] Price Jr., R.H., Mayer, B. and Beitz, A.J., Nitric oxide synthase neurons in rat brain express more NMDA receptor mRNA than non-NOS neurons, Neuroreport, 4 (1993) 807-810.
    • (1993) Neuroreport , vol.4 , pp. 807-810
    • Price R.H., Jr.1    Mayer, B.2    Beitz, A.J.3
  • 35
    • 0025856774 scopus 로고
    • Citrulline in the rat brain; immunohistochemistry and coexistence with NADPH-diaphorase
    • [35] Pasqualotto, B.A., Hope, B,T. and Vincent. S.R., Citrulline in the rat brain; immunohistochemistry and coexistence with NADPH-diaphorase, Neusci. Lett., 128 (1991) 155-160.
    • (1991) Neusci. Lett. , vol.128 , pp. 155-160
    • Pasqualotto, B.A.1    Hope, B.T.2    Vincent, S.R.3
  • 36
    • 0023912670 scopus 로고
    • Vascular endothelial cells synthesize nitric oxide from L-arginine
    • [36] Palmer, R.M., Ashton, D.S. and Moncada, S., Vascular endothelial cells synthesize nitric oxide from L-arginine, Nature, 333 (1988) 664-666.
    • (1988) Nature , vol.333 , pp. 664-666
    • Palmer, R.M.1    Ashton, D.S.2    Moncada, S.3
  • 38
    • 0026904235 scopus 로고
    • Sodium nitriprusside alter dark voltage and light responses in isolated retinal rods during whole cell recording
    • [38] Schmidt, K.F., Noll, G.N. and Yamamoto, Y., Sodium nitriprusside alter dark voltage and light responses in isolated retinal rods during whole cell recording. Vis. Neurosci., 9 (1992) 205-209.
    • (1992) Vis. Neurosci. , vol.9 , pp. 205-209
    • Schmidt, K.F.1    Noll, G.N.2    Yamamoto, Y.3
  • 39
    • 0002510855 scopus 로고
    • Schmitt, F.O. and Worden, F.G. (Eds), MIT Press, MA
    • [39] Sokoloff, L. In Schmitt, F.O. and Worden, F.G. (Eds), The Neuroscience: Third Study Program, MIT Press, MA, 1974, pp. 885-898.
    • (1974) The Neuroscience: Third Study Program , pp. 885-898
    • Sokoloff, L.1
  • 40
    • 0026739959 scopus 로고
    • Nitric oxide synthase and GABA colocalize in lamina II of rat spinal cord
    • [40] Valtschanoff, J.G., Weinberg, R.J., Rustioni, A. and Schmidt, H.H., Nitric oxide synthase and GABA colocalize in lamina II of rat spinal cord, Neurosci. Lett., 148 (1992) 6-10.
    • (1992) Neurosci. Lett. , vol.148 , pp. 6-10
    • Valtschanoff, J.G.1    Weinberg, R.J.2    Rustioni, A.3    Schmidt, H.H.4
  • 41
    • 0027303020 scopus 로고
    • Neurons in rat cerebral cortex that synthesize nitric oxide: NADPH diaphorase histochemistry, NOS immunohistochemistry, and colocalization with GABA
    • [41] Valtschanoff, J.G., Weinberg, R.J., Kharazia, V.N., Schmidt, H.H., Nakane, M. and Rustioni, A., Neurons in rat cerebral cortex that synthesize nitric oxide: NADPH diaphorase histochemistry, NOS immunohistochemistry, and colocalization with GABA, Neurosci. Lett., 157 (1993) 157-161.
    • (1993) Neurosci. Lett. , vol.157 , pp. 157-161
    • Valtschanoff, J.G.1    Weinberg, R.J.2    Kharazia, V.N.3    Schmidt, H.H.4    Nakane, M.5    Rustioni, A.6
  • 43
    • 0018846092 scopus 로고
    • Pain. The role of substantia gelatinosa as a gate control
    • [43] Wall, P.D., Pain. The role of substantia gelatinosa as a gate control, Res. Nerv. Mental Disease, 58 (1980) 205-231.
    • (1980) Res. Nerv. Mental Disease , vol.58 , pp. 205-231
    • Wall, P.D.1
  • 44
    • 0025191432 scopus 로고
    • Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists
    • [44] Watkins, J.C., Krogsgaard-larsen, P. and Honore, T., Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists, Trends Pharmacol. Sci., 11 (1990) 25-33.
    • (1990) Trends Pharmacol. Sci. , vol.11 , pp. 25-33
    • Watkins, J.C.1    Krogsgaard-Larsen, P.2    Honore, T.3
  • 45
    • 0015502252 scopus 로고
    • Synaptic organization in the olfactory glomerulus of the mouse
    • [45] White, E.L., Synaptic organization in the olfactory glomerulus of the mouse. Brain Res., 37 (1972) 69-80.
    • (1972) Brain Res. , vol.37 , pp. 69-80
    • White, E.L.1
  • 46
    • 0018358930 scopus 로고
    • Changes in the visual system of monocularly sutured or enucleated cats demonstrable with cytochrome oxidase histochemistry
    • [46] Wong-Riley, M.T.T., Changes in the visual system of monocularly sutured or enucleated cats demonstrable with cytochrome oxidase histochemistry, Brain Res., 171 (1979) 11-28.
    • (1979) Brain Res. , vol.171 , pp. 11-28
    • Wong-Riley, M.T.T.1
  • 47
    • 0024561501 scopus 로고
    • Cytochrome oxidase: An endogenous metabolic marker for neuronal activity
    • [47] Wong-Riley, M.T.T., Cytochrome oxidase: an endogenous metabolic marker for neuronal activity, Trends Neurosci., 12 (1989) 94-101.
    • (1989) Trends Neurosci. , vol.12 , pp. 94-101
    • Wong-Riley, M.T.T.1
  • 48
    • 0021165033 scopus 로고
    • The effect of impulse blockage on cytochrome oxidase activity in the monkey visual system
    • [48] Wong-Riley, M.T.T. and Carroll, E.W., The effect of impulse blockage on cytochrome oxidase activity in the monkey visual system, Nature, 307 (1984) 262-264.
    • (1984) Nature , vol.307 , pp. 262-264
    • Wong-Riley, M.T.T.1    Carroll, E.W.2
  • 49
    • 0022649947 scopus 로고
    • Localization of cytochrome oxidase in the mammalian spinal cord and dorsal root ganglia, with quantitative analysis of ventral horn cells in monkeys
    • [49] Wong-Riley, M.T.T. and Kageyama, G.H., Localization of cytochrome oxidase in the mammalian spinal cord and dorsal root ganglia, with quantitative analysis of ventral horn cells in monkeys, J. Comp. Neurol., 245 (1986) 41-61.
    • (1986) J. Comp. Neurol. , vol.245 , pp. 41-61
    • Wong-Riley, M.T.T.1    Kageyama, G.H.2
  • 50
    • 0024893513 scopus 로고
    • Effect of retinal impulse blockage on cytochrome oxidase-rich zones in the macaque striate cortex: II quantitative electron-microscopic (EM) analysis of neuropil
    • [50] Wong-Riley, M.T., Truck, T.C., Tripathi, S.C. and Hoppe, D.A., Effect of retinal impulse blockage on cytochrome oxidase-rich zones in the macaque striate cortex: II quantitative electron-microscopic (EM) analysis of neuropil, Vis. Neurosci., 2 (1989) 499-514.
    • (1989) Vis. Neurosci. , vol.2 , pp. 499-514
    • Wong-Riley, M.T.1    Truck, T.C.2    Tripathi, S.C.3    Hoppe, D.A.4


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