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Volumn 735, Issue 2, 1996, Pages 197-207

Estrogen uncouples noradrenergic activation of Fos expression in the female rat preoptic area

Author keywords

Brainstem; c fos; Gonadotrophin; Sexual behavior

Indexed keywords

ESTRADIOL; ESTROGEN; NORADRENALIN;

EID: 0030574064     PISSN: 00068993     EISSN: None     Source Type: Journal    
DOI: 10.1016/0006-8993(96)00611-7     Document Type: Article
Times cited : (15)

References (47)
  • 1
    • 0027428681 scopus 로고
    • Functional antagonism between the estrogen receptor and Fos in the regulation of c-fos protooncogene transcription
    • [1] Ambrosino, C., Cicatiello, L., Cobellis, G., Addeo, R., Sica, V., Bresciani, F. and Weisz, A., Functional antagonism between the estrogen receptor and Fos in the regulation of c-fos protooncogene transcription, Mol. Endocrinol., 7 (1993) 1472-1483.
    • (1993) Mol. Endocrinol. , vol.7 , pp. 1472-1483
    • Ambrosino, C.1    Cicatiello, L.2    Cobellis, G.3    Addeo, R.4    Sica, V.5    Bresciani, F.6    Weisz, A.7
  • 2
    • 0028933274 scopus 로고
    • Progesterone enhances an estradiol-induced increase in fos immunoreactivity in localized regions of female rat forebrain
    • [2] Auger, P.A. and Blaustein, J.D., Progesterone enhances an estradiol-induced increase in fos immunoreactivity in localized regions of female rat forebrain, J. Neurosci., 15 (1995) 2272-2279.
    • (1995) J. Neurosci. , vol.15 , pp. 2272-2279
    • Auger, P.A.1    Blaustein, J.D.2
  • 3
    • 0025745211 scopus 로고
    • Noradrenergic activation of immediate early genes in rat cerebral cortex
    • [3] Bing, G., Filer, D., Miller, J.C. and Stone, E.A., Noradrenergic activation of immediate early genes in rat cerebral cortex, Mol. Brain Res., 11 (1991) 43-46.
    • (1991) Mol. Brain Res. , vol.11 , pp. 43-46
    • Bing, G.1    Filer, D.2    Miller, J.C.3    Stone, E.A.4
  • 5
    • 0025217782 scopus 로고
    • c-fos induction by estrogen in specific rat brain areas
    • [5] Cattaneo, E. and Maggi, A., c-fos induction by estrogen in specific rat brain areas, Eur. J. Pharmacol., 188 (1990) 153-159.
    • (1990) Eur. J. Pharmacol. , vol.188 , pp. 153-159
    • Cattaneo, E.1    Maggi, A.2
  • 6
    • 0028854158 scopus 로고
    • Changing patterns of Fos expression in brainstem catecholaminergic neurons during the rat oestrous cycle
    • [6] Conde, G.L., Bicknell, R.J. and Herbison, A.E., Changing patterns of Fos expression in brainstem catecholaminergic neurons during the rat oestrous cycle, Brain Res., 672 (1995) 68-76.
    • (1995) Brain Res. , vol.672 , pp. 68-76
    • Conde, G.L.1    Bicknell, R.J.2    Herbison, A.E.3
  • 7
    • 0018876246 scopus 로고
    • Noradrenergic and dopaminergic projections to the medial preoptic area of the rat. A combined horseradish peroxidase/catecholamine fluorescence study
    • [7] Day, T.A., Blessing, W. and Willoughby, J.O., Noradrenergic and dopaminergic projections to the medial preoptic area of the rat. A combined horseradish peroxidase/catecholamine fluorescence study, Brain Res., 193 (1980) 543-548.
    • (1980) Brain Res. , vol.193 , pp. 543-548
    • Day, T.A.1    Blessing, W.2    Willoughby, J.O.3
  • 8
    • 0022259377 scopus 로고
    • Preoptic catecholamine, GABA and glutamate release in ovariectomized and ovariectomized-oestrogen primed rats utilizing a push-pull cannula technique
    • [8] Demling, J., Fuchs, E., Baumert, M. and Wuttke, W., Preoptic catecholamine, GABA and glutamate release in ovariectomized and ovariectomized-oestrogen primed rats utilizing a push-pull cannula technique, Neuroendocrinology, 41 (1990) 212-218.
    • (1990) Neuroendocrinology , vol.41 , pp. 212-218
    • Demling, J.1    Fuchs, E.2    Baumert, M.3    Wuttke, W.4
  • 9
    • 0025098472 scopus 로고
    • 2 noradrenergic receptors in hypothalamus of female rats
    • 2 noradrenergic receptors in hypothalamus of female rats, Neurochem Int., 16 (1990) 1-9.
    • (1990) Neurochem Int. , vol.16 , pp. 1-9
    • Etgen, A.M.1    Karkanias, G.B.2
  • 10
    • 0026690830 scopus 로고
    • Estradiol and progesterone modulation of norepinephrine neurotransmission: Implications for the regulation of female reproductive behavior
    • [10] Etgen, A.M., Ungar, S. and Petitti, N., Estradiol and progesterone modulation of norepinephrine neurotransmission: implications for the regulation of female reproductive behavior, J. Neuroendocrinol., 4 (1992) 255-271.
    • (1992) J. Neuroendocrinol. , vol.4 , pp. 255-271
    • Etgen, A.M.1    Ungar, S.2    Petitti, N.3
  • 11
    • 0021346931 scopus 로고
    • Differential co-existence of neuropeptide Y (NPY)-like immunoreactivity with catecholamines in the central nervous system of the rat
    • [11] Everitt, B.J., Hokfelt, T., Terenius, L., Tatemoto, K., Mutt, V. and Goldstein, M., Differential co-existence of neuropeptide Y (NPY)-like immunoreactivity with catecholamines in the central nervous system of the rat, Neuroscience, 11 (1984) 443-462.
    • (1984) Neuroscience , vol.11 , pp. 443-462
    • Everitt, B.J.1    Hokfelt, T.2    Terenius, L.3    Tatemoto, K.4    Mutt, V.5    Goldstein, M.6
  • 12
    • 0028123751 scopus 로고
    • Analysis of brainstem A1 and A2 noradrenergic inputs to the preoptic area using microdialysis in the rat
    • [12] Fernandez-Galaz, C., Dyer, R.G. and Herbison, A.E., Analysis of brainstem A1 and A2 noradrenergic inputs to the preoptic area using microdialysis in the rat, Brain Res., 636 (1994) 227-232.
    • (1994) Brain Res. , vol.636 , pp. 227-232
    • Fernandez-Galaz, C.1    Dyer, R.G.2    Herbison, A.E.3
  • 13
    • 0027316138 scopus 로고
    • Characterization of tritiated noradrenaline release from the rat preoptic area with microdialysis in vivo
    • [13] Fernandez-Galaz, C., Herbison, A.E. and Dyer, R.G., Characterization of tritiated noradrenaline release from the rat preoptic area with microdialysis in vivo, J. Neurochem., 60 (1993) 1806-1815.
    • (1993) J. Neurochem. , vol.60 , pp. 1806-1815
    • Fernandez-Galaz, C.1    Herbison, A.E.2    Dyer, R.G.3
  • 14
    • 0022578773 scopus 로고
    • Evidence for estrogen-receptive GABAergic neurons in the preoptic/anterior hypothalamic area of the rat brain
    • [14] Flugge, G., Oertel, W.H. and Wuttke, W., Evidence for estrogen-receptive GABAergic neurons in the preoptic/anterior hypothalamic area of the rat brain, Neuroendocrinology, 43 (1986) 1-5.
    • (1986) Neuroendocrinology , vol.43 , pp. 1-5
    • Flugge, G.1    Oertel, W.H.2    Wuttke, W.3
  • 15
    • 0018617369 scopus 로고
    • Effect of intraventricular infusion of catecholamines on LH release in ovariectomized and ovariectomized-steroid primed rats
    • [15] Gallo, R.W. and Drouva, S.V., Effect of intraventricular infusion of catecholamines on LH release in ovariectomized and ovariectomized-steroid primed rats, Neuroendocrinology, 29 (1979) 149-162.
    • (1979) Neuroendocrinology , vol.29 , pp. 149-162
    • Gallo, R.W.1    Drouva, S.V.2
  • 16
    • 0027181143 scopus 로고
    • Distribution of estrogen receptor-immunoreactive cells in the preoptic area of the ewe: Co-localization with glutamic acid decarboxylase but not luteinizing hormone-releasing hormone
    • [16] Herbison, A.E., Robinson, J.E. and Skinner, D.C., Distribution of estrogen receptor-immunoreactive cells in the preoptic area of the ewe: co-localization with glutamic acid decarboxylase but not luteinizing hormone-releasing hormone, Neuroendocrinology, 51 (1993) 751-759.
    • (1993) Neuroendocrinology , vol.51 , pp. 751-759
    • Herbison, A.E.1    Robinson, J.E.2    Skinner, D.C.3
  • 17
    • 0029591616 scopus 로고
    • Regulation of GABA transporter activity and mRNA expression by estrogen in rat preoptic area
    • [17] Herbison, A.E., Augood, S.J., Simonian, S.X. and Chapman, C., Regulation of GABA transporter activity and mRNA expression by estrogen in rat preoptic area, J. Neurosci., 15 (1995) 8302-8309.
    • (1995) J. Neurosci. , vol.15 , pp. 8302-8309
    • Herbison, A.E.1    Augood, S.J.2    Simonian, S.X.3    Chapman, C.4
  • 18
    • 0028958945 scopus 로고
    • A receptor subunit mRNA expression in preoptic area and bed nucleus of the stria terminalis of female rat brain
    • A receptor subunit mRNA expression in preoptic area and bed nucleus of the stria terminalis of female rat brain, J. Neurosci., 15 (1995) 2328-2337.
    • (1995) J. Neurosci. , vol.15 , pp. 2328-2337
    • Herbison, A.E.1    Fenelon, V.S.2
  • 19
    • 0024991592 scopus 로고
    • Oestrogen modulation of excitatory Al noradrenergic input to rat medial preoptic area GABA neurones demonstrated by microdialysis
    • [19] Herbison, A.E., Heavens, R.P. and Dyer, R.G., Oestrogen modulation of excitatory Al noradrenergic input to rat medial preoptic area GABA neurones demonstrated by microdialysis, Neuroendocrinology, 52 (1990) 161-168.
    • (1990) Neuroendocrinology , vol.52 , pp. 161-168
    • Herbison, A.E.1    Heavens, R.P.2    Dyer, R.G.3
  • 20
    • 0029060574 scopus 로고
    • Increased fos expression in preoptic calcitonin gene-related peptide (CGRP) neurones following mating but not the luteinizing hormone surge in female rats
    • [20] Herbison, A.E., King, I.S., Tan, K.K.C. and Dye. S., Increased Fos expression in preoptic calcitonin gene-related peptide (CGRP) neurones following mating but not the luteinizing hormone surge in female rats, Neuroendocrinology, 7 (1995) 377-385.
    • (1995) Neuroendocrinology , vol.7 , pp. 377-385
    • Herbison, A.E.1    King, I.S.2    Tan, K.K.C.3    Dye, S.4
  • 21
    • 0026793061 scopus 로고
    • Localization of oestrogen receptors in preoptic neurons containing neurotensin but not tyrosine hydroxylase, cholecystokinin or luteinizing hormone-releasing hormone in the male and female rat
    • [21] Herbison, A.E. and Theodosis, D.T., Localization of oestrogen receptors in preoptic neurons containing neurotensin but not tyrosine hydroxylase, cholecystokinin or luteinizing hormone-releasing hormone in the male and female rat, Neuroscience, 50 (1992) 283-292.
    • (1992) Neuroscience , vol.50 , pp. 283-292
    • Herbison, A.E.1    Theodosis, D.T.2
  • 22
    • 0017624738 scopus 로고
    • 3H-Oestradiol in catecholamine neurones of the rat brainstem: Combined localization by autoradiography and formaldehyde-induced fluorescence
    • 3H-Oestradiol in catecholamine neurones of the rat brainstem: combined localization by autoradiography and formaldehyde-induced fluorescence, J. Comp. Neurol., 176 (1977) 607-630.
    • (1977) J. Comp. Neurol. , vol.176 , pp. 607-630
    • Heritage, A.S.1    Grant, L.D.2    Stumpf, W.E.3
  • 23
    • 0027309213 scopus 로고
    • c-Fos and related immediate early gene products as markers of activity in neuroendocrine systems
    • [23] Hoffman, G.E., Smith, M.S. and Verbalis, J.G., c-Fos and related immediate early gene products as markers of activity in neuroendocrine systems, Front. Neuroendocrinol., 14 (1993) 173-213.
    • (1993) Front. Neuroendocrinol. , vol.14 , pp. 173-213
    • Hoffman, G.E.1    Smith, M.S.2    Verbalis, J.G.3
  • 24
    • 0023277535 scopus 로고
    • Induction of c-fos-like protein in spinal cord neurons following sensory stimulation
    • [24] Hunt, S.P., Pini, A. and Evan, G., Induction of c-fos-like protein in spinal cord neurons following sensory stimulation, Nature, 328 (1987) 632-634.
    • (1987) Nature , vol.328 , pp. 632-634
    • Hunt, S.P.1    Pini, A.2    Evan, G.3
  • 25
    • 0025351020 scopus 로고
    • Regional induction of c-fos-like proteins in rat brain after estradiol administration
    • [25] Insel, T.R., Regional induction of c-fos-like proteins in rat brain after estradiol administration, Endocrinology, 126 (1990) 1849-1853.
    • (1990) Endocrinology , vol.126 , pp. 1849-1853
    • Insel, T.R.1
  • 26
    • 0026774982 scopus 로고
    • c-fos expression in noradrenergic A2 neurons of the rat during the estrous cycle and after steroid hormone treatments
    • [26] Jennes, L., Jennes, M.E., Purvis, C. and Nees, M., c-fos expression in noradrenergic A2 neurons of the rat during the estrous cycle and after steroid hormone treatments, Brain Res., 586 (1992) 171-175.
    • (1992) Brain Res. , vol.586 , pp. 171-175
    • Jennes, L.1    Jennes, M.E.2    Purvis, C.3    Nees, M.4
  • 27
    • 0027519963 scopus 로고
    • Mandatory neuropeptide-steroid signaling for the preovulatory luteinizing hormone-releasing hormone discharge
    • [27] Kalra, S.P., Mandatory neuropeptide-steroid signaling for the preovulatory luteinizing hormone-releasing hormone discharge, Endocr. Rev., 14 (1993) 507-538.
    • (1993) Endocr. Rev. , vol.14 , pp. 507-538
    • Kalra, S.P.1
  • 28
    • 0023088671 scopus 로고
    • A1 noradrenergic input to medial preoptic-medial septal area: An electrophysiological study
    • [28] Kim, Y.I., Dudley, C.A. and Moss, R.L., A1 noradrenergic input to medial preoptic-medial septal area: an electrophysiological study, Neuroendocrinology, 45 (1987) 77-85.
    • (1987) Neuroendocrinology , vol.45 , pp. 77-85
    • Kim, Y.I.1    Dudley, C.A.2    Moss, R.L.3
  • 29
    • 0021325016 scopus 로고
    • The influence of progesterone and estradiol on the acute changes in pulsatile luteinizing hormone release induced by ovariectomy on diestrus day 1 in the rat
    • [29] Leipheimer, R.E., Bona-Gallo, A. and Gallo, R.V., The influence of progesterone and estradiol on the acute changes in pulsatile luteinizing hormone release induced by ovariectomy on diestrus day 1 in the rat, Endocrinology, 114 (1984) 1605-1613.
    • (1984) Endocrinology , vol.114 , pp. 1605-1613
    • Leipheimer, R.E.1    Bona-Gallo, A.2    Gallo, R.V.3
  • 30
    • 0021917727 scopus 로고
    • Medial preoptic area involvement in norepinephrine-induced suppression of pulsatile luteinizing hormone release in ovariectomized rats
    • [30] Leipheimer, R.E. and Gallo, R.V., Medial preoptic area involvement in norepinephrine-induced suppression of pulsatile luteinizing hormone release in ovariectomized rats, Neuroendocrinology, 40 (1985) 345-361.
    • (1985) Neuroendocrinology , vol.40 , pp. 345-361
    • Leipheimer, R.E.1    Gallo, R.V.2
  • 31
    • 0021812842 scopus 로고
    • Glutamic acid decarboxylase-containing axons synapse on LHRH neurons in the rat medial preoptic area
    • [31] Leranth, C., MacLusky, N.J., Sakamoto, H., Shanabrough, M. and Naftolin, F., Glutamic acid decarboxylase-containing axons synapse on LHRH neurons in the rat medial preoptic area, Neuroendocrinology, 40 (1985) 536-539.
    • (1985) Neuroendocrinology , vol.40 , pp. 536-539
    • Leranth, C.1    MacLusky, N.J.2    Sakamoto, H.3    Shanabrough, M.4    Naftolin, F.5
  • 32
    • 0019490762 scopus 로고
    • Electrical stimulation of the mesencephalic noradrenergic pathway-effects on LH levels in the blood of ovariectomized and ovariectomized-steroid primed rats
    • [32] Leung, P., Arendash, G., Whitmoyer, D., Gorski, R. and Sawyer, C.H., Electrical stimulation of the mesencephalic noradrenergic pathway-effects on LH levels in the blood of ovariectomized and ovariectomized-steroid primed rats, Endocrinology, 109 (1981) 720-728.
    • (1981) Endocrinology , vol.109 , pp. 720-728
    • Leung, P.1    Arendash, G.2    Whitmoyer, D.3    Gorski, R.4    Sawyer, C.H.5
  • 33
    • 0026808546 scopus 로고
    • Tyrosine hydroxylase mRNA levels increase in A1 but not locus coeruleus noradrenergic neurones in proestrus rats but not in dioestrus or androgen sterilised animals
    • [33] Liaw, J.J., He, J.R. and Barraclough, C.A., Tyrosine hydroxylase mRNA levels increase in A1 but not locus coeruleus noradrenergic neurones in proestrus rats but not in dioestrus or androgen sterilised animals, J. Neuroendocrinol., 4 (1992) 599-603.
    • (1992) J. Neuroendocrinol. , vol.4 , pp. 599-603
    • Liaw, J.J.1    He, J.R.2    Barraclough, C.A.3
  • 35
    • 0025470775 scopus 로고
    • 1-Adrenoceptor augmentation of β-stimulated cAMP formation is enhanced by estrogen and reduced by progesterone in rat hypothalamic slices
    • 1-Adrenoceptor augmentation of β-stimulated cAMP formation is enhanced by estrogen and reduced by progesterone in rat hypothalamic slices. J. Neurosci., 10 (1990) 2842-2849.
    • (1990) J. Neurosci. , vol.10 , pp. 2842-2849
    • Petitti, N.1    Etgen, A.M.2
  • 36
    • 0015820726 scopus 로고
    • Atlas of estradiol-concentrating cells in the central nervous system of the female rat
    • [36] Pfaff, D. and Keiner, M., Atlas of estradiol-concentrating cells in the central nervous system of the female rat, J. Comp. Neurol., 151 (1973) 121-158.
    • (1973) J. Comp. Neurol. , vol.151 , pp. 121-158
    • Pfaff, D.1    Keiner, M.2
  • 37
    • 0027295850 scopus 로고
    • Sexual stimulation activates c-fos within estrogen-concentrating regions of the female rat forebrain
    • [37] Pfaus, J.G., Kleopoulos, S.P., Mobbs, C.V., Gibbs, R.B. and Pfaff, D.W., Sexual stimulation activates c-fos within estrogen-concentrating regions of the female rat forebrain, Brain Res., 624 (1993) 253-267.
    • (1993) Brain Res. , vol.624 , pp. 253-267
    • Pfaus, J.G.1    Kleopoulos, S.P.2    Mobbs, C.V.3    Gibbs, R.B.4    Pfaff, D.W.5
  • 38
    • 0019430592 scopus 로고
    • Distribution of estrogen concentrating, neurophysin-containing magnocellular neurons in the rat hypothalamus as demonstrated by a technique combining stereoautoradiography and immunohistology in the same tissue
    • [38] Rhodes, C.H., Morrell, J.I. and Pfaff, D.W., Distribution of estrogen concentrating, neurophysin-containing magnocellular neurons in the rat hypothalamus as demonstrated by a technique combining stereoautoradiography and immunohistology in the same tissue, Neuroendocrinology, 33 (1981) 18-23.
    • (1981) Neuroendocrinology , vol.33 , pp. 18-23
    • Rhodes, C.H.1    Morrell, J.I.2    Pfaff, D.W.3
  • 39
    • 0027250911 scopus 로고
    • c-fos proto-oncogene activity induced by mating in the preoptic area, hypothalamus and amygdala in the female rat: Role of afferent input via the pelvic nerve
    • [39] Rowe, D.W. and Erskine, M.S., c-fos proto-oncogene activity induced by mating in the preoptic area, hypothalamus and amygdala in the female rat: role of afferent input via the pelvic nerve, Brain Res., 621 (1993) 25-34.
    • (1993) Brain Res. , vol.621 , pp. 25-34
    • Rowe, D.W.1    Erskine, M.S.2
  • 40
    • 0023891990 scopus 로고
    • Expression of c-fos protein in brain: Metabolic mapping at the cellular level
    • [40] Sagar, S.M., Sharp, F.R. and Curran, T., Expression of c-fos protein in brain: metabolic mapping at the cellular level, Science, 240 (1988) 1328-1331.
    • (1988) Science , vol.240 , pp. 1328-1331
    • Sagar, S.M.1    Sharp, F.R.2    Curran, T.3
  • 41
    • 0023690530 scopus 로고
    • 3H]ORG.2058, a synthetic progestin, and antibodies to tyrosine hydroxylase in hypothalamus by combined autoradiography and immunocytochemistry
    • 3H]ORG.2058, a synthetic progestin, and antibodies to tyrosine hydroxylase in hypothalamus by combined autoradiography and immunocytochemistry, Endocrinology, 123 (1988) 1110-1118.
    • (1988) Endocrinology , vol.123 , pp. 1110-1118
    • Sar, M.1
  • 42
    • 0020580616 scopus 로고
    • Absence of oestradiol concentration in cell nuclei of LHRH-immunoreactive neurones
    • [42] Shivers, B.D., Harlan, R.E., Morrell, J.I. and Pfaff, D.W., Absence of oestradiol concentration in cell nuclei of LHRH-immunoreactive neurones, Nature, 304 (1983) 345-347.
    • (1983) Nature , vol.304 , pp. 345-347
    • Shivers, B.D.1    Harlan, R.E.2    Morrell, J.I.3    Pfaff, D.W.4
  • 43
    • 0023864279 scopus 로고
    • The glucose oxidase-DAB-nickel method in peroxidase histochemistry of the nervous system
    • [43] Shu, S., Ju, G. and Fan, L., The glucose oxidase-DAB-nickel method in peroxidase histochemistry of the nervous system, Neurosci. Lett., 85 (1988) 169-171.
    • (1988) Neurosci. Lett. , vol.85 , pp. 169-171
    • Shu, S.1    Ju, G.2    Fan, L.3
  • 44
    • 0025232316 scopus 로고
    • Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: An in situ hybridization study
    • [44] Simerly, R.B., Chang, C., Muramatsu, M. and Swanson, L.W., Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: An in situ hybridization study, J. Comp. Neurol., 294 (1993) 76-95.
    • (1993) J. Comp. Neurol. , vol.294 , pp. 76-95
    • Simerly, R.B.1    Chang, C.2    Muramatsu, M.3    Swanson, L.W.4
  • 46
    • 0028247235 scopus 로고
    • Intraneuronal convergence of tactile and hormonal stimuli associated with female reproduction in rats
    • [46] Tetel, M.J., Celentano, D.C. and Blaustein, J.D., Intraneuronal convergence of tactile and hormonal stimuli associated with female reproduction in rats, J. Neuroendocrinol., 6 (1994) 211-216.
    • (1994) J. Neuroendocrinol. , vol.6 , pp. 211-216
    • Tetel, M.J.1    Celentano, D.C.2    Blaustein, J.D.3
  • 47
    • 0027184761 scopus 로고
    • Origin of noradrenergic projections to gnrh perikarya containing areas of the medial septum-diagonal band and preoptic area
    • [47] Wright, D.E. and Jennes, L., Origin of noradrenergic projections to GnRH perikarya containing areas of the medial septum-diagonal band and preoptic area, Brain Res., 621 (1993) 272-278.
    • (1993) Brain Res. , vol.621 , pp. 272-278
    • Wright, D.E.1    Jennes, L.2


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