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Margaret B Allison Departments of Internal Medicine, and Molecular and Integrative Physiology, University of Michigan, 1000 Wall Street, 6317 Brehm Tower, Ann Arbor, Michigan 48105, USA

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Martin G Myers Jr Departments of Internal Medicine, and Molecular and Integrative Physiology, University of Michigan, 1000 Wall Street, 6317 Brehm Tower, Ann Arbor, Michigan 48105, USA

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specialized subsets of neurons in certain hypothalamic and brainstem nuclei ( Tartaglia 1997 , Elias et al . 2000 , Scott et al . 2009 , Patterson et al . 2011 ). Mutations that inactivate LepRb, as well as antagonists of LepRb activation, confirm that

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Martina Holubová Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic

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Jana Zemenová Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
Department of Analytical Chemistry, University of Chemistry and Technology, Prague, Czech Republic

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Barbora Mikulášková Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic

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Vladimíra Panajotova Apigenex Limited, Prague, Czech Republic

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Jiří Stöhr Apigenex Limited, Prague, Czech Republic

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Martin Haluzík First Faculty of Medicine, Charles University, Prague, Czech Republic

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Jaroslav Kuneš Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic

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Blanka Železná Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic

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Lenka Maletínská Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic

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nucleus and in A1/A2 regions of the medulla oblongata ( Yamada et al . 2009 ) in the brainstem. The fibers of these cells project to the paraventricular nucleus (PVN), the basal nucleus of the amygdala, and other regions throughout the brain ( Yamada et

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Elizabeth M Simpson School of Agricultural, Environmental and Veterinary Sciences, Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia
Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW, Australia

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Iain J Clarke School of Agriculture Food and Ecosystem Sciences, Faculty of Science, The University of Melbourne, Parkville, VIC, Australia

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Christopher J Scott School of Dentistry and Medical Science, Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia

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Cyril P Stephen School of Agricultural, Environmental and Veterinary Sciences, Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia
Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW, Australia

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Alexandra Rao School of Agriculture Food and Ecosystem Sciences, Faculty of Science, The University of Melbourne, Parkville, VIC, Australia

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Allan J Gunn School of Agricultural, Environmental and Veterinary Sciences, Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia
Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW, Australia

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diabetes mellitus ( Wang et al. 2022 ). There are various indications that GLP-1 may regulate the gonadotrophic axis, possibly at the level of the GnRH neurons. Brainstem-derived neural elements directly contact GnRH neurons in male mice ( Vastagh et

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Lourdes M Andino Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA

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Daniel J Ryder Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA

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Alexandra Shapiro Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA

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Michael K Matheny Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA

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Yi Zhang Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA
Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA

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Melanie K Judge Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA

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K Y Cheng Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA

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Nihal Tümer Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA
Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA

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Philip J Scarpace Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA
Departments of, Pharmacology and Therapeutics, Aging and Geriatrics, Department of Veterans Affairs Medical Center, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida 32610, USA

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the hypothalamus, particularly the arcuate nucleus (ARC) and the nucleus of the solitary track (NTS) in the brainstem ( DeBold et al . 1988 ). The cleaved peptides are released after the action of two proprotein convertases known as protein convertase

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Peixin Li Department of Comprehensive Surgery, Medical and Health Center, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
Human Performance Laboratory, College of Health and Human Performance, East Carolina University, Greenville, North Carolina, USA

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Zhijian Rao East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
Human Performance Laboratory, College of Health and Human Performance, East Carolina University, Greenville, North Carolina, USA
Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA

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Brenton Thomas Laing East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
Human Performance Laboratory, College of Health and Human Performance, East Carolina University, Greenville, North Carolina, USA
Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA

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Wyatt Bunner East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
Human Performance Laboratory, College of Health and Human Performance, East Carolina University, Greenville, North Carolina, USA
Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA

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Taylor Landry East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
Human Performance Laboratory, College of Health and Human Performance, East Carolina University, Greenville, North Carolina, USA
Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA

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Amber Prete East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA

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Yuan Yuan East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
Human Performance Laboratory, College of Health and Human Performance, East Carolina University, Greenville, North Carolina, USA

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Zhong-Tao Zhang Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, People’s Republic of China

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Hu Huang East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
Human Performance Laboratory, College of Health and Human Performance, East Carolina University, Greenville, North Carolina, USA
Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA
Department of Physiology, East Carolina University, Greenville, North Carolina, USA

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information from the gut to the brainstem ( Iggo 1957 ). Physical restructure of the stomach may result in the impairment of this signaling. Although it has been reported that the density of vagal afferents in the NTS and DMV is significantly elevated after

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T J Kowalski Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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B D Spar Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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L Markowitz Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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M Maguire Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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A Golovko Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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S Yang Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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C Farley Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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J A Cook Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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G Tetzloff Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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L Hoos Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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R A Del Vecchio Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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T M Kazdoba Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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M F McCool Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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J J Hwa Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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L A Hyde Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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H Davis Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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G Vassileva Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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J A Hedrick Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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E L Gustafson Department of CV/Metabolic Diseases,
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA

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.38 Brainstem 1.05, 0.15 1222, 993 2.05, 4.70 3.00, 4.40 8.09, 6.82 3.90, 5.10 Spinal cord 1.01, 0.53 564, 565 0.75, 1.04 0.47, 0.51 14.3, 9.21 5.11, 5.66 Table 3 Body weight, plasma leptin, insulin, glucose, corticosterone, triglycerides and free fatty

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Saadia Basharat
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Jennifer A Parker Division of Diabetes, University College London, Brunel University, Endocrinology and Metabolism, Department of Investigative Medicine, Imperial College London, Hammersmith Hospital Campus, 6th Floor, Commonwealth Building, Du Cane Road, London W12 0NN, UK

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Kevin G Murphy
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Stephen R Bloom
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Julia C Buckingham Division of Diabetes, University College London, Brunel University, Endocrinology and Metabolism, Department of Investigative Medicine, Imperial College London, Hammersmith Hospital Campus, 6th Floor, Commonwealth Building, Du Cane Road, London W12 0NN, UK

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Christopher D John
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JS Saper CB 1997 Leptin activates neurons in ventrobasal hypothalamus and brainstem . Endocrinology 138 839 – 842 . ( doi:10.1210/endo.138.2.5033 ) Gaillard RC Spinedi E Chautard T Pralong FP 2000 Cytokines, leptin, and the

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Donald Pfaff Laboratory of Neurobiology and Behaviour, Rockefeller University, 1230 York Avenue, New York, New York 10021, USA

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apparent redundancy between ascending NA and muscarinic cholinergic afferents to the hypothalamus helps to guarantee that the system will not fail, thus exemplifying a design characteristic prominent in brainstem arousal system neurobiology. In any case

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K Alexander H Iwen Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

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Oezge Senyaman Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

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Arne Schwartz Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

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Maren Drenckhan Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

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Britta Meier Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

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Dirk Hadaschik Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

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Johannes Klein Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

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tissue in vitro . Journal of Clinical Investigation 37 1549 – 1555 . Williams DL Bowers RR Bartness TJ Kaplan JM Grill HJ 2003 Brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein gene expression in brown fat

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T Nanmoku Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan

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K Takekoshi Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan

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T Fukuda Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan

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K Ishii Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan

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K Isobe Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan

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Y Kawakami Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan

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receptors have been reported to be expressed in numerous areas of the central nervous system (CNS), such as the hypothalamus and brainstem. Interestingly, PrRP has been colocalized with tyrosine hydroxylase (TH)-expressing medullary A1 and A2 neurons

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