%0 Journal Article %J Neurobiology of Disease %D 2017 %T Neuroendocrine signaling modulates specific neural networks relevant to migraine %A Martins-Oliveira, M. %A Akerman, S. %A Holland, P.R. %A Hoffmann, J.R. %A Tavares, I. %A Goadsby, P.J. %B Neurobiology of Disease %V 101 %P 16 - 26 %8 2017 %G eng %U https://www.scopus.com/inward/record.uri?eid=2-s2.0-85013073536&doi=10.1016%2fj.nbd.2017.01.005&partnerID=40&md5=649b845a03a224eb54437c14e68d4f0f %0 Journal Article %J Frontiers in Neuroanatomy %D 2017 %T Reticular formation and pain: The past and the future %A Martins, I. %A Tavares, I. %B Frontiers in Neuroanatomy %V 11 %8 2017 %G eng %U https://www.scopus.com/inward/record.uri?eid=2-s2.0-85029141878&doi=10.3389%2ffnana.2017.00051&partnerID=40&md5=989f93cd393e2ba0f89bf6eba1988bb1 %0 Journal Article %J Oncotarget %D 2017 %T TRPV1 in pain control from the brain %A Martins, D. %A Silva, M. %A Tavares, I. %B Oncotarget %V 8 %P 16101 - 16102 %8 2017 %G eng %U https://www.scopus.com/inward/record.uri?eid=2-s2.0-85014647057&doi=10.18632%2foncotarget.13316&partnerID=40&md5=6eb622bb3926c11b3bef339170e6113f %N 10 %0 Journal Article %J Frontiers in Aging Neuroscience %D 2016 %T Amidated and ibuprofen-conjugated kyotorphins promote neuronal rescue and memory recovery in cerebral hypoperfusion dementia model %A Santos, S.S. %A Santos, S.M. %A Pinto, A.R.T. %A Ramu, V.G. %A Heras, M. %A Bardaji, E. %A Tavares, I. %A Castanho, M.A.R.B. %B Frontiers in Aging Neuroscience %V 8 %8 2016 %G eng %U https://www.scopus.com/inward/record.uri?eid=2-s2.0-84960090988&doi=10.3389%2ffnagi.2016.00001&partnerID=40&md5=ae7d997d0849b7cd04de873e05806f3d %N JAN %0 Journal Article %J International Journal of Impotence Research %D 2016 %T Effects of prolonged ingestion of epigallocatechin gallate on diabetes type 1-induced vascular modifications in the erectile tissue of rats %A Lombo, C. %A Morgado, C. %A Tavares, I. %A Neves, D. %B International Journal of Impotence Research %V 28 %P 133 - 138 %8 2016 %G eng %U https://www.scopus.com/inward/record.uri?eid=2-s2.0-84966622126&doi=10.1038%2fijir.2016.19&partnerID=40&md5=9248b5a1dae6f8c6307360b896404d45 %N 4 %0 Journal Article %J ACS Chemical Neuroscience %D 2016 %T Endothelium-Mediated Action of Analogues of the Endogenous Neuropeptide Kyotorphin (Tyrosil-Arginine): Mechanistic Insights from Permeation and Effects on Microcirculation %A Perazzo, J. %A Lopes-Ferreira, M. %A Sá Santos, S. %A Serrano, I. %A Pinto, A. %A Lima, C. %A Bardaji, E. %A Tavares, I. %A Heras, M. %A Conceição, K. %A Castanho, M.A.R.B. %B ACS Chemical Neuroscience %V 7 %P 1130 - 1140 %8 2016 %G eng %U https://www.scopus.com/inward/record.uri?eid=2-s2.0-84983424711&doi=10.1021%2facschemneuro.6b00099&partnerID=40&md5=97025cf7c1482eb0e7f36321c514dce5 %N 8 %0 Journal Article %J Neuropharmacology %D 2016 %T Endovanilloid control of pain modulation by the rostroventromedial medulla in an animal model of diabetic neuropathy %A Silva, M. %A Martins, D. %A Charrua, A. %A Piscitelli, F. %A Tavares, I. %A Morgado, C. %A Di Marzo, V. %B Neuropharmacology %V 107 %P 49 - 57 %8 2016 %G eng %U https://www.scopus.com/inward/record.uri?eid=2-s2.0-84962223598&doi=10.1016%2fj.neuropharm.2016.03.007&partnerID=40&md5=181407b07a69c7ccda894a4535b0d34e %0 Journal Article %J MedChemComm %D 2016 %T Improvement of the pharmacological properties of amidated kyotorphin by means of iodination %A Oliveira, M.C. %A Gano, L. %A Santos, I. %A Correia, J.D.G. %A Serrano, I.D. %A Santos, S.S. %A Ribeiro, M. %A Perazzo, J. %A Tavares, I. %A Heras, M. %A Bardaji, E. %A Castanho, M.A. %B MedChemComm %V 7 %P 906 - 913 %8 2016 %G eng %U https://www.scopus.com/inward/record.uri?eid=2-s2.0-84971246172&doi=10.1039%2fc6md00028b&partnerID=40&md5=1fa0fe4c7eacfbcbaf69a83917cd8a3e %N 5 %0 Journal Article %J Pain %D 2016 %T Neuropeptide y inhibits the trigeminovascular pathway through NPY Y1 receptor: Implications for migraine %A Oliveira, M.-M. %A Akerman, S. %A Tavares, I. %A Goadsby, P.J. %B Pain %V 157 %P 1666 - 1673 %8 2016 %G eng %U https://www.scopus.com/inward/record.uri?eid=2-s2.0-84979693125&doi=10.1097%2fj.pain.0000000000000571&partnerID=40&md5=40a35dd44a88becb266c6a45ceed6cb5 %N 8 %0 Journal Article %J Neurobiology of Disease %D 2016 %T Pain modulation from the brain during diabetic neuropathy: Uncovering the role of the rostroventromedial medulla %A Silva, M. %A Costa-Pereira, J.T. %A Martins, D. %A Tavares, I. %B Neurobiology of Disease %V 96 %P 346 - 356 %8 2016 %G eng %U https://www.scopus.com/inward/record.uri?eid=2-s2.0-84991573920&doi=10.1016%2fj.nbd.2016.10.002&partnerID=40&md5=f0f01ee17a463cdae09264da9889957d %0 Journal Article %J Biopolymers - Peptide Science Section %D 2015 %T Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives %A Serrano, I.D. %A Ramu, V.G. %A Pinto, A.R.T. %A Freire, J.M. %A Tavares, I. %A Heras, M. %A Bardaji, E.R. %A Castanho, M.A.R.B. %B Biopolymers - Peptide Science Section %V 104 %P 1 - 10 %8 2015 %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-84922449755&partnerID=40&md5=26dce64d838eb5632b6ade19e03f59b7 %N 1 %0 Journal Article %J Stem Cell Research and Therapy %D 2013 %T Human neural stem cell transplantation in spinal cord injury models: How far from clinical application? %A Tavares, I. %B Stem Cell Research and Therapy %V 4 %8 2013 %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-84879118468&partnerID=40&md5=27ad4142d7083a7e199ebdc591533f0e %N 3 %0 Journal Article %J Neuropharmacology %D 2013 %T Noradrenaline increases pain facilitation from the brain during inflammatory pain %A Martins, I. %A De Vries, M.G. %A Teixeira-Pinto, A. %A Fadel, J. %A Wilson, S.P. %A Westerink, B.H.C. %A Tavares, I. %B Neuropharmacology %V 71 %P 299 - 307 %8 2013 %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-84878130625&partnerID=40&md5=2c9e8697aea7e25b920f90a054f75150 %0 Journal Article %J Brain Research Bulletin %D 2013 %T Pronociceptive changes in the activity of rostroventromedial medulla (RVM) pain modulatory cells in the streptozotocin-diabetic rat %A Silva, M. %A Amorim, D. %A Almeida, A. %A Tavares, I. %A Pinto-Ribeiro, F. %A Morgado, C. %B Brain Research Bulletin %V 96 %P 39 - 44 %8 2013 %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-84878458392&partnerID=40&md5=832084a317df0ed23f4e08640c52c527 %0 Journal Article %J Amino Acids %D 2013 %T Side-effects of analgesic kyotorphin derivatives: Advantages over clinical opioid drugs %A Ribeiro, M.M.B. %A Santos, S.S. %A Sousa, D.S.C. %A Oliveira, M. %A Santos, S.M. %A Heras, M. %A Bardaji, E. %A Tavares, I. %A Castanho, M.A.R.B. %B Amino Acids %V 45 %P 171 - 178 %8 2013 %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-84879218707&partnerID=40&md5=285240d80919c2c155b194faea27dc79 %N 1 %0 Journal Article %J Journal of Neuroscience Research %D 2012 %T Decrease in the expression of N-methyl-D-aspartate receptors in the nucleus tractus solitarii induces antinociception and increases blood pressure %A Marques-Lopes, J. %A Martins, I. %A Pinho, D. %A Morato, M. %A Wilson, S.P. %A Albino-Teixeira, A. %A Tavares, I. %B Journal of Neuroscience Research %V 90 %P 356 - 366 %8 2012/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-83155192218&partnerID=40&md5=1d8b60ea110c272c505cf50cb502ca99 %N 2 %0 Journal Article %J Neurobiology of Disease %D 2011 %T Changes in serotoninergic and noradrenergic descending pain pathways during painful diabetic neuropathy: The preventive action of IGF1 %A Morgado, C. %A Silva, L. %A Pereira-Terra, P. %A Tavares, I. %B Neurobiology of Disease %V 43 %P 275 - 284 %8 2011/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-79955945729&partnerID=40&md5=f7bee29800f0ebc8a4f470d662cb0861 %N 1 %0 Journal Article %J Molecular Pharmaceutics %D 2011 %T Chemical conjugation of the neuropeptide kyotorphin and ibuprofen enhances brain targeting and analgesia %A Ribeiro, M.M.B. %A Pinto, A.R.T. %A Domingues, M.M. %A Serrano, I. %A Heras, M. %A Bardaji, E.R. %A Tavares, I. %A Castanho, M.A. %B Molecular Pharmaceutics %V 8 %P 1929 - 1940 %8 2011/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-80053482714&partnerID=40&md5=de17983a1b842b8bc27b1635d6bd5b78 %N 5 %0 Journal Article %J Journal of Pain %D 2011 %T Does chronic pain alter the normal interaction between cardiovascular and pain regulatory systems? Pain modulation in the hypertensive-monoarthritic rat %A Pinho, D. %A Morato, M. %A Couto, M.R. %A Marques-Lopes, J. %A Tavares, I. %A Albino-Teixeira, A. %B Journal of Pain %V 12 %P 194 - 204 %8 2011/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-79551584750&partnerID=40&md5=0848e649f4bea9ba4051924f12222814 %N 2 %0 Journal Article %J British Journal of Pharmacology %D 2011 %T Inhibition of nociceptive responses after systemic administration of amidated kyotorphin %A Ribeiro, M.M.B. %A Pinto, A. %A Pinto, M. %A Heras, M. %A Martins, I. %A Correia, A. %A Bardaji, E. %A Tavares, I. %A Castanho, M. %B British Journal of Pharmacology %V 163 %P 964 - 973 %8 2011/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-79955630518&partnerID=40&md5=2ccced36d35d671b54085e7f909553e1 %N 5 %0 Journal Article %J Diabetes, Obesity and Metabolism %D 2011 %T Minocycline completely reverses mechanical hyperalgesia in diabetic rats through microglia-induced changes in the expression of the potassium chloride co-transporter 2 (KCC2) at the spinal cord %A Morgado, C. %A Pereira-Terra, P. %A Cruz, C.D. %A Tavares, I. %B Diabetes, Obesity and Metabolism %V 13 %P 150 - 159 %8 2011/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-78650633484&partnerID=40&md5=90b086f794d9333de354bfff7da9bf6f %N 2 %0 Journal Article %J European Journal of Pain %D 2011 %T Reversal of inflammatory pain by HSV-1-mediated overexpression of enkephalin in the caudal ventrolateral medulla %A Martins, I. %A Cabral, L. %A Pinto, A. %A Wilson, S.P. %A Lima, D. %A Tavares, I. %B European Journal of Pain %V 15 %P 1008 - 1014 %8 2011/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-80455164738&partnerID=40&md5=bde7b980b8fc0a6c2c5782866a1dc8bd %N 10 %0 Journal Article %J Diabetes, Obesity and Metabolism %D 2011 %T α-Lipoic acid normalizes nociceptive neuronal activity at the spinal cord of diabetic rats %A Morgado, C. %A Pereira-Terra, P. %A Tavares, I. %B Diabetes, Obesity and Metabolism %V 13 %P 736 - 741 %8 2011/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-79959411442&partnerID=40&md5=f84c2f0ac6c0aac699918634d5e181ff %N 8 %0 Journal Article %J Dor fetal: Mecanismos neurobiológicos e consequênciasActa Medica Portuguesa %D 2010 %T Fetal pain: Neurobiological causes and consequences %A Gonçalves, N. %A Rebelo, S. %A Tavares, I. %B Dor fetal: Mecanismos neurobiológicos e consequênciasActa Medica Portuguesa %V 23 %P 419 - 426 %8 2010/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-77958535772&partnerID=40&md5=08d7b3ffdffcc6ee7abe78f4f6f02171 %N 3 %0 Journal Article %J Brain Research %D 2010 %T The hyperalgesic effects induced by the injection of angiotensin II into the caudal ventrolateral medulla are mediated by the pontine A5 noradrenergic cell group %A Marques-Lopes, J. %A Pinho, D. %A Albino-Teixeira, A. %A Tavares, I. %B Brain Research %V 1325 %P 41 - 52 %8 2010/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-77949911938&partnerID=40&md5=1565b81e827dcee387133f036a759b81 %0 Journal Article %J European Journal of Pain %D 2010 %T Neuronal hyperactivity at the spinal cord and periaqueductal grey during painful diabetic neuropathy: Effects of gabapentin %A Morgado, C. %A Terra, P.P. %A Tavares, I. %B European Journal of Pain %V 14 %P 693 - 699 %8 2010/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-77955551014&partnerID=40&md5=8d7eadb31f26b66b152fa0f99511554c %N 7 %0 Journal Article %J Brain Research Reviews %D 2009 %T Descending control of nociception: Specificity, recruitment and plasticity %A Heinricher, M.M. %A Tavares, I. %A Leith, J.L. %A Lumb, B.M. %B Brain Research Reviews %V 60 %P 214 - 225 %8 2009/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-63449092750&partnerID=40&md5=35c2b06c8daa87065c6960be2f74c6cb %N 1 %0 Journal Article %J Neuroscience %D 2009 %T Microinjection of angiotensin II in the caudal ventrolateral medulla induces hyperalgesia %A Marques-Lopes, J. %A Pinto, M. %A Pinho, D. %A Morato, M. %A Patinha, D. %A Albino-Teixeira, A. %A Tavares, I. %B Neuroscience %V 158 %P 1301 - 1310 %8 2009/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-60149095326&partnerID=40&md5=004af738f3ba9f7af0d6ec0396ca59ba %N 4 %0 Journal Article %J Neuroscience Letters %D 2008 %T Diabetes affects the expression of GABA and potassium chloride cotransporter in the spinal cord: A study in streptozotocin diabetic rats %A Morgado, C. %A Pinto-Ribeiro, F. %A Tavares, I. %B Neuroscience Letters %V 438 %P 102 - 106 %8 2008/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-43549114243&partnerID=40&md5=ef72a8c9579521fe76fdac91cdd33dda %N 1 %0 Journal Article %J European Journal of Neuroscience %D 2008 %T Dynamic of migration of HSV-1 from a medullary pronociceptive centre: Antinociception by overexpression of the preproenkephalin transgene %A Martins, I. %A Pinto, M. %A Wilson, S.P. %A Lima, D. %A Tavares, I. %B European Journal of Neuroscience %V 28 %P 2075 - 2083 %8 2008/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-55949120169&partnerID=40&md5=1e32fff1d5944df9ace9ab6ac655aa46 %N 10 %0 Journal Article %J Molecular and Cellular Neuroscience %D 2008 %T Opioids modulate pain facilitation from the dorsal reticular nucleus %A Pinto, M. %A Castro, A.R. %A Tshudy, F. %A Wilson, S.P. %A Lima, D. %A Tavares, I. %B Molecular and Cellular Neuroscience %V 39 %P 508 - 518 %8 2008/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-56249149196&partnerID=40&md5=d5b65ab1dc8eb6bbe168373b7526fc3e %N 4 %0 Journal Article %J Journal of Comparative Neurology %D 2008 %T Participation of μ-opioid, GABAB, and NK1 receptors of major pain control medullary areas in pathways targeting the rat spinal cord: Implications for descending modulation of nociceptive transmission %A Pinto, M. %A Sousa, M. %A Lima, D. %A Tavares, I. %B Journal of Comparative Neurology %V 510 %P 175 - 187 %8 2008/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-50249092715&partnerID=40&md5=60eb5ef2b493f4f6ee00d359bbb2ca01 %N 2 %0 Journal Article %J Diabetes/Metabolism Research and Reviews %D 2007 %T C-fos expression at the spinal dorsal horn of streptozotocin-induced diabetic rats %A Morgado, C. %A Tavares, I. %B Diabetes/Metabolism Research and Reviews %V 23 %P 644 - 652 %8 2007/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-36749086568&partnerID=40&md5=a23926fb36d756d3d4c3cdee1ee9d237 %N 8 %0 Journal Article %J Journal of Anatomy %D 2007 %T From neuroanatomy to gene therapy: Searching for new ways to manipulate the supraspinal endogenous pain modulatory system %A Tavares, I. %A Lima, D. %B Journal of Anatomy %V 211 %P 261 - 268 %8 2007/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-34548020294&partnerID=40&md5=0a5b136a7ac38a8a3bbccd0676d4a88d %N 2 %0 Journal Article %J Neuroscience %D 2007 %T Neuronal activation at the spinal cord and medullary pain control centers after joint stimulation: A c-fos study in acute and chronic articular inflammation %A Pinto, M. %A Lima, D. %A Tavares, I. %B Neuroscience %V 147 %P 1076 - 1089 %8 2007/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-34547118578&partnerID=40&md5=3015dcf47a16ad95dc9c8b984b4a7927 %N 4 %0 Journal Article %J Neuroscience Letters %D 2006 %T Correlation of noxious evoked c-fos expression in areas of the somatosensory system during chronic pain: Involvement of spino-medullary and intra-medullary connections %A Pinto, M. %A Lima, D. %A Tavares, I. %B Neuroscience Letters %V 409 %P 100 - 105 %8 2006/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-33750378060&partnerID=40&md5=84e8f947c610ab3b53fb3c61c62ad441 %N 2 %0 Journal Article %J Brain Research Bulletin %D 2006 %T Differential expression of NK1 and GABAB receptors in spinal neurones projecting to antinociceptive or pronociceptive medullary centres %A Castro, A.R. %A Morgado, C. %A Lima, D. %A Tavares, I. %B Brain Research Bulletin %V 69 %P 266 - 275 %8 2006/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-33645061252&partnerID=40&md5=86cc606f5c88e5ecd3a80a40a5c84b10 %N 3 %0 Journal Article %J Journal of Neuroscience Research %D 2006 %T Inhibition of nociceptive responses of spinal cord neurones during hypertension involves the spinal GABAergic system and a pain modulatory center located at the caudal ventrolateral medulla %A Morato, M. %A Pinho, D. %A Sousa, T. %A Tavares, I. %A Albino-Teixeira, A. %B Journal of Neuroscience Research %V 83 %P 647 - 655 %8 2006/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-33644917111&partnerID=40&md5=307a7b9d8cdfbbb7816d25cd44d208d6 %N 4 %0 Journal Article %J Brain Research %D 2006 %T Lesion of the caudal ventrolateral medulla prevents the induction of hypertension by adenosine receptor blockade in rats %A Pinho, D. %A Sousa, T. %A Morato, M. %A Tavares, I. %A Albino-Teixeira, A. %B Brain Research %V 1073-1074 %P 374 - 382 %8 2006/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-33644948305&partnerID=40&md5=e5efe418a7849699519b6a0eabf3545b %N 1 %0 Journal Article %J Drug Discovery Today: Disease Mechanisms %D 2006 %T Medullary control of nociceptive transmission: Reciprocal dual communication with the spinal cord %A Almeida, A. %A Leite-Almeida, H. %A Tavares, I. %B Drug Discovery Today: Disease Mechanisms %V 3 %P 305 - 312 %8 2006/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-33847060105&partnerID=40&md5=819df6e6a93af5944b0ff0d8ec0766f8 %N 3 %0 Journal Article %J Neuroscience %D 2006 %T Secondary hyperalgesia in the monoarthritic rat is mediated by GABAB and NK1 receptors of spinal dorsal horn neurons: A behavior and c-fos study %A Castro, A.R. %A Pinto, M. %A Lima, D. %A Tavares, I. %B Neuroscience %V 141 %P 2087 - 2095 %8 2006/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-33747161263&partnerID=40&md5=a18a738c49a2a6eed50c76fb9fc20e98 %N 4 %0 Journal Article %J Neuroscience %D 2005 %T Imbalance between the expression of NK1 and GABAB receptors in nociceptive spinal neurons during secondary hyperalgesia: A c-Fos study in the monoarthritic rat %A Castro, A.R. %A Pinto, M. %A Lima, D. %A Tavares, I. %B Neuroscience %V 132 %P 905 - 916 %8 2005/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-18044366195&partnerID=40&md5=369d9a15878447ac480833d07774c5f4 %N 4 %0 Journal Article %J Medical Education %D 2004 %T The molecular metamorphosis of embryology: Implications for medical education %A Tavares, I. %B Medical Education %V 38 %P 544 %8 2004/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-2442567966&partnerID=40&md5=1ac4bf5e456007b6b1b98d0f817f04e6 %N 5 %0 Journal Article %J Brain Research %D 2004 %T Nociceptive spinal neurons expressing NK1 and GABAB receptors are located in lamina I %A Castro, A.R. %A Pinto, M. %A Lima, D. %A Tavares, I. %B Brain Research %V 1003 %P 77 - 85 %8 2004/// %G eng %U http://www.scopus.com/inward/record.url?eid=2-s2.0-1542298862&partnerID=40&md5=7c921c7a1eeaf335705477c98da58bcd %N 1-2