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Sandra E. Rodriguez-Cruz, Ph.D. U.S. Department of Justice Drug Enforcement Administration Southwest Laboratory 2815 Scott Street Vista, CA 92081 [email: sandra.e.rodriguez-cruz -at- usdoj.gov]. Effects of Desipramine on NE Pressor Response and Myocardial NE Uptake Figure 1 summarizes the peak pressor responses to intravenous NE before and after desipramine treatment in both cardiac pacing and infusion protocol animals. NE injection caused an abrupt increase of blood pressure, which returned to the basal value within 3 min. It increased mean aortic pressure by 3540 mmHg in animals at baseline week 0 ; . The pressor response to NE was potentiated in animals after 8 wk of desipramine treatment. In contrast, the pressor response at week 8 did not differ from the baseline values in control animals receiving no desipramine. Figure 1 also shows that the magnitude of the pressor response to NE was smaller in desipramine-treated CHF and NE animals compared with their respective control sham and vehicle animals. The efficacy of desipramine on NE inhibition was also evidenced by the reduction of myocardial NE uptake activity Fig. 2 ; . Figure 2 also shows that compared with the sham-operated and vehicle-infused animals, myocardial NE uptake activity was reduced in the CHF and NE-infused animals without desipramine treatment. Resting Hemodynamics Table 1 shows the resting hemodynamics and plasma NE concentration in the pacing protocol aniDownloaded from ajpheart.physiology on March 15, 2008. That of the adult and that the lower total body catecholamine fractional extraction in the newborn was instead related to an immaturity of extraneuronal transporter mechanisms, a notion that will require formal testing with specific extraneuronal uptake blocking agents such as disprocynium24 13, 20 ; . In adult lungs, norepinephrine and epinephrine removal occurs via a transporter situated within the endothelial cells of the pulmonary microvasculature 6, 31 ; . However, despite its location at an extraneuronal site, this transporter is not only inhibited by specific inhibitors of neuronal catecholamine uptake such as desipramine 6, 14 ; but also has an amino acid sequence identical to the neuronal catecholamine transporter 5 ; . Two findings of the present study point to a close functional similarity between the catecholamine transporter in the newborn and adult lungs. First, in accord with the two- to fourfold difference seen in adult lungs 14, 19 ; , pulmonary norepinephrine clearance in newborn lambs was 2.3-fold more efficient than for epinephrine. Second, as in adult dogs 14 ; , desipramine reduced pulmonary [3H]norepinephrine and [3H]epinephrine extractions in newborn lambs to undetectable levels Fig. 4 ; . Collectively, these results suggest that, in contrast to the major roles of both neuronal and extraneuronal uptake processes in the systemic circulation 10, 12, 13, ; , removal of circulating catecholamines by the lungs occurs primarily via the neuronal-like uptake mechanism located within the pulmonary microvasculature 6, 31 ; . Although the basis for this difference is not fully understood at present, a likely contributory factor is the differing spatial arrangement of uptake mechanisms at these two sites, in that the pulmonary catecholamine transporter resides on the diffusional endothelial surface 31 ; , whereas catecholamines in systemic tissues are exposed to extraneuronal uptake mechanisms en route to the neuronal transporter situated on perivascular and parenchymal sympathetic elements 17 ; . In addition to its inhibitory effect on neuronal uptake processes, desipramine also acts centrally to reduce sympathetic outflow 15 ; , an action accompanied by a marked reduction in sympathetic nerve activity to organs such as skeletal muscle 18 ; and the kidney 15, 41 ; . As most of the norepinephrine released by sympathetic nerves is recaptured, an effect of desipramine on neuronal uptake alone would increase the norepinephrine concentration at the neuroeffector junction and thereby result in a greater spillover of norepinephrine into plasma 17 ; . However, norepinephrine spillover in normal adult humans and animals is either unchanged 14, 15, 20, ; or reduced by 1336% after desipramine 18, 28, 40 ; , indicating that the two actions of this compound either counteract one another or slightly favor central sympathoinhibition. In contrast, desipramine caused a 56% reduction in the total body spillover of norepinephrine in newborn lambs Fig. 3 ; , an observation that not only suggests that this agent exerted a predominant central sympathoinhibitory effect in the newborn, but also supports an important role for. Abstract high-affinity binding of desipramine to rat brain: a presynaptic marker for noradrenergic uptake sites rehavi * * clinical psychobiology branch, nimh; national institutes of health, bethesda, maryland, a.
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Steady-state determinations; venipuncture is performed in the facility's clinical laboratory, with use of a vacuum container system Venoject KT200LH ; proven not to contain interfering plasticizers in the rubber stopper; samples are rapidly centrifuged and the plasma is stored in Teflon-capped glass tubes; plasma is stored at room temperature but protected from light; and samples are shipped by mail and analyzed within two to three days of collection. The standard data-collection form, required to be completed before assay, contains the following information: patient demographics age, gender, weight, race, smoking history medical and psychiatric diagnoses based on the Diagnostic and Statistical Manual, 3rd edition, revised; complete medication history for at least the past week, including dosing history for the agent to be assayed and all concomitant medications; and the Clinical Global Impressions Rating Scale. Outpatient data, primarily from the one county facility, are included in the data set, but 80% of all concentrations are measured in inpatients, who are receiving their medications from the facility's nursing service. Data are stored in a microcomputer data base and are available for downloading. The TCAs are analyzed by a validated "high-performance" thin-layer chromatographic method developed by The University of Texas Mental Sciences Institute 11 ; . Sensitivities by this method are as low as 5 ng for desipramine ; . The standard curves used for routine analysis are linear from 5 to 200 ng mL. Between-day coefficients of variation CVs ; are 6% from 25 ng mL 200 ng mL. For in situ quantification of the developed chromatographic plates we used a Zeiss or a Shimadzu scanning densitometer. Measurements were made in the reflectance mode for ultraviolet absorption. A deuterium light source was used with a monochromator and set to the optimum wavelength for each TCA. Figure 2 illustrates the mean of and standard deviation for Cpss of IM.! plus desipramine DM1 ; in 25 patients from whom two or more samples were obtained at the same dosage of IMI. These data illustrate the reproducibility of the assay under field-test conditions, because variability in the observed concentrations is the result of patient-specific variables e.g., compliance, potential timing errors by nursing stafi ; as well as the variability inherent in the assay. The data were analyzed with a Macintosh U# microcomputer with 68020 and 68881 processors, with use of StatView 512K plus# , Microsoft Excel# and spreadsheet. They were plotted by using MacDraw# , ricket Graph# , C and ensuring. A boy of 10 earuing .10 n-eek bought hi-q, a clotlres. put 10 cents a wceh il the school bank, sperrt 10 cents " for a show, " and gave the rest to his family, The 1Z-year-oi isou of a plumber earned .55 selling papers, and magazines. He gave some of bis money to his mother' " to use fol dre- s, "saved 10' cents a n'eek, spent 20 cents a rveek ol his orvn pleasures, and bought mjlk and r-, oughnuts once a \t.eel dorvn ton-n while he nas -selliagpepers. A 10-year-old -Syrian boy, whc-sefatiler \ras an autcxrrobileneclianic. t, arnerl .60 a v'eek. He had becn selling papets for a month, and hatl 91.3i in the 'bought school balk. He solne of his clothes. contributed some money to the family, anrl had 10 cents ir week " for shotls." A 13-year-old boy aird his two brothers earnetl .50a neek selling papers. They bought dinner and supper on Saturday and breakflst on Sunday at restaurarits and paid their carfare to the do$'n-tos-n clistrict r, vherethey sold papers. The rest of their money $'as used foI: family expen-ses. " We're poor, and mother can't give us any to spend, " the boys said. 'l'he father, a laborer, was frequeutly out of rvork, and the family had received aid during the year from the Associated Charities, A 15-year-okl Italian boy vhose faiher was a laborer and whose fnmiiy had beet assisteclby charity saial that he contrilruted all his earnings 93 a rveek ; towarrl family experrses, becausq as he s: rid, " I tlon't r!'ant any spending mongJi." A 13-year-old boy, son of a Russian-Jewish manufacturer, earned about a week selling and carrying papers. IIe contributed none of his earnings tonard the support of the family but helped to buy his own clothes, put g5 a rveek in the bank, and had 75 cents for spending money. The 14-year-old son of a Russian-Jewish hotel keeper earnecl 913.75 a week. IIe spent all his morey for himself-ciothes. shorvs, and meals rlorvn tor.vn when he sold late. A 12-year-old l-roywhose sister, a stenographer, nas the chief support of the family, earned .45a week selling and carlying papers. FIe spent 50 cents a n'eek on moyies and candy and sometimes bought doughnuts and fruit when selling clown to\yn, but gave tbe rest of his money to the family. IIe hatl hacl in the bank but had drawn it out to help pay rent. A Russian-Jewish boy earning .65 a weeh said that he sornetimes gave a small sum to iis mother but spent most of it. The father n'as a traveling salesman, and the family lived in a good neighborhood in a comfortable frame house with gugh q6mf6rts and luxuries as French doors, a sun parlor, and electric lights, The boy, thougb only 12 years of age, had a juvenile-court record and was reportecl as unmanageable. IIe sold papers nntil 10.30 Saturday night, in spite of his mother's objections. A boy of 14 whose mother was a widow earned .10 a week. IIe said that he gave his money to his mother for his cloihes, except what he spent on motion pictures. EIis mother , saidthat he used his uroney for his clothe, s, school lunches, amusements, and srrvings. " I hardly get a week from him, " she said. " But I going to pin him dorrn soon and -ceeif I can get urore help from him, becauseI need it." The 10-year-old son of a Poli-sh Jew rr'ho kept a grocery store, earnecl .75 a \'!'eek. After six months of selling he had in one balk anci in tire school bank, and he bought ail his clothes. His pal'eDts colroborated his statement and dextroamphetamine.

Desipramine has also been reported to enhance the anorectic effects of d-amphetamine, phentermine, and diethylpropion, but did not modify those of phenmetrazine and chlorphentermine. Is suicidal, abuse, or malicious intent suspected? NO Is the home situation of concern? e.g., patient lives alone or family caregiver seems unreliable ; NO Is the patient symptomatic? e.g., weak, drowsy, dizzy, tremulous, palpitations ; NO Have more than 6 hours elapsed since the TCA ingestion and the patient is still asymptomatic? NO Does the patient have significant underlying cardiovascular or neurological disease, or is he she taking a cardiodepressant drug or MAO inhibitor? NO Can you estimate the maximum amount ingested? YES Has the patient ingested a potentially toxic dose? * Amitriptyline 5 mg kg Clomipramine 5 mg kg Desipramine 2.5 mg kg Doxepin 5 mg kg Doxepin cream 5 mg kg Imipramine 5 mg kg Nortriptyline 2.5 mg kg Protriptyline 1 mg kg Trimipramine 2.5 mg kg NO Observe at home. Instruct caller to call poison center back if symptoms appear. Consider poison center-initiated follow-up within 4 hours of initial call. Consider referral to emergency services should new symptoms develop and dextromethorphan.
Trial subjects, sedation was common and hypotension was observed in some subjects. Guanfacine. A 2004 retrospective chart review9 by Posey and colleagues found some benefit from guanfacine for children and adolescents with PDDs. The review of 80 subjects, aged 3 to 18 years, included 46 patients with autistic disorder, 6 patients with Asperger's disorder, and 28 patients with PDD not otherwise specified PDD-NOS ; . Taking an average dose of 2.6 mg day, 23.8% of subjects responded to guanfacine, showing improvements in hyperactivity, inattention, insomnia, and tics. Patients with Asperger's or PDD-NOS responded more often 38% ; than patients with autistic disorder 13% ; , and patients with comorbid mental retardation responded at a lower rate 18% ; than those patients without comorbid mental retardation 38% ; . Transient sedation was common among subjects taking guanfacine; hypotension was not reported as an adverse effect. Antidepressants Tricyclic antidepressants. In a 1966 study10 of nortriptyline in 10 autistic children, Kurtis found some benefit for hyperactivity, aggressiveness, and antisocial behavior. Some subjects experienced side effects of restlessness, confusion, and weight gain. A 1971 study11 of imipramine in preschool children by Campbell and colleagues found that it was generally unsuitable for treatment of autism and that it was not well tolerated. In 1994, a case study12 of imipramine in a patient with Asperger's disorder described marked improvement; however, it was unclear whether the imipramine was treating the symptoms associated with Asperger's disorder or an accompanying mood or anxiety disorder. Clomipramine. The use of the serotonin reuptake blocker clomipramine to treat children and adults with PDDs has been met with varying success and adverse effects. In a study13 of 35 adults with PDDs, clomipramine reduced total repetitive thoughts and behaviors as well as aggression and improved some aspects of social relatedness including eye contact and verbal responsivity ; in 18 subjects 51% ; . However, seizures did occur in 3 subjects, including 2 subjects with a history of seizures who were taking anticonvulsants. A study14 of 24 autistic subjects aged 6 to 18 years found clomipramine to be superior to placebo and the antidepressant desipramine in improving autistic symptoms, anger, and compulsive and ritualized behaviors. Clomipramine and desipramine were equally efficacious and superior to placebo in reducing hyperactivity. A study15 of young autistic patients 3 to 8 years of age found that clomipramine was not therapeutic for autism and produced adverse effects such as sedation and a worsening of behaviors such as aggression, irritability, and hyperactivity. Clomipramine appears to be less well tolerated and less effective in younger children than in adults or adolescents.

Desipramine msds CONTRAINDICATIONS: Glaucoma, urethral or ureteral spasm, recent myocardial infarction, severe coronary heart disease, epilepsy. 5hould not be given within two weeks of treatment with a monoamine oxidase inhibitor. RELATIVE CONTRAINDICATIONS: 1 ; Patients with a history of paroxysmal tachycardia. 2 ; Patients receiving concomitant therapy with thyroid, anticholinerqics or sympathomimetics may experience potentiation of effects of these drugs. 3 ; Safety in pregnancy has not been established. 4 ; Perform liver function studies in patients suspect of having hepatic disease. PRECAUTIONS: 1 ; Desipramine hydrochloride and diamox. 10 Rao ML, Ruhrmann S, Retey B, Liappis N, Fuger J, Kraemer M, Kasper S & Moller HJ. Low plasma thyroid indices of depressed patients are attenuated by antidepressant drugs and influence treatment outcome. Pharmacopsychiatry 1996 29 5 ; 180186. 11 Baumgartner A, Graf KJ, Kurten I & Meinhold H. The hypothalamicpituitarythyroid axis in psychiatric patients and healthy subjects: Parts 14. Psychiatry Research 1988 24 3 ; 271332. 12 Hoflich G, Kasper S, Danos P & Schmidt R. Thyroid hormones, body temperature, and antidepressant treatment. Biological Psychiatry 1992 31 8 ; 859862. 13 Strieder TG, Prummel MF, Tijssen JG, Endert E & Wiersinga WM. Risk factors for and prevalence of thyroid disorders in a crosssectional study among healthy female relatives of patients with autoimmune thyroid disease. Clinical Endocrinology Oxf ; 2003 59 3 ; 396401. 14 Bianco AC, Salvatore D, Gereben B, Berry MJ & Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocrine Reviews 2002 23 1 ; 3889. 15 Eravci M, Pinna G, Meinhold H & Baumgartner A. Effects of pharmacological and nonpharmacological treatments on thyroid hormone metabolism and concentrations in rat brain. Endocrinology 2000 141 3 ; 10271040. 16 Baumgartner A, Dubeyko M, Campos-Barros A, Eravci M & Meinhold H. Subchronic administration of fluoxetine to rats affects triiodothyronine production and deiodination in regions of the cortex and in the limbic forebrain. Brain Research 1994 635 12 ; 6874. 17 Campos-Barros A, Meinhold H, Stula M, Muller F, Kohler R, Eravci M, Putzien O & Baumgartner A. The influence of desipramine on thyroid hormone metabolism in rat brain. Journal of Pharmacology and Experimental Therapeutics 1994 268 3 ; 11431152. 18 Atterwill CK. Effect of acute and chronic tri-iodothyronine T3 ; administration to rats on central 5-HT and dopamine-mediated behavioural responses and related brain biochemistry. Neuropharmacology 1981 20 2 ; 131144. 19 Schneider MJ, Fiering SN, Pallud SE, Parlow AF, St Germain DL & Galton VA. Targeted disruption of the type 2 selenodeiodinase gene DIO2 ; results in a phenotype of pituitary resistance to T4. Molecular Endocrinology 2001 15 12 ; 21372148. 20 Mentuccia D, Proietti-Pannunzi L, Tanner K, Bacci V, Pollin TI, Poehlman ET, Shuldiner AR & Celi FS. Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor. Diabetes 2002 51 3 ; 880883. 21 Peeters RP, van Toor H, Klootwijk W, de Rijke YB, Kuiper GG, Uitterlinden AG & Visser TJ. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. Journal of Clinical Endocrinology and Metabolism 2003 88 6 ; 28802888. 22 Appelhof BC, Brouwer JP, Van Dyck R, Fliers E, Hoogendijk WJ, Huyser J, Schene AH, Tijssen JG & Wiersinga WM. Triiodothyronine addition to paroxetine in the treatment of major depressive disorder. Journal of Clinical Endocrinology and Metabolism 2004 89 12 ; 62716276. 23 Diagnostic and Statistical Manual of Mental Disorders. 4th edn: DSM-IV. ed. Washington, D.C: American Psychiatric Association, 1994. 24 Heuser I, Yassouridis A & Holsboer F. The combined dexamethasone CRH test: a refined laboratory test for psychiatric disorders. Journal of Psychiatric Research 1994 28 4 ; 341356. 25 Rush AJ, Giles DE, Schlesser MA, Orsolak PJ, Weissenburger JE, Folton CL, Fairchild CJ & Roffwarg HP. Dexamethasone response, thyrotropin-releasing hormone stimulation, rapid eye movement latency, and subtypes of depression. Biological Psychiatry 1997 41 9 ; 915928. Of the 27.4 key X-ray by overlying bone, I scans of with I's' uptake studies. A pulse and dicloxacillin.

Desipramine pills 1. McNeill W. Plagues and Peoples. New York: Doubleday, 1977: 340. 2. Lane J, Goldstein J. Evaluation of 21st-century risks of smallpox vaccination and policy options. Ann Intern Med. 2003 Mar 18; 138 6 ; : 488-93. 3. Henderson DA, Inglesby TV, Bartlett JG, Ascher MS, Eitzen E, Jahrling PB, Hauer J, Layton M, McDade J, Osterholm MT, O'Toole T, Parker G, Perl T, Russell PK, Tonat K. Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 1999; 281: 2127-2137. Gross CP, Sepkowitz KA. The myth of the medical breakthrough: smallpox, vaccination, and Jenner reconsidered. Int J Infect Dis 1998; 3: 54-60. Radetsky M. Smallpox: a history of its rise and fall. Pediatr Infect Dis J 1999; 18: 85-93. Preston R. The Demon in the Freezer. New York: Random House, 2002: 233. 7. Henderson DA. The eradication of smallpox. Sci 1976; 235: 25-33. Hough T, Sedgwick W. The human mechanism: Its physiology and hygiene and the sanitation of its surroundings. Boston: Ginn & Company, 1906: 564. 9. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization, 1988: 1460. Reference out-of-print. See the World Health Organization, Communicable Disease Surveillance and Response Web site. Available at: who.int emc diseases. Desipramine and add HCV therapy may cause significant adverse effects. IFN reduces total white blood cell counts, and can cause neutropenia. It also decreases CD4 cell counts, although the CD4 percentage usually does not change. IFN can reduce HIV RNA somewhat approximately a 0.5 log10 decrease ; . IFN may also produce flulike symptoms, depression, peripheral neuropathy, and other symptoms. Ribavirin can cause anemia and other adverse effects. Zidovudine and didanosine should be avoided, if possible, in patients taking HCV treatment. HCV treatment should not be given during pregnancy, and women receiving HCV treatment should avoid and diflunisal. Increasing serotonin levels in the nerve synapses eg, tricyclic antidepressants [TCAs], such as amitriptyline [Elavil], imipramine [Tofranil], and desipramine [Norpramin], and the selective serotonin reuptake inhibitors [SSRIs], such as citalopram [Celexa], fluoxetine [Prozac], paroxetine [Paxil], sertraline [Zoloft], and escitalopram [Lexapro] ; . Use of these drugs has become increasingly widespread. However, some patients are nonresponsive or respond slowly to these medications, while other patients may develop serious side effects eg, serotonin syndrome, cardiac dysrhthmias, hypotension, convulsions, CNS depression, or worsening of depression ; . Antidepressant drug selection may be more effectively guided by pharmacogenetic testing. Molecular tests are currently available for genes encoding the hepatic enzymes responsible for drug metabolism cytochrome P450 enzymes ; , for the serotonin receptor, and for the serotonin transporter.1 and desipramine.

Yes. k m e wqmerr have nausea, vomiting, dizziness, headache, breast knderne% abdominal pain, or a , heavieror lighter: mensmalperiod, Nausea and vomiting are most commoa. Wth combined pills about 20% of women vomit With progestin-only Dflls and dihydroergotamine.

Tolerability of these agents. Of the TCAs, desipramine has the lowest risk of antihistamine effects. TCAs are moderate antagonists of the muscarinic acetylcholine receptors as well as the 1-adrenergic receptors. Central and peripheral effects associated with anticholinergic activity include memory impairment, increased heart rate 1020 beats per minute ; , dry mouth, blurred vision, constipation, and urinary retention. Hypotensive effects associated with peripheral 1-adrenergic inhibition may cause orthostasis, dizziness, and syncope. Central and peripheral effects on the cholinergic and adrenergic systems are often most profound in the elderly, and dose adjustments should be made for patients older than age 65. The effect of TCAs on sodium channels in the heart can cause prolongation of the QT interval at therapeutic doses. This effect is similar to the action of type Ia antiarrhythmic medications such as quinidine. TCAs should be avoided in persons treated with antiarrhythmic med-ications. High-dose tricyclic therapy may precipitate first degree heart block and may be proarrhythmic in susceptible patients. TCAs are very dangerous in overdose due to accelerated heart rate associated with anticholinergic effects and delayed conduction in the myocardium due to blockade of sodium channels. These combined effects have led to fatal arrhythmias. Seizures seen in overdose may also be related to sodium channel blockade. The future of healthcare requires a partnership among all those who are devoted to preventing illness in the healthy and restoring health in the ill. No one approach, therapy, or model will work for all people or illnesses. We must work together, across philosophical and other divides, to find productive solutions and dilaudid.

Selected References Farkas, D. F. 1984 ; "Subjunctive Complements in Rumanian, " in P. Baldi, ed., Papers from the XIIth Linguistic Symposium on Romance Languages, Amsterdam Philadelphia, John Benjamins Publishing Company, 355372. Farkas, D. F. 1992 ; "On the Semantics of Subjunctive Complements, " in H. Hirschbhler and K. Koerner, eds., Romance Languages and Modern Linguistic Theory, Papers from the XX LSRL, Ottawa, 1990, John Benjamins, Amsterdam, 69104. Horn, L. R. 1993 ; "Economy and Redundancy in a Dualistic Model of Natural Language, " in S. Shore and M. Vilkuna, eds., SKY 1993: Yearbook of the Linguistic Association of Finland, 3372. Meireles, J. A., and E. Raposo 1992 ; "Tense and Binding Theory in Portuguese, " in D. P. Macedo and D. A. Koike, eds., Romance Linguistics: The Portuguese Context, Bergin & Garvey, Westport, CT, 217238. Quer, J. 1998 ; Mood at the Interface, Doctoral dissertation, Utrecht Institute of Linguistics OTS. Rivero, M.-L. 1971 ; "Mood and Presupposition in Spanish, " Foundations of Language 7, 305336. Rivero, M.-L. 1991 ; "Exceptional Case Marking Effects in Rumanian Subjunctive Complements, " in D. Wanner and D. A. Kibbee, eds., New Analyses in Romance Linguistics, Benjamins, Amsterdam, 273298. Villalta, E. 2000 ; "Spanish Subjunctive Clauses Require Ordered Alternatives, " in B. Jackson and T. Matthews, eds., Proceedings of Semantics and Linguistic Theory SALT ; X, Ithaca, NY, Cornell University, 239256 and dionex.

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