bluuebunny/crossref_metadata_2025_split huggingface dataset:
The critical role of leukotriene B4 in antigen‐induced mechanical hyperalgesia in immunised rats
Authors: Cunha Joice Maria , Sachs Daniela , Canetti Claudio Azevedo , Poole Stephen , Ferreira Sérgio Henrique , Cunha Fernando Queiroz 
Published: July 2003

We investigated the mediators responsible for mechanical hypersensitivity induced by antigen challenge in rats immunised with ovalbumin (OVA).
Challenge with OVA (12.5–100 μg, intraplantar) caused a dose‐ and time‐dependent mechanical hypersensitivity, which peaked 3 h after, decreased thereafter and reached control levels 24 h later.
Levels of TNFα, IL‐1β and cytokine‐induced neutrophil chemoattractant 1 (CINC‐1) were increased in paw skin after antigen challenge.
OVA‐evoked hypersensitivity was partially inhibited (about 51%) by pretreatment with anti‐TNFα, IL‐1β and IL‐8 sera or with IL‐1 receptor antagonist (IL‐1ra), but not anti‐NGF serum. Pretreatment with thalidomide (45 mg kg−1) or pentoxifylline (100 mg kg−1) also partially inhibited the hypersensitivity at 1–3 h after challenge.
Pretreatment with indomethacin (5 mg kg−1) or atenolol (1 mg kg−1) reduced the OVA‐induced hypersensitivity at 1 and 3 h, but not at 5 h after challenge, while the combination of B1 and B2 bradykinin receptor antagonists was ineffective over the same times.
Pretreatment with MK886 (5‐lipoxygenase‐activating protein inhibitor, 3 mg kg−1), CP 105696 (LTB4 receptor antagonist; 3 mg kg−1) or dexamethasone (0.5 mg kg−1) inhibited the hypersensitivity from 1 to 5 h. Furthermore, LTB4 levels were increased in the paw skin of challenged rats.
In conclusion, our results suggest that the TNFα‐, IL‐1β‐ and CINC‐1‐driven release of prostaglandins, sympathetic amines and LTB4 mediates the first 3 h of mechanical hypersensitivity induced by antigen challenge in rats. At 5 h after OVA administration, although TNFα has some role, LTB4 is the critical nociceptive mediator.

British Journal of Pharmacology (2003) 139, 1135–1145. doi:10.1038/sj.bjp.0705346
Delphinidin, an active compound of red wine, inhibits endothelial cell apoptosis via nitric oxide pathway and regulation of calcium homeostasis
Authors: Martin Sophie , Giannone Grégory , Andriantsitohaina Ramaroson , Carmen Martinez M 
Published: July 2003

Epidemiological studies have suggested that moderate consumption of natural dietary polyphenolic compounds might reduce the risk of cardiovascular disease and also protect against cancer. The present study investigates the effects of delphinidin, an anthocyanin present in red wine, on bovine aortic endothelial cells apoptosis.
Based on flow cytometry, terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling analysis and detection of mitochondrial cytochrome c release, we show that delphinidin (10−2 g l−1) alone had no effect either on necrosis or on apoptosis, but it significantly reduced apoptosis elicited by actinomycin D (1 μg ml−1, 24 h) and 7β‐hydroxycholesterol (10 μg ml−1, 18 h).
The protective effect of delphinidin was abolished by inhibitors of nitric oxide‐synthase (NOS) (L‐NA, 100 μM and SMT, 100 μM), guanylyl cyclase (ODQ, 100 μM) and MAP kinase (PD98059, 30 μM).
Western blot analysis and protein detection by confocal microscopy demonstrate that the antiapoptotic effect of delphinidin was associated with an increased endothelial NOS expression mediated by a MAP kinase pathway.
Finally, delphinidin alone had no effect on cytosolic‐free calcium ([Ca2+]i), but normalized the changes in [Ca2+]i produced by actinomycin D towards the control values, suggesting that the antiapoptotic effect of delphinidin is associated with the maintenance of [Ca2+]i in the physiological range.
All of the observed effects of delphinidin may preserve endothelium integrity, the alteration of which lead to pathologies including cardiovascular diseases, such as atherosclerosis, and is often associated with cancers. In conclusion, the protective effect of delphinidin against endothelial cell apoptosis contributes to understand the potential benefits of a consumption rich in polyphenols.

British Journal of Pharmacology (2003) 139, 1095–1102. doi:10.1038/sj.bjp.0705347
Acetylcholine and tachykinins involvement in the caffeine‐induced biphasic change in intracellular Ca2+ in bovine airway smooth muscle
Authors: Montaño Luis M , Carbajal Verónica , Arreola José L , Barajas‐López Carlos , Flores‐Soto Edgar , Vargas Mario H 
Published: July 2003

Caffeine has been widely used as a pharmacological tool to evaluate Ca2+ release from the sarcoplasmic reticulum in isolated smooth muscle cells. However, in nervous tissue this drug also causes neurotransmitters release, which might cause additional effects when smooth muscle strips are evaluated. To assess this last possibility, simultaneous measurements of contraction and cytosolic Ca2+ concentration (using Fura–2/AM) were carried out in bovine airway smooth muscle strips during caffeine stimulation.
A first stimulation (S1, n=11) with caffeine (10 mM) induced a biphasic change in cytosolic Ca2+, which consisted of a transient Ca2+ peak (254±40 nM, X±SEM) followed by a plateau (92±13 nM), and a transient contraction (204.72±31.56 mg tension mg tissue−1). A second caffeine stimulation (S2) produced a similar response but these parameters had a different magnitude. The S2/S1 ratios for these parameters were 0.69±0.02, 0.83±0.06 and 1.01±0.03, respectively. Addition of ω‐conotoxin GVIA (1 μM) and tetrodotoxin (3.1 μM) before S2 significantly diminished these S2/S1 ratios (0.26±0.05, 0.26±0.09 and 0.64±0.11, respectively, n=5, P<0.05), implicating the neurotransmitters release involvement in the response to caffeine. A similar effect (P<0.01) was observed with atropine (1 μM, n=4), the fragment 4–11 of substance P (SP) (an SP receptor antagonist, 10 μM, n=5), and with both substances (n=4).
We discarded a direct effect of ω‐conotoxin GVIA (1 μM) plus tetrodotoxin (3.1 μM) or of atropine (1 μM) plus SP fragment 4–11 on smooth muscle cells because they did not modify caffeine responses in isolated tracheal myocytes.
We confirmed by HPLC that caffeine increased the release of acetylcholine (from 0.43±0.19 to 2.07±0.56 nM mg tissue−1, P<0.02) in bovine airway smooth muscle strips. Detection of substance P by ELISA was not statistically different after caffeine stimulation (geometric means before and after caffeine, 0.69 vs. 1.97 pg ml−1 mg tissue−1, respectively, P=0.053).
We concluded that acetylcholine and tachykinins release are involved in the caffeine‐induced biphasic changes in cytosolic Ca2+ concentration.

British Journal of Pharmacology (2003) 139, 1203–1211. doi:10.1038/sj.bjp.0705348
Sodium (2‐sulfonatoethyl) methanethiosulfonate prevents S‐nitroso‐L‐cysteine activation of Ca2+‐activated K+ (BKCa) channels in myocytes of the guinea‐pig taenia caeca
Authors: Lang Richard J , Harvey John R , Mulholland Emily L 
Published: July 2003

The modulation of large conductance Ca2+‐activated K+ (BKCa) channels by the nitric oxide (NO·) donor, S‐nitroso‐L‐cysteine (NOCys) and three sulfhydryl‐specific methanethiosulfonate (MTS) reagents, positively charged 2‐aminoethyl MTS hydrobromide (MTSEA C3H9NO2S2HBr) and [2‐(trimethylammonium) ethyl MTS bromide (MTSET C6H16NO2S2Br), and negatively charged sodium (2‐sulfonatoethyl) MTS (MTSES C3H7O5S3Na) were compared in excised inside‐out membrane patches of the guinea‐pig taenia caeca.
In membrane patches bathed in a low Ca2+ (15 nM) high K+ physiological salt solution, 1–3 BKCa channels opened with a low probability (N.Po) of 0.019±0.011 at 0 mV. N.Po readily increased with membrane depolarization, raised Ca2+ concentration or upon the addition of NOCys (10 μM for 2–5 min) such that 5–15 open BKCa channels were evident.
MTSEA (2.5 mM) decreased, while MTSES (2.5 mM) increased N.Po (at 0 mV) and the number of open BKCa channels at positive potentials. These changes in channel activity remained after a prolonged washout of these two MTS reagents.
MTSET (2.5 mM) increased N.Po (at 0 mV) and voltage‐dependently decreased BKCa current amplitudes in a manner readily reversed upon washout.
Pre‐exposure of excised membrane patches to MTSES or N‐ethylmaleimide (NEM 1 mM), a specific alkylating agent of cysteine sulfhydryls, but not MTSEA or MTSET, prevented the excitatory actions of NOCys (10 μM).
It was concluded that NOCys‐evoked increases in BKCa channel activity occur via the S‐nitrosylation of cysteine residues within basic regions of the channel α subunit that have an accessible water interface.

British Journal of Pharmacology (2003) 139, 1153–1163. doi:10.1038/sj.bjp.0705349
Adrenomedullin upregulates M2‐muscarinic receptors in cardiomyocytes from P19 cell line
Authors: Buys Sophie , Smih Fatima , Pathak Atul , Philip‐Couderc Pierre , Verwaerde Patrick , Montastruc Jean‐Louis , Rouet Philippe , Senard Jean‐Michel 
Published: July 2003

The effects of AM on expression of muscarinic (M) receptors from P19‐derived cardiomyocytes were examined.
RT–PCR experiments revealed expression of M1–M4 receptor genes. Immuno‐histochemistry indicated that M2 expression is restricted to contractile cells. Carbachol inhibition of isoprenaline‐induced increase in beating rate was prevented by atropine and methoctramine (pA2: 8.1). Inhibition of [3H]‐NMS binding by atropine (pKi: −8.4±0.2) and methoctramine (pKi: −8.3±0.2) suggests that M2 is the functional expressed isoform.
[3H]‐NMS binding and semiquantitative RT–PCR studies showed a dome shaped time course of M2 expression with a maximum at 7 days of differentiation followed by a progressive decline.
AM concentration‐dependently upregulated M2 receptor mRNA during late differentiation stages in P19 cells but also in rat atrial cardiomyocytes. This effect was potentiated by factor H. AM (100 nM) plus factor H (50 nM) treatment of P19 cells for 24 h significantly increased [3H]‐NMS‐specific binding (Bmax: 81±7 vs 31±6 fmol mg−1 prot). The effect of AM on mRNA levels was prevented by AM receptor antagonist AM22–52 (1 μM) but not by CGRP antagonist, CGRP8–37 (1 μM).
The mRNA levels encoding CRLR receptor declined with culture duration, whereas those encoding L1/G10D receptor remained stable.
Our findings demonstrate that AM regulates M2 receptors expression in cardiomyocytes probably through a mechanism involving L1/G10D receptors. The ‘in vivo’ significance of this phenomenon remains to be demonstrated.

British Journal of Pharmacology (2003) 139, 1219–1227. doi:10.1038/sj.bjp.0705350
Comparative regional haemodynamic effects of the nitric oxide synthase inhibitors, S‐methyl‐L‐thiocitrulline and L‐NAME, in conscious rats
Authors: Wakefield Ian D , March Julie E , Kemp Philip A , Valentin Jean‐Pierre , Bennett Terence , Gardiner Sheila M 
Published: July 2003

The regional haemodynamic effects of the putative nNOS inhibitor, S‐methyl‐L‐thiocitrulline (SMTC), were compared with those of the nonselective NOS inhibitor, NG‐nitro‐L‐arginine methyl ester (L‐NAME), in conscious, male Sprague–Dawley rats.
SMTC (0.3 mg kg−1 bolus) produced a significant, short‐lived, pressor effect associated with renal, mesenteric and hindquarters vasoconstriction; the same dose of L‐NAME did not affect mean blood pressure (BP), although it caused bradycardia and mesenteric vasoconstriction.
At the highest dose tested (10 mg kg−1), L‐NAME produced a significantly greater bradycardia and fall in mesenteric vascular conductance than SMTC, although the initial pressor response to SMTC was greater, but less sustained, than that to L‐NAME.
Infusion of SMTC or L‐NAME (3 mg kg−1 h−1) induced rises in BP and falls in renal, mesenteric and hindquarters vascular conductances, but the effects of L‐NAME were greater than those of SMTC, and L‐NAME also caused bradycardia.
The renal vasodilator response to acetylcholine was markedly attenuated by infusion of L‐NAME, but unaffected by SMTC. The hindquarters vasodilatation induced by salbutamol was attenuated by L‐NAME, but not by SMTC. The mesenteric vasodilator response to bradykinin was modestly enhanced by SMTC, but not by L‐NAME. The depressor and renal, mesenteric and hindquarters vasodilator responses to sodium nitroprusside were enhanced by L‐NAME, whereas SMTC modestly enhanced the hypotensive and renal vasodilator effects of sodium nitroprusside, but attenuated the accompanying tachycardia.
The results are consistent with the cardiovascular effects of low doses of SMTC being attributable to nNOS inhibition.

British Journal of Pharmacology (2003) 139, 1235–1243. doi:10.1038/sj.bjp.0705351
Superoxide dismutase mimetic M40403 improves endothelial function in apolipoprotein(E)‐deficient mice
Authors: Jiang Fan , Guo Yanan , Salvemini Daniela , Dusting Gregory J 
Published: July 2003

Overproduction of superoxide anions in the vascular wall contributes to endothelial dysfunction in vascular disease. A superoxide‐generating reduced β‐nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major source of oxidative radicals in vascular tissues. We studied the effects of a synthetic manganese‐containing superoxide dismutase (SOD) mimetic, M40403, on NADPH oxidase‐dependent superoxide generation and on endothelial dysfunction.
In rat aortic smooth muscle cells, NADPH (100 μM) markedly stimulated superoxide production as detected by lucigenin (5 μM)‐enhanced chemiluminescence. M40403 reduced NADPH oxidase‐dependent superoxide production in a concentration‐dependent manner, with IC50 being 31.6 μM. In contrast, native Cu/Zn SOD (up to 300 U ml−1) had no effect. Angiotensin II (100 nM) increased the NADPH oxidase activity by 70%, and treatment with M40403 (10 μM) reduced this increased superoxide to the control level.
In aortae from apolipoprotein(E)‐deficient mice (apoE0) with hyperlipidemia and atherosclerosis, superoxide production is largely derived from NADPH oxidase. The attenuation of endothelial nitric oxide vasodilator function parallels the increase in vascular superoxide production at different stages of the disease. Acute incubation of such aortic rings with M40403 significantly suppressed superoxide production and improved endothelium‐dependent vasorelaxation to a level comparable to that in wildtype control mice.
In summary, the cell‐permeable SOD mimetic M40403 was found to reverse endothelial dysfunction in apoE0 aorta ex vivo by decreasing NADPH oxidase‐dependent superoxide levels. The advantages of synthetic SOD mimetics over the native Cu/Zn SOD enzyme, such as greater cell permeability and stability, confer significant therapeutic potential in vascular disease.

British Journal of Pharmacology (2003) 139, 1127–1134. doi:10.1038/sj.bjp.0705354
Role of endogenous adenosine in the acute and late response to allergen challenge in actively sensitized Brown Norway rats
Authors: Ellis K M , Mazzoni L , Fozard J R 
Published: July 2003

Endogenous adenosine has been suggested to amplify the response of airway mast cells to allergen in vivo. We have sought evidence for this by monitoring the acute and late‐phase response to allergen in Brown Norway (BN) rats actively sensitised to ovalbumin (OA) and treated either with adenosine deaminase (ADA) linked covalently to polyethylene glycol (PEG‐ADA; Adagen®) to decrease adenosine availability or with erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine (EHNA), an inhibitor of ADA, plus S‐(4‐nitrobenzyl)‐6‐thioinosine (NBTI), an inhibitor of facilitated adenosine transport, to increase adenosine availability.
The cardiovascular effects of adenosine (0.01–3 mg kg−1 i.v.) were significantly reduced in PEG‐ADA‐treated animals and augmented in EHNA/NBTI‐treated animals. The difference in sensitivity to adenosine in the treated groups was 33‐ and 15‐fold, at the level of 30% reduction in blood pressure and heart rate, respectively.
The acute response to allergen, given either intravenously or intratracheally, was quantified as bronchoconstriction. The late phase to allergen was measured as the influx and activation of immunoinflammatory cells into the bronchoalveolar lavage fluid 24 h after challenge.
Despite evidence of a substantial difference in adenosine availability following pretreatment with PEG‐ADA or EHNA/NBTI, there were no differences in either the acute or late response to allergen in the actively sensitised BN rat.
Our data suggest no role for endogenous adenosine in determining the response to allergen under our experimental conditions.

British Journal of Pharmacology (2003) 139, 1212–1218. doi:10.1038/sj.bjp.0705355
Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membrane steroid transporters
Authors: Pariante Carmine M , Kim Richard B , Makoff Andrew , Kerwin Robert W 
Published: July 2003

Incubation of LMCAT fibroblast cells with antidepressants potentiates glucocorticoid receptor (GR)‐mediated gene transcription in the presence of dexamethasone and cortisol, but not of corticosterone. We have shown that antidepressants do so by inhibiting the LMCAT cell membrane steroid transporter (which is virtually identical to the multidrug resistance P‐glycoprotein) and thus by increasing dexamethasone or cortisol intracellular concentrations. However, previous experiments with the antidepressant fluoxetine in the presence of dexamethasone have produced negative results (Pariante et al. (2001). Br. J. Pharmacol., 134, 1335–1343).
We have since re‐examined the effects of fluoxetine on GR‐mediated gene transcription in the presence of dexamethasone. Moreover, we have examined the effects of fluoxetine on GR‐mediated gene transcription in the presence of cortisol and corticosterone, and on the intracellular accumulation of radioactive cortisol and corticosterone. Finally, we have examined the effects of fluoxetine on inhibition of P‐glycoprotein activity in Caco‐2 cells.
We now find that fluoxetine (1–10 μM) enhances GR‐mediated gene transcription in the presence of dexamethasone and cortisol (+140–170%), but not of corticosterone, and increases the intracellular accumulation of 3H‐cortisol (+5–15%), but not of 3H‐corticosterone. Moreover, fluoxetine (10 μM) induces approximately 30% inhibition of PGP activity in Caco‐2 cells.
Our results show that fluoxetine, like other antidepressants, inhibits membrane steroid transporters.

British Journal of Pharmacology (2003) 139, 1111–1118. doi:10.1038/sj.bjp.0705357
P2Y‐Receptors stimulating the proliferation of human mesangial cells through the MAPK42/44 pathway
Authors: Vonend Oliver , Grote Tobias , Oberhauser Vitus , von Kügelgen Ivar , Rump Lars Christian 
Published: July 2003

Mesangial cell proliferation is observed in a number of kidney diseases. The sympathetic cotransmitter ATP is suspected to play a major role in proliferative processes. Therefore, the effects of exogenous ATP on human mesangial cells in culture were studied.
Fresh human kidney cortex was processed to obtain mesangial cells in culture. Effects of nucleotides on [3H]thymidine incorporation, the activation of mitogen‐activated protein kinase and the cell number were studied. The involved P2‐receptors were characterized pharmacologically. In addition, we searched for mRNA for P2Y‐ and P2X‐receptors by RT–PCR.
ATP (0.1–300 μM) and related nucleotides induced a significant increase in [3H]thymidine incorporation up to 220% of control. The adenine nucleotides ATP and ADP were about equally effective. Also ATP‐γ‐S, UTP, ADP‐β‐S and 2‐m‐thio‐ADP induced a weaker response. UDP and α‐β‐methylene‐ATP failed to induce an effect on [3H]thymidine uptake.
ATP (100μM) induced a fast activation of the MAPK42/44 pathway. The effects of ATP on MAPK42/44 activation and [3H]thymidine incorporation were reduced by the MAPK inhibitor PD 98059. Platelet‐derived growth factor (PDGF 5 ng ml−1) increased the cell number to more than 122% of control. ATP (10 μM) on top of PDGF amplified PDGF induced cell proliferation to 136% of control.
RT–PCR products for P2Y1,2,4,6,11,12‐ and P2X1,2,4,5,6,7‐receptor subtypes were detected in human mesangial cells.
ATP has mitogenic effects on human mesangial cells. DNA synthesis is increased by the activation of the MAPK42/44 pathway. ATP amplifies PDGF‐induced cell hyperplasia.

British Journal of Pharmacology (2003) 139, 1119–1126. doi:10.1038/sj.bjp.0705358
Nicotine and nicotinic receptor antagonists potentiate the antidepressant‐like effects of imipramine and citalopram
Authors: Popik Piotr , Kozela Ewa , Krawczyk Martyna 
Published: July 2003

Epidemiological and clinical observations suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in depressive illness. Nonetheless, there is no clearcut evidence that nicotine and/or nAChR antagonists produce an antidepressant effect.
In the tail‐suspension test (C57/Bl male mice), nicotine (0.8–1.2 mg kg−1 s.c. or i.p.) given 15–60 min before the measurement exerted no effect on immobility.
Given 30 min before the measurement, citalopram (2 mg kg−1) produced a slight decrease in immobility; coadministration of nicotine (0.8 mg kg−1, 15 but not 40 min before the test) to citalopram‐treated mice resulted in a robust decrease in immobility. Imipramine (4 mg kg−1) did not affect immobility, but given in combination with 0.8 mg kg−1 of nicotine (15 but not 40 min before the test), a decrease in immobility was observed. Nicotine (0.8 and 1.2 mg kg−1) also produced an enhancement in the anti‐immobility effect of imipramine (20 mg kg−1).
We further investigated if nAChR antagonists would influence the antidepressant‐like effects of imipramine and citalopram. Unexpectedly, mecamylamine (1–2.5 mg kg−1) and dihydro‐β‐erythroidine (2 mg kg−1) potentiated the antidepressant‐like effect of imipramine (4–20 mg kg−1). Mecamylamine (2.5 mg kg−1) but not dihydro‐β‐erythroidine also increased the antidepressant‐like effect produced by 2 mg kg−1 of citalopram.
The interaction between nAChR antagonists and antidepressants appeared synergistic.
Neither nAChR ligands, antidepressants nor combinations of the two, affected locomotor activity.
The present results demonstrate an unexpected interaction between nAChR ligands and imipramine and citalopram in the tail‐suspension test.

British Journal of Pharmacology (2003) 139, 1196–1202. doi:10.1038/sj.bjp.0705359
Anti‐inflammatory and analgesic effects of paeonol in carrageenan‐evoked thermal hyperalgesia
Authors: Chou Tz‐Chong 
Published: July 2003

Paeonol was tested for its anti‐inflammatory and analgesic effects in a rat model of carrageenan‐evoked thermal hyperalgesia. The possible mechanisms involved in these effects were also investigated.
Pre‐ and post‐treatment with paeonol (30, 50 or 100 mg kg−1, i.p.) dose‐dependently inhibited the carrageenan‐evoked thermal hyperalgesia.
Treatment with paeonol dose‐dependently inhibited tumour necrosis factor‐α (TNF‐α) and interleukin‐lβ (IL‐1β) formation, but enhanced IL‐10 production in the rat paw exudates both at the early (1.5 h) and late phase (4 h) after carrageenan injection. However, inhibition of IL‐6 formation by paeonol was only observed at the late phase.
Paeonol dose‐dependently decreased the formation of prostaglandin E2 (PGE2) in rat paw exudates with a greater inhibition at the late phase. However, inhibition of nitrate generation was observed only during the late phase (at 4 h after carrageenan injection), accompanied by an attenuation of inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2) protein expression in paw tissue.
Elevated myeloperoxidase activity, an indicator of neutrophil infiltration, in carrageenan‐injected paws was also dose‐dependently reduced in paeonol‐treated rats.
Our results suggest that the mechanisms by which paeonol exerts its anti‐inflammatory and analgesic effects in this inflammatory model may be associated with decreased production of proinflammatory cytokines, NO and PGE2 and increased production of IL‐10, an anti‐inflammatory cytokine, in carrageenan‐injected rat paws. In addition, attenuation of the elevated iNOS and COX‐2 protein expression as well as neutrophil infiltration in carrageenan‐injected paws may also be involved in the beneficial effects of paeonol.

British Journal of Pharmacology (2003) 139, 1146–1152. doi:10.1038/sj.bjp.0705360