International Journal of Research in Pharmacy and Biosciences Volume 4, Issue 3, 2017, PP 27-38 ISSN 2394-5885 (Print) & ISSN 2394-5893 (Online)

Impact of Aqueous Extract of Hildegardia Barteri on Calcium Channel Activity Dependent Voltages Michodjehoun Loetitia, Seibou Toleba Soumanou, Koukoui Omedine, Adoho Chimene Assou Eudoxie, Gbenou Joachim, Sezan Alphonse* Laboratory of Biomembranes and Cell Signaling, University of Abomey Calavi, Benin *Corresponding Author: Sezan Alphonse, Laboratory of Biomembranes and Cell Signaling, University of Abomey Calavi, 06 BP 3041 Cotonou, Benin.

ABSTRACT The present study was carried out with the aim of evaluating the diuretic, naturiuretic activity and the action of the aqueous extract of the leaves of Hildegardia barteri on the function of voltage dependent calcium channels. After oral gavage of the aqueous extract of the leaves of Hildegardia barteri at doses of rats 10; 25; 50; 67; 5; 100; 135; 202, 5 mg / kg bw, to wistar rats, the volume of urinary excretion was measured as well as natriuresis-natraemia; Kaliuresis-kaliemie; Chloruresis-chloramemia; Calcium-calcium, magnesuria- magnesemia, urinary urea, creatinuria, urinary pH, and blood transaminases (ASAT-ALAT). The results show that the basal diuresis after 6 h is 6.05 ± 0.85 and 11.6 ± 0.7 after 24 h. The pH between 8.9 and 10.05 with a standard error of 9.7 ± 0.3. Important diuretic activity was observed at a dose of 67.5 mg / kg (147.5 ± 17.5) bw compared to furosemide (as a reference drug) at 20 mg / kg bw (92.25 ± 6.75). The aqueous extract of Hildegardia barteri leaves at a dose of 67.5 mg / kg bw may therefore be a loop diuretic or a thiazide diuretic; And also facilitates the elimination of urea and creatinine. Elevation of serum calcium suggests that the active molecule in the aqueous extract of the leaves of Hildegardia barteri is a beta adrenergic agonist or a beta adrenergic antagonist by binding to the beta-1-adrenergic receptor; Thereby inhibiting the effects of adrenaline; Blocking the entry of extracellular calcium and thus inducing cardiac muscle relaxation. This may justify its use in tradithérapie as an antihypertensive. Thus, at a dose of 10 mg / kg bw, the aqueous extract of the leaves of Hildegardia barteri could be an antihypertensive agent.

Keywords: Hildegardia barteri, diuretic activity, calcium channels dependent voltages INTRODUCTION Parka biglobosa, Creative andesine, Trida procumbent, Hildegard a barteri ... etc. Are Research in the field of phototherapy does not used by traditional healers in the date nowadays and is expanding in the world. treatment of cardiovascular disease? Indeed, several pharmacological studies are carried out all over the world in the framework Thanks to modern techniques, we are of the research of new active molecules through elucidating the functioning of the organism on the valorisation of the plants. In Africa, the particle scale. Thus, one realizes that the traditional medicine uses many medicinal herbal transmembrane channels, these microscopic recipes for the treatment of various diseases. pores which are on the surface of the cell, play a primordial role in the exchanges between the In Benin, the low purchasing power of cell and its environment. Input and output of populations and the high cost of treatment limit ions such as sodium and calcium determine the the purchase of pharmaceutical products and function of vital organs such as the heart, rural populations depend on traditional medicine muscles, neurons, etc. For example, calcium to meet their therapeutic needs (Nondichao). channels play a crucial role in the contraction of Plants are recognized as a wonderful source of the heart muscle (PHARMATERM, vol 5) medicines. Currently more than 1000 species of plants are used as medicines in traditional Hildegard a barteri (Kariya), a tree of the family therapeutics (Merles and Farnsworth, 1995). was essentially an ornamental in However, for most of them the scientific West Africa (Hildegardia notes, 2009); evidence is not yet elucidated. Heliotropism Cultivated for its beautiful flowers (Hildergadia indium, Lantana camera, Persia Americana,

International Journal of Research in Pharmacy and Biosciences V4 ● I3 ● 2017 27 Impact of Aqueous Extract of Hildegardia Barteri Leaves on Calcium Channel Activity Dependent Voltages

Notes, 2007). In the old system of classification, paper. The filtrate obtained is evaporated at 60 ° it had been placed in the . The C. using the Rotavapor® rotary evaporator. The is named in homage to Saint Hildegard de paste deposited on the bottom of the flask of the Binge for his contribution to herbal medicine evaporator is recovered in jars and dried in an (Schott, H. W., Endlicher, S. F. L. (Carolus oven at 45°C. After thorough drying, the Gerald, 1832)). Its seeds have important extracts are scraped with the stainless steel nutritional properties and traditionally, the spatula, crushed in porcelain mortar and then aqueous decoct ate of its leaves in association kept in glass bottles previously labelled. These with the leaves of Croton zambesicus, extracts will be used to prepare the Commiphora Africana, Osmium basilicas and concentration ranges tested. Cola nitride is used in bath in the treatment of Qualitative Photochemical Study hypertension in Benin. Photochemical screening is based on differential Our work will consist in evaluating according to reactions (coloring and precipitation) of the the pharmacological norms the impact of the main groups of chemical compounds contained aqueous extract of the leaves of Hildegard in plants according to the method of barteri on the diuresis of the wester rat; on the HOUGHTON P.J. and RAMAN A. (1998) activity of calcium channels dependent voltages; revised and adapted to the conditions of the And to determine its possible effects on cardiac Laboratory of Pharmacognosy and Essential muscle relaxation. Oils MATERIALS AND METHODS Evaluation of the Diuretic Activity of Hardware Hildegard Barteri Material Composition of experimental groups and preparation of animals It consists of the leaves of Hildegard barteri harvested in Dassel in March 2016 by the team In order to evaluate the diuretic activity with the of the botanical garden of UAC. The leaves EAHb, we have disposed wester rats of around were dried outdoors in a room outside the weight (180-220g), and of male sex. These rats laboratory from March 16, 2016 to April 21, were fasted for 18 hours before each test with 2016 at room temperature; Finely ground with a free access to tap water only before and after RETSCH knife mill. The powder obtained is receiving salt water overload (except for the then stored in jars of transparent glasses covered basic diuresis package). entirely with aluminium foil and deposited in Our study was based on 09 batches of rats the laboratory at ambient temperature in order to distributed as follows: lot 1 (base diuresis): avoid external contamination 50ml / kg body weight distilled water, lot2 Animal Material (Furosemide, MR): 20mg / kg body weight The animal material consists of blood (serum) Furosemide. Lots 3; 4; 5; 6; 7; 8; 9 have in place of Furosemide the aqueous extract of Hb and urine from male Wister rats weighing between 180g and 220g, bred at the laboratory in the respective doses: 10; 25; 50; 67.5; 100; of the Biomembranes Laboratory and Cell 135 and 202.5 mg / kg body weight. Signalling. These animals have free access to Determination of basic diuresis food and water. For the measurement of basal diuresis, batch Methods 50mg / kg / b/w of oral distilled water (oesophageal gavages) was administered to lot Preparation of the aqueous extract of the 1. Urinary excretion was measured 6H and 24H leaves of Hildegard a barteri after administration. To obtain the aqueous extract of the leaves of Hildegard a barteri To 100 g of powder weighed Determination of diuretic activity using a Sartorius® analytical balance 1L of The methodology used by these authors has distilled water is added, all in a 2L glass flask. been seen and adapted to our laboratory The mixture is brought to boiling with stirring conditions. The principle consists in measuring for 30 minutes on a heating calotte at 60.degree. the volume of urinary excretion in wester rats After cooling, the obtained decoct ate is filtered after giving them by oesophageal gavages 50 ml three times with hydrophilic cotton and filter / kg of body weight of 1.8% NaCl solution and

28 International Journal of Research in Pharmacy and Biosciences V4 ● I3 ● 2017 Impact of Aqueous Extract of Hildegardia Barteri Leaves on Calcium Channel Activity Dependent Voltages then administering them some time after the lateral decubitus, and held by the skin of the EAHb at the respective doses mentioned Above: neck. The pressure of the thumb on the neck, D10; D25; D50; D67, 5; D100; D135 and D202, behind the angle of the jaw, allows compression 5 mg / kg body weight to batches 3-9 of the jugular vein, and therefore a venous stasis respectively. Lot 2 received only Furosemide towards the head, favouring the filling of the (MR), and lot 1 was distilled water. After the retro-orbital sinus. By making a slight traction treatment, each batch being composed of two on the upper eyelid with the index finger, we rats, they are placed (each rat) in metabolic create exophthalmoses facilitating the taking of cages (01 rats per cage). blood by means of tube with hematocrit not heparinised. The end of the tube is slowly For each group, urinary excretion of 6 hours and introduced into the lateral angle of the eye. 24 hours was measured and a blood sample is Progression through the tissues is facilitated by taken 24 hours after treatment on each wester printing a small pipette rotation. As soon as the rat. After placing them each in the metabolic venous plexus is reached, the blood spurts into cages, the following parameters were measured: the per orbital space and ascends by capillary latency (the appearance of the first urine drops action in the tube. The volume of blood after the gavages), the urinary volume after 6H collected is 0.5 to 2 ml. Before the tube is and 24H and the urine pH 24H after removed, the compression is released and the administration. The volume of urinary excretion bleeding ceases spontaneously when the ocular (VEU) is obtained by the formula: VEU = VE / pressure normalizes. The recovered blood is VA X 100; With VE = Volume of excretion; used for the determination of the various VA = Volume administered. VEU <80% = ant biochemical parameters. diuretic activity; VEU between 80-110 = no activity; VEU between 110-130% = low Determination of biochemical parameters activity; VEU between 130-150% = moderate Determination of Calcium activity and VEU ≥ 150% = high activity. Principle Feeding of Wistar Rats The CPC method described (derived from Animals and accommodation conditions Moorhead and Briggs) is used to determine the All animals are of EOPS sanitary status (free of total calcium concentration in serum, plasma or specific pathogenic organisms). Upon receipt, urine. In an alkaline medium, O-cresolphthalein the rats are randomly placed in groups of 09 in complexion or CPC reacts with calcium ions to standard cages for an acclimatization period (2 form a dark red colored complex whose weeks) before being used in the different absorbance, measured at 570 nm, is proportional experiments. During this period the animals to the calcium concentration in the specimen. have free access to food and water and are kept Determination of Magnesium in an animal house at a constant temperature (22 ± 2) ° C subjected to a 12 / 12h light / dark Principle cycle. Method based on that described by Girdler, Administration of the Extract of the EAHb Hath, and Khayam-Bashi. The camalgite, a metallochromic indicator, forms a colored It is done orally with a syringe with an complex, in an alkaline medium, with oesophageal probe. This ensures that the rat has magnesium. The absorbance of the complex is swallowed the expected dose. measured at 510-550 nm and is proportional to Blood Collection the magnesium concentration in the specimen. EGTA limits the interference of calcium, The blood sample is taken according to the whereas potassium cyanide reduces that of experimental protocol employed by Weiss et al. heavy metals. Polyvinylpyrrolidone and a (2000), and modified by Descat (2002). surfactant reduce the interference of proteins Puncture of the retro-orbital sinus was and lipid levels. performed. The animal is held in one hand in

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Screening photochemical Table10. Result of screening phytochemical Chemical groups Result before after AlcaloÏdes

Yellowprecipitate +++

Polyphenolic compounds

Tannins Dark green color+++

Catechin tannins Pink precipitate++

Gallic tannins Blue or black color -

Flavonoîdes Orangecolor+++Flavones

Anthocyanins Red,blue-purplish or greenish color-

Leuco Red cherry or purplish Anthocyanins color -

30 International Journal of Research in Pharmacy and Biosciences V4 ● I3 ● 2017 Impact of Aqueous Extract of Hildegardia Barteri Leaves on Calcium Channel Activity Dependent Voltages

Quinon Pink or red purplish derivatives color +++

Saponosides Foam rating greater than or aqua to 1cm+++

terpene compound

Triterpénoîdes Green color+++

Cardenolide Blue color-

Cyanogenic derivatives Brown color-

Mucilage’s

Flaky precipitate+++

Coumarins Intense fluorescence in test tube at 365 nm+++

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Reducing Bright red precipitation compounds +++

Anthracene derivatives

Free anthracene Red color-

+++Abondant ++ Little abondant + Löw - Absent The results of the screening phytochimic Evolution of urinary excretion volume under enabled us to highlight the presence of the great the effect of EAHb groups of metabolites such as the quinoid alkaloids, tannins, flavonoîdes, derivatives, the saponosides, the triterpénoîdes, mucilage’s, coumarone and the compounds reducing. Study of the diuretic activity of the aqueous extract of the sheets of hildegardia barteri Variation of the urinary volume of 6h and 24h

Figure22. Urinary volume of excretion FIG. 22 shows the evolution of the volume of urinary excretion calculated after obtaining the various urine volumes under the effect of Furosemide and EAHb-Furosemide (MR) at the dose of 20mg / kg of PC causes an increase compared to the control of the volumes of urinary excretion. But the diuretic activity is very low (60.5 ± 4.5)% in 6h and (92.25 ± Figure21.urinary volumes of 6 hours and 24 hours 6.75)% in 24h-EAHb did not induce diuretic activity at a dose of 67.5 mg / kg b/w in 6 h (90 Figure 21 shows the variation in urinary ± 10)% but induced a significant diuretic volumes of 6 hours and 24 hours-Furosemide activity at the same dose in 24 h (147.5 ± (MR) at a dose of 20mg / kg PC induces an 17.5)%. None of the doses gave diuretic activity increase over the control of urinary volumes in 6 h from the first hour to the 6th hour. The overload Variation of urinary pH under the effect of elimination time is within the first three hours EAHb after administration. -EAHb causes a significant increase compared to the control and Furosemide of the urinary volumes from the second hour after administration and continues until the 24th hour. The action is important at the dose of 67.5 mg / kg bw (29.5 ± 3.5) mL in 24h Figure 23: Urinary pH

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The urinary pH is basic and varied, very low The serum calcium levels increased strongly at at the different doses of the extract the different doses of EAHb compared to compared to the control and the control (89.5 ± 0.5) and Furosemide (95 ± 4). It Furosemide. Nevertheless, there is a photo therefore induces significant hypocalcaemia at a at the dose of 25mg / kg of pc (10.05 ± 0.05) dose of 67.5 mg / kg b/w (117.5 ± 2.5) Calcuritis varies slightly at different doses of the EAHb compared to control (45.25 ± 0.45) and Variation of urinary urea at different doses of Furosemide (32.87 ± 8.33).But at a dose of 67.5 EAHb mg / kg b/w (63.85 ± 3.45), Kaliuria showed a peak of significance Calcium and calcium are important at a dose of 67.5mg / kg b/w Variation of Magnesemia and magnesuria under the effect of EAHb

Figure 24: Urinary Urea The elimination of urea at different doses of EAHb is low compared to the control (13 ± 1) g / L and compared to Furosemide (16.8 ± 1.6) g / L. However, it is higher at the dose of 50 mg / kg b/w (14.2 ± 0.6) g / L Variation of creatinuria under the effect of Figure27. Magnesemia - Magnesuria EAHb Magnesemia increases progressively at different doses of the extract compared to the control (21.5 ± 0.5) and Furosemide (19.5 ± 1). However, it is important at doses of 50mg / kg b/w (25.2 ± 0.8) and 67.5mg / Kg b/w (24.8 ± 0.7). The same is true for Magnesemia or only the dose of 202.5mg / kg b/w (33.78 ± 2.08) is proportional to Furosemide (32.86 ± 2.06)

Variation of Natremia-Natriuria under the Figure25.Urinary creatinuria effect of EAHb The elimination of creatinine at different doses of EAHb is low compared to control (153.5 ± 7.5) and Furosemide (199 ± 3). Nevertheless, it showed a peak indicating an important elimination at a dose of 100 mg / kg b/w (279 ± 9) Changes in serum calcium and calcium under the effect of EAHb

Figure28. Natremia-Natriuria Natremia does not vary at all by the different doses of the extract. The values are proportional to the control and Furosemide values. On the other hand, natriuresis increases very strongly at the different doses of the extract and has a peak at the dose of 25mg / kg b/w (179.65 ± 0.55) Figure26. Serum calcium-calcium excretion and 50mg / kg b/w (177.65 ± 2.55)

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Changes in calcium-Kaliuria under the effect ASAT varies significantly with the doses of the of EAHb extract compared to the control (145.5 ± 4.5) and Furosemide (125.5 ± 0.5) and is significant at doses of 50mg / kg b/w (203 ± 16) and 135 mg / kg b/w (197.5 ± 23.5). The ALAT, on the other hand, hardly varies at the different doses of the extract. DISCUSSION Our study is based on the evaluation of the diuretic properties of the aqueous extract of the leaves of Hildegardia barteri. The yield of the

extraction is 13.18% with an extract with a dark Figure29. Serum potassium-kaliuresis green appearance; Glossy and highly soluble in The serum potassium does not vary at all at the water. This rate is slightly higher than those of different doses of the extract. Kaliuria, on the Joachim D. GBENOU et al (2015) who found other hand, increases significantly at the 10%; And significantly lower than those of different doses of the extract compared to the Sanogo et al (2009) who found 19%; For control (19.17 ± 0.33) and Furosemide (11.39 ± aqueous extraction. This difference in yield 0.48). It had a peak at the dose of 100 mg / kg might be in the techniques and different stages b/w (21.82 ± 0.52) of extraction or would be dependent on the nature and properties of each plant. This shows, Chloremia-chloruria variation under the effect however, that the leaves of Hildegardia barteri of EAHb contain active ingredients which are extractable by water. The results of the screening show that the aqueous extract of Hildegardia barteri by decoction is rich in Alkaloids, tannins, Flavonoîdes (flavones), quinine derivatives, Saponosides, Triterpénoîdes, Mucilage’s, Coumarone and reducing compounds. Results are similar to those obtained by Sango et al. (2009) who put these chemical compounds in Figure30. Serum chloride-Chlorurie evidence in the recipe "Nitrokoudang" used in traditional medicine in Mali for the treatment of Chloraemia does not vary at all at the different arterial hypertension unlike alkaloids and doses of the extract. Chloruria, on the other triterpénoîdes; And those obtained by GBENOU hand, increased significantly with respect to et al, unlike leucoanthocyanins.Ouattara (2006) controls (27.85 ± 0.65) and Furosemide (162.25 finds that the presence of reducing compounds ± 0.75) at doses of 25mg / kg b/w (222.55 ± makes it possible to treat coughs. Kini (1993) 2.55) and 50mg / kg b/w (185.9 ± .0.8) finds that tannins are used against diarrhea and Variation of Transaminases (ASAT-ALAT) hemorrhages by tightening fabrics. Adjanohoun under the Effect of Eahb et al (1989) attribute the haemostatic effect to the presence of tannins. Indeed, flavonoîdes ASAT-ALAT(Ul/L) have diuretic properties especially those of falconine types (Bruneton, 2010). But our 300 extract specifically contains those of flavones 200 types. This may justify the low diuretic activity 100 obtained with the different doses in addition to 0 that of 67.5 mg / kg b/w in 24 h. Lot Lot Lot Lot Lot Lot Lot Lot Lot The diuretic action of Furosemide was brief. 1 2 3 4 5 6 7 8 9 Indeed, the volume of urinary excretion of Furosemide (92.25 ± 6.75) is low at that of ASAT ALAT EAHb at the dose of 67.5mg / kg b/w (147.5 ±

17.5) in 24h. This is markedly different from the Figure31. ASAT-ALAT

34 International Journal of Research in Pharmacy and Biosciences V4 ● I3 ● 2017 Impact of Aqueous Extract of Hildegardia Barteri Leaves on Calcium Channel Activity Dependent Voltages results of GBENOU Et al., Who by their work phosphorylation of the canal by the pkA on the evaluation of the diuretic properties of therefore leads to the opening of the canal and the aqueous extract of Elias Guinness obtained the massive entry of calcium into the cell. Some natriuresis and diuretic activity at doses of of the calcium entering the cell will bind to the 135mg / kg b/w and 202.5mg / kg b/w with the ryanodine receptors (RyR) of the sarcoplasmic aqueous extract of Elates guineensis The reticulum, resulting in a calcium release from observed hypernatriuresis shows an inhibition of the reticulum. The release of calcium from the renal reabsorption of Na + ions. This indicates cisterns of the sarcoplasmic reticulum is the natriuresis and diuretic effect of the aqueous dependent on the intracellular calcium extract of Hildegardia barteri at the dose 67.5mg concentration. This calcium will be added to / kg b/w. Hypocalcaemia and observed that already present in the intracellular medium hypomagnesaemia assume that the aqueous and to form the actin-myosin bridges necessary extract of Hildegardia Barteri contains an active for the contraction The contractility of the molecule that may be a loop diuretic or a cardiac muscle is modulated according to the thiamine diuretic. quantity of Ca2 + entered into the cell which Urinary pH is basic (9.7 ± 0.3); Which is not leads to a more or less release Important consistent with the results of GBENOU et al or calcium from the sarcoplasmic reticulum and the urine pH is acidic (7.35 ± 1.25). This thus the formation of a variable actin-myosin difference between the pH values would be a bridge number. Beta adrenergic receptors are consequence of the physiological difference of therefore responsible for an increase in the the organisms of the animals tested; Or diet. Its cardiac contraction force. The aqueous extract small variation with respect to the control shows of Hildegardia barteri thus acts by binding to the that the aqueous extract of Hildegardia barteri beta adrenergic receptors by inhibiting the does not influence too much the acid-base activity of these receptors; This inhibition balance of the organism. Also, the aqueous suppress the peripheral effects of the extract of Hildegardia barteri by stimulating sympathetic hence its relaxing vaso-cardio renal urinary excretion facilitates the elimination properties. The active molecule contained in the of wastes from the body which are urea and aqueous extract of Hildegardia barteri producing creatinine. these relaxing vaso-cardio effects would therefore be a parasympathomimetic. In sum, Hypocalcaemia observed indicates a high the aqueous extract of Hildegardia barteri at a elevation of extracellular calcium. Indeed, dose of 67.5 mg / kg b/w may be a loop diuretic extracellular calcium is 10 times higher than or a thiamine diuretic; And at a dose of 10 mg / intracellular calcium. However, cardiac kg b/w an antihypertensive or a low natriuresis contraction is due to an increase in intracellular (77.1 ± 8.6). The variation of ASAT suggests calcium after stimulation of beta adrenergic that the extract would have a hepatic impairment receptors by adrenaline. The beta-adrenergic from the dose 50mg / kg b/w which would result receptor, when activated by adrenaline interacts in leakage of transaminases from hepatocytes with a heterotrimeric G-stimulating protein (Gs) that activate adenylyl cycles. When activated by CONCLUSION the alpha subunit of a G protein, adenylate The aqueous extract of Hildegardia barteri by cycles catalyzes the transformation of ATP into decoction is rich in alkaloids, catechuic tannins, camp. The main effect of camp is the activation flavonoîdes (flavones), quinine derivatives, of protein kinas A (pkA). This kinas will then Saponosides, Triterpénoîdes, Mucilage’s, phosphorylated the Ca2 + channels dependent Coumarone and reducing compounds. At the on type L of the plasma membrane. The L-type dose of 67.5mg / kg b/w it could be a loop calcium channels are concentrated at the bottom diuretic or a thiamine diuretic. But at the dose of of the tubules T in contact with a terminal 10mg / kg of pc, it could be an antihypertensive. cistern of the sarcoplasmic reticulum. The cisterns of the sarcoplasmic reticulum contain REFERENCES channels filled with calcium, and the receptors [1] Adjanohoun EJ, Adjakidjè, Ahji MRA et al. with ryanodine. 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Citation: M. Loetitia, S. Soumanou, K. Omedine, A. Assou Eudoxie, G. Joachim and S. Alphonse, "Impact of Aqueous Extract of Hildegardia Barteri Leaves on Calcium Channel Activity Dependent Voltages", International Journal of Research in Pharmacy and Biosciences, vol. 4, no. 3, pp. 27-38, 2017. Copyright: © 2017 S. Alphonse, et al.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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