AQUEOUS EXTRACT OF GROUND MATERIAL OF PLANARIAN ORGANISMS

Abstract

The present invention relates to an aqueous extract useful notably for the regeneration of human or animal cells, notably mammalian cells, comprising an aqueous extract free of any insoluble solid debris of ground planarian organisms having a regeneration capacity, containing at least the intracellular components of the cells of said organisms of a cell lysate of said cells of said organisms.

Claims

1. An aqueous extract useful notably for the regeneration of human or mammalian animal cells, comprising an aqueous extract free of any insoluble solid debris of ground organisms of the Platyhelminthes type having a regeneration capacity, said organisms being aquatic flatworms of the planarian type which are non-parasitic and non-pathogenic in humans or mammalian animals, said aqueous extract containing at least the intracellular components of the cells of said organisms of a cell lysate of said cells of said whole organisms.

2. The aqueous extract as claimed in claim 1 characterized in that said organisms are of the species Schmidtea mediterranea.

3. The aqueous extract as claimed in claim 1 characterized in that said aqueous extract of ground material comprises a centrifugation supernatant of said ground material.

4. The aqueous extract as claimed in claim 1 characterized in that said aqueous extract of ground material further comprises a cell culture medium, preferably a culture medium capable of culturing human or animal cells to be regenerated.

5. The aqueous extract as claimed in claim 1 characterized in that said aqueous extract of ground material comprises the grinding of 50 to 200 mg worms per mL aqueous solution; preferably 75 to 150 mg worms per mL aqueous solution, said aqueous extract of ground material being further diluted preferably more than 1:5 and less than 1:100, preferably diluted between 1:10 and 1:50.

6. The aqueous extract as claimed in claim 5 characterized in that said aqueous extract of ground material comprises the grinding of 110 mg worms per mL aqueous solution; said aqueous extract of ground material being further diluted 1:20.

7. The aqueous extract as claimed in claim 1 characterized in that a spectrum of said preparation by MALDI TOF mass spectrometry comprises the 16 characteristic majority peaks mentioned in the following Table 1, wherein the individual characteristic peaks are numbered in the first column, and the following parameters have the following meanings: M/z: ratios (mass in daltons/charge) on the x-axis of the different characteristic peaks of the spectrum, S/N: ratios (peak intensity/background noise intensity) of the different characteristic peaks of the spectrum, TABLE-US-00003 TABLE 1 M/Z S/N standard standard M/Z deviation S/N deviation 1 8618.401 118.031 10852424.610 11358052.088 2 8270.340 143.008 4620996.274 5564954.057 3 7696.982 133.512 5240359.923 7010776.551 4 7236.251 151.442 8121705.361 11556323.264 5 6803.343 116.896 10708147.034 18373045.879 6 6261.480 163.376 11319617.938 13604702.931 7 5790.573 116.345 21402383.693 37624416.818 8 5330.950 180.245 23085485.049 21438811.717 9 4787.963 120.365 22731248.668 23171439.149 10 4298.636 175.285 24470357.501 21953618.321 11 3793.559 113.425 21664847.045 17673326.341 12 3282.861 172.508 24634530.736 27003268.283 13 2792.441 122.205 22551669.576 22432014.766 14 2294.281 174.311 20589324.299 17568023.101 15 1807.544 115.976 19890585.114 18182405.582 16 1395.545 119.208 33019669.177 29193485.572.

8. A lyophilisate of an aqueous extract of ground material as claimed in claim 1.

9. A process for preparing an aqueous extract as claimed in claim 1 characterized in that the steps are carried out in which: a) said living organisms, preferably washed with water and not fed for at least one week, are placed in an aqueous liquid medium containing preferably a cell culture medium; b) the aqueous preparation obtained in step a) is ground until lysis of the cells of said organisms is obtained, preferably the ground material debris being between 5 and 10 μm in size, c) insoluble debris is removed by centrifugation; and the supernatant is collected, and d) preferably, the centrifugation supernatant is diluted in an aqueous solution more than 1:5 and less than 1:100, preferably diluted between 1:10 and 1:50, said solution comprising preferably still components of a cell culture medium capable of culturing human or animal cells to be regenerated.

10. Use of an aqueous extract or lyophilisate as claimed in claim 1 for the manufacture of a composition useful for regenerating human or mammalian animal cells.

11. Use of an aqueous extract or lyophilisate as claimed in claim 10 for the manufacture of a composition useful for regenerating human or mammalian animal stem cells.

12. Use of an aqueous extract or lyophilisate as claimed in claim 10 in combination with suitable carriers and/or excipients for the manufacture of a food, cosmetic or dermatological composition.

13. A cosmetic composition with an anti-ageing effect on the skin comprising an aqueous or lyophilized extract as claimed in claim 1 and excipients suitable for topical application to the skin of said composition in the form of gel, lotion, cream, ointment or soap.

14. Use of an aqueous extract or lyophilisate as claimed in claim 1 for regenerating human or mammalian animal cells.

15. Use of an aqueous extract or lyophilisate as claimed in claim 10 for regenerating human or mammalian animal stem cells.

Description

[0040] Other features and advantages of the present invention will become clearer by reading the description of the examples that follow, which is illustrative and non-limiting, with reference to the following figures.

[0041] FIGS. 1A to and 1C represent the growth on day 9 of human dental stem cells treated with planarian extracts from Example 3A diluted 1:20 (FIG. 1A: aqueous extract (A1), extract containing PBS (A2) and extracts containing cell culture medium (A3) diluted 1:5 (FIG. 1B) and 1:100 (FIG. 1C).

[0042] FIG. 2 represents microphotographs showing the growth of human stem cells treated with extract A diluted 1:20 for 9 days (B2) and before treatment (B1). The cells are stained with Giemsa.

[0043] FIG. 3 shows the lack of growth on day 9 of human cells treated with ground whole planarians not free of solid debris of Example 1.

[0044] FIG. 4 shows the growth of human cells treated with the solubilized lyophilized extract of Example 3B.

1—METHODS

[0045] 1.1 Planarians:

[0046] Planarians of the species Schmidtea mediterranea are kept at 19° C. in sterile water filtered on activated carbon/ceramic cartridge and on 0.22 μm Millipore filter membrane, without antibiotics. The water is changed every two to three days in order to eliminate waste such as planarian waste. The planarians are fed calf liver once a week. They are deprived of food 1 week before the experiments to purge them. Their average weight is 2.2 mg/worm.

[0047] 1.2 Stem Cells:

[0048] Human dental pulp stem cells (CLS 300702) are maintained under standard in vitro culture conditions in DMEM/F12 (GibCoBRL) cell culture medium supplemented with foetal calf serum (10%) and antibiotic compounds such as penicillin and streptomycin. (5000 U/mL, 5000 μg/mL respectively), at a temperature of 37° C. under a 5% CO.sub.2 atmosphere. The cells are split once a week, after trypsinization (0.05%) to loosen the adherent cells, by a 1:3 dilution in DMEM/F12 culture medium (GibCoBRL) supplemented with foetal calf serum (10%) and an antibiotic cocktail (penicillin-streptomycin), gentamicin, vancomycin, ciprofloxacin) (5000 U/mL, 5000 μg/mL, 50 μg/mL, 10 μg/mL, 20 μg/mL respectively), after treatment with trypsin 0.05%, (GibCoBRL).

EXAMPLE 1

Preparation of the Planarian Extract (Protocol A)

[0049] 1a) The planarians (25 individuals) are taken and washed twice with PBS (phosphate buffered saline, 1×) at pH=7.2, at room temperature, then placed in 550 μL of water (extract A1) or PBS (extract A2) or DMEM/F12 (GibCoBRL) culture medium (extract A3), at a concentration of 110 mg planarians/mL or 50 planarians/mL, at 4° C.

[0050] The planarians are ground with a plastic pestle, then the extract is passed 10 times (in and out) through a 23 G syringe to break up the cells, the ground debris being between 5 and 10 μm in size.

[0051] 1b) The extract is then centrifuged at 200 g for 5 minutes, at a temperature of 4° C.

[0052] The centrifuged extract then has two phases, a dense phase at the bottom of the tube and a supernatant aqueous phase. The supernatant aqueous phase is then collected (about 500 μL) and stored frozen at a temperature of −80° C., or frozen in liquid nitrogen (−196° C.), as a 100 μL aliquot before use.

EXAMPLE 2

Preparation of Lyophilized Planarian Extract (Protocol B)

[0053] An aqueous extract of centrifugation supernatant of ground planarians containing culture medium, frozen are prepared according to protocol A above, is placed in a 2 mL glass lyophilization flask with stopper placed at a temperature of −20° C. overnight before lyophilization. Lyophilization is carried out in a COSMOS freeze-dryer from the company CRYOTEC (France) overnight. The lyophilisate is then stored at +4° C. in the dark until use. Before use the lyophilisate is resuspended in 500 μL sterile distilled water.

[0054] 2. Cell Regeneration Results.

EXAMPLE 3A

Incubation of Human Stem Cells with the Aqueous Extract Obtained According to Protocol A

[0055] Centrifugation supernatants of ground planarians of the species S. mediterranea obtained in step 1b) of Example 1 are added at different final dilutions of 1:5, 1:20 and 1:100 to human dental stem cells at 5×10.sup.3 cells/well, of a 48-well plate, cultured in DMEM/F12 medium (GibCoBRL) supplemented with foetal calf serum (10%) and penicillin and streptomycin (5000 U/mL, 5000 μg/mL respectively), at 37° C. and under 5% CO.sub.2 atmosphere. The cells are then maintained under the following conditions: 37° C., 5% CO.sub.2 atmosphere for 9 days. After 9 days the cells are counted and the growth determined.

[0056] FIGS. 1A to 1C show the growth of human stem cells treated with extracts A1 to A3 diluted 1:5 (FIG. 1A), extract A3 (with culture medium) diluted 1:20 (FIG. 1B), and extract A3 (with culture medium) diluted 1:100 (FIG. 1C), for 9 days. (*p<0.05). The relative cell multiplication ratio was quantified on the y-axis compared with a control with no extract of ground material.

[0057] FIG. 2 shows the growth of human stem cells treated with extract A containing culture medium (A3) diluted 1:20 for 9 days (A2) and control before treatment (A1). The cells are stained with Giemsa.

[0058] A maximum increase with more than 50% increase in the number of cells is observed in the presence of extract A3 containing culture medium diluted 1:20 compared with the control culture without extract according to the invention, whereas for the 1:5 and 1:100 dilutions the growth is less than or equal to the control.

[0059] A maximum increase with more than 40% increase in the number of cells is observed in the presence of the aqueous extracts with water alone (A1) and containing PBS (A2) diluted 1:20 compared with the culture control without extract according to the invention.

[0060] On the other hand, FIG. 3 shows the absence of growth on day 9 of human cells treated with uncentrifuged ground whole planarians, i.e. not free of solid debris obtained in Example 1a).

EXAMPLE 3B

Incubation of Human Stem Cells with Lyophilized Planarian Extract (According to Protocol B)

[0061] The lyophilisate (B) is resuspended in 500 μL of water, then added at a final dilution of 1:20 to human dental stem cells at 5×10.sup.3 cells/well, of a 48-well plate, in culture in DMEM/F12 medium (GibCoBRL) supplemented with foetal calf serum (10%) and penicillin and streptomycin (5000 U/mL, 5000 μg/mL respectively), at 37° C. and under 5% CO.sub.2 atmosphere. The cells are then maintained under the following conditions: 37° C., 5% CO.sub.2 atmosphere for 9 days.

[0062] After 9 days the cells are counted and the growth determined. After 9 days, an increase in the number of cells in the presence of extract B of about 27.7% is observed as shown in FIG. 4.

[0063] FIG. 4 shows the growth of human stem cells treated with extract B diluted 1:20 for 9 days. (*p<0.05) The relative cell multiplication ratio was quantified on the y-axis compared with a control without extract of ground material.

EXAMPLE 4

MALDI-TOF Mass Spectrum of the Planarian Extract

[0064] Mass spectrometry is a known physical analytical technique for detecting and identifying molecules of interest by measuring their mass. Its principle lies in the gas phase separation of charged molecules (ions) according to their mass/charge ratio (m/z). The applications of mass spectrometry are very broad and mainly concern the identification of peptides or proteins, the analysis of their amino acid sequence or the detection of post-translational modifications.

[0065] Mass spectrometry in its MALDI-TOF (matrix-assisted laser desorption ionization-time-of-flight) variant has established itself in biological laboratories in recent years. Indeed, its advantages are numerous: (1) speed of identification (in a few minutes); (2) accuracy of identification (without the need to know the type of microorganism sought); and (3) low cost per sample (less than 50 cents per sample).

[0066] Among the mass spectrometer manufacturers, two complete MALDI-TOF systems are available for sale, marketed by Bruker Daltonics (Germany).

[0067] 1. A sample of aqueous extract with water alone A1 diluted 1:20 of Example 3A was deposited on a HCCA matrix, trichloroacetic acid, water, and acetonitrile. The analysis is performed on a Microflex LT10 MALDI-TOF mass spectrometer. The results are collected with the MALDI Biotyper RTC software.

[0068] One μL of u supernatant is deposited on the target plate of the spectrometer and dried for 10 minutes. One μL of saturated HCCA matrix solution is added on top, dried for 10 minutes, then a mass spectrum of the protein extract is made on a Microflex™ LT (Bruker).

[0069] 2. The spectrum acquisition method includes the following steps and features:

[0070] introduce the plate (Microflex target reference model 224989 known as MSP 96) containing the deposits into the Microflex LT mass spectrometer,

[0071] start the computer associated with the spectrometer to start the analyses, and

[0072] launch the acquisition of the MALDI-TOF mass spectra.

[0073] The parameters applied to the mass spectrometer are as follows:

[0074] positive linear mode, Electrode IS1: 20.00 kV, Electrode IS2: 18.05 kV, Focusing electrode: 6 kV, Laser frequency: 60 Hz, Detector gain: 8.8×, Post-ion-extraction (PIE): 120 ns, Mass range: 700 to 20000 Da.

[0075] The spectra are obtained by an automatic method controlled by the FLEXCONTROL® software from the manufacturer BRUKER DALTONICS® and the parameters for each spot are as follows:

[0076] serial numbers of 40 shots: 6 on different positions of the spot (6×40=240 spectra),

[0077] so that the shots have scanned the whole sample homogeneously, the acquisition is made on 6 different positions according to a hexagonal geometry,

[0078] pre-shots: 10 shots at 40% of the maximum laser power are used to desalinate the sample (contamination by mineral salts),

[0079] laser power: 30% to 45% regulated via the FLEXCONTROL® software,

[0080] spectrum selection: over a mass range of 2000 to 20,000 Da.

[0081] The acquisition of the spectra is finally carried out via the BIOTYPER® software from the manufacturer BRUKER DALTONICS® which allows the automatic method described above to be applied to a series of samples taking into account the criteria mentioned above and a quality score or validation score which represents the addition of 2 scores n1+n2 (n1 being a function of the number of peaks and n2 being a function of the background signal/noise ratio):

[0082] n1 is the score assigned according to the number of characteristic peaks in the spectrum n, where: n1=0 for n≤8, n1=1 for 8<n≤27, n1=2 for 27<n≤43, n1=3 for 43<n≤78, n1=4 for 78<n≤86, n1=5 for 86<n≤110, n1=6 for 110<n, and

[0083] n2 is the score assigned according to the value of the signal-to-noise ratio (Rmax) of the peak of greatest intensity in the spectrum, with n2=0 for Rmax≤6.8, n2=1 for 6.8<Rmax≤26.8, n2=2 for 26.8<Rmax≤52.6, n2=3 for 52.6<Rmax≤208.6, n2=4 for 208.2<Rmax≤398.6, n2=5 for 398.6<Rmax≤1,092.2, n2=6 for 1,092.2<Rmax.

[0084] A spectrum is taken into account if its validation score (n1+n2) is greater than 2.

[0085] The full spectrum is shown in Table 2 below, with the largest peaks given in Table 1 above.

[0086] In Table 2, the values given are average values over 3 extracts and 3 measurements per extract. “SD” is the standard deviation.

TABLE-US-00002 TABLE 2 m/z S/N m/z (SD) S/N (SD) 8604.48 171.52 2944111.66 2325738.78 8558.14 103.75 3757582.77 2412169.59 8364.32 270.77 4299073.53 3953124.73 8231.72 370.12 6273650.35 4516995.49 8109.81 473.70 14474095.01 11993621.48 8091.08 485.10 16468398.81 10785668.45 8066.99 473.89 10995647.50 9275395.50 8040.23 453.94 5195376.26 413314.92 8028.26 448.60 1362266.53 564362.67 8007.05 458.07 1529078.69 723901.78 7977.47 449.60 1934246.85 606979.25 7956.26 430.41 3779700.78 2089476.26 7926.83 439.17 6343305.77 2204916.89 7915.14 445.50 5271199.78 3945913.58 7888.82 422.60 9915944.44 6394858.15 7845.95 451.04 8949566.35 8892715.74 7774.23 390.89 10047314.25 14751532.02 7766.87 396.60 17998107.53 16324726.64 7739.54 417.36 6983093.88 4683065.73 7711.45 420.11 11638867.28 11162939.84 7682.37 447.41 2849076.46 26573.96 7620.78 384.09 1522404.95 1571602.58 7603.31 366.14 3797954.75 301700.94 7507.22 462.35 4988724.05 1053369.21 7460.86 447.47 3010910.15 786290.91 7453.34 443.82 1473989.18 754971.29 7441.65 442.85 2268420.85 265803.84 7428.84 436.23 990780.63 482569.27 7411.46 434.77 3113006.65 44381.36 7379.53 413.93 2507654.97 237260.33 7357.69 419.02 3439236.21 1696465.36 7348.32 417.87 4953557.73 865045.30 7337.73 413.55 5789551.76 904998.52 7327.41 406.71 1938361.88 100617.30 7298.87 418.81 8970671.17 10923542.62 7291.71 416.32 15579329.31 11046360.56 7233.87 458.44 2108878.03 1112809.94 7224.58 467.28 2188902.66 1253603.56 7211.60 462.63 1277388.33 46435.77 7183.03 474.47 10858543.09 6841857.42 7166.12 461.61 6005883.09 4377180.05 7141.72 462.27 8454369.88 12773497.18 7127.32 462.44 15980137.91 13198728.24 7117.16 460.20 1943880.50 1297607.73 7098.11 474.95 28478914.80 34393160.51 7089.16 479.62 40768433.01 42971633.85 7068.69 472.09 3149404.57 1069351.59 7057.38 475.83 4015369.66 840859.73 7049.75 475.55 3557870.44 341332.63 7046.15 475.01 3404514.08 572811.01 7029.85 469.40 16173381.98 27409009.49 7019.69 465.68 29617067.96 31933238.72 6999.99 447.67 10403410.49 4241581.40 6994.31 450.26 12077581.56 3743384.83 6971.95 439.31 19264755.03 20608829.34 6958.98 433.46 7134836.63 5304127.76 6948.13 440.32 9541839.49 15202317.68 6927.62 429.41 19426439.15 15239899.38 6905.24 428.66 8416940.87 2205389.06 6896.02 426.82 5501032.42 1797378.54 6873.20 404.03 5662071.47 988813.38 6862.21 407.24 5647756.06 486820.14 6849.90 398.50 4232957.36 2380406.49 6843.00 401.23 2871706.78 8206.17 6831.95 396.09 11137649.21 7908745.51 6820.90 395.54 4224912.36 1165458.98 6805.35 398.01 4634248.86 2098831.45 6800.77 396.39 5973899.73 1989363.37 6782.34 393.37 19055281.15 21136742.86 6770.31 391.57 35509917.83 13034885.15 6745.15 407.32 18571000.28 15262519.68 6725.36 408.71 8653775.85 4308862.55 6709.87 408.66 5238132.91 1539867.36 6700.89 409.86 7534629.94 2915163.71 6696.13 411.06 8830295.99 3256750.86 6680.99 407.15 4231387.69 593937.32 6654.14 430.44 3521998.94 1238912.77 6640.58 422.93 3211633.91 246128.86 6625.94 423.15 1532349.37 792001.80 6615.85 426.74 6569850.42 2709202.72 6600.71 441.14 5420849.20 2607427.19 6581.25 440.63 4607565.27 5977204.13 6571.96 433.59 8440513.66 5900474.08 6560.55 441.43 6770162.75 4190931.56 6548.88 443.03 8297991.19 897107.33 6539.51 441.18 1698707.19 918513.03 6520.81 429.87 4671420.38 784239.83 6510.06 437.54 11852564.16 1975111.53 6497.56 430.01 9963548.39 4648988.58 6486.81 435.57 11018822.76 5444923.89 6478.80 431.50 10627202.29 7294336.61 6471.06 431.57 6997871.01 6763605.29 6457.19 441.74 9893297.41 8332244.06 6453.29 438.94 3714855.88 283840.79 6442.34 432.99 13686239.46 11824081.49 6430.23 428.59 5363664.11 3097124.33 6418.96 432.14 5051217.13 1408786.51 6406.03 428.78 4700220.72 4284253.70 6401.90 428.42 5939522.66 4703337.99 6387.38 431.14 4660595.31 684934.44 6376.39 431.18 4951125.32 1356190.69 6362.96 431.07 2672270.13 1511767.26 6355.85 431.23 6478221.94 2029795.02 6337.93 429.77 14364514.88 13011112.00 6334.17 429.91 23516628.10 10002697.44 6315.15 419.82 53493918.67 60231591.15 6301.95 415.75 4271746.45 1331550.38 6296.98 415.38 7983195.65 3877555.77 6289.60 421.89 4707429.99 374730.32 6282.32 424.31 7918858.10 7263748.27 6266.95 425.22 24637014.27 5239080.77 6256.93 425.36 20987838.34 1490238.07 6237.88 427.33 29937581.00 13197002.41 6211.75 416.15 22008681.24 24713621.54 6195.65 418.84 33438558.07 29633341.75 6182.69 409.79 15858769.83 1500875.04 6167.23 403.94 4936405.49 1627499.18 6163.90 404.28 5019684.98 2599607.88 6156.47 407.31 2624490.77 1286496.35 6147.22 401.26 7887713.01 12198784.12 6143.52 399.94 14105662.43 13934913.91 6131.16 394.92 6354446.85 8095590.50 6118.66 384.91 32928869.15 22660659.81 6108.38 379.45 33705975.23 37481913.75 6085.16 372.75 21732618.28 24358022.96 6076.11 369.49 41806833.28 10520817.79 6058.74 364.32 5401884.41 2873516.50 6053.17 364.09 5289816.75 4967671.09 6049.05 360.71 5039738.82 4484807.34 6039.69 359.70 7950100.05 3741188.19 6028.98 362.47 2869743.69 1127718.20 6022.25 362.63 6313650.43 3642689.26 6018.84 362.50 8471752.32 3281285.87 6006.88 359.80 5409871.27 3113330.06 5993.85 362.93 11073405.03 7987999.30 5989.40 363.15 14780907.47 8952105.05 5976.57 357.54 8220268.73 3780515.24 5965.81 359.65 35958240.78 61288743.82 5958.71 362.18 66081970.83 71289746.18 5949.95 364.41 11209352.45 2940139.47 5939.47 361.28 7387542.62 3210857.02 5934.00 358.69 5099206.50 281578.79 5927.71 356.18 5285416.84 2063775.29 5921.72 357.90 5141686.87 3613314.69 5913.57 352.22 7891140.07 5273019.26 5907.89 351.46 8761129.52 4214337.97 5897.28 343.10 16943379.29 13133259.91 5887.39 335.68 9519092.77 5864957.51 5875.52 339.85 11843506.86 9571102.04 5865.73 338.82 11879994.37 10762952.96 5852.10 350.61 3491143.90 815315.18 5847.66 347.41 2478062.53 684480.52 5839.13 348.83 11178026.11 8787186.69 5833.41 345.72 3786800.88 1356341.36 5828.30 349.66 6738523.40 5523587.00 5820.71 343.85 15333784.17 9579858.47 5812.92 346.25 16233521.23 12858822.74 5801.36 337.53 5914522.21 2838342.56 5793.34 335.16 3836244.22 1878433.00 5788.87 333.69 5546783.31 1135522.40 5779.83 338.17 3085730.60 467020.28 5774.44 339.69 4216817.00 1505309.25 5761.75 341.14 26029693.44 19860563.73 5745.50 352.24 15330816.80 403931.59 5738.63 352.36 1375856.71 250523.03 5728.45 355.77 21143197.37 13187223.44 5721.62 359.69 9986411.36 6367273.06 5710.31 351.04 17962783.76 7625526.14 5698.31 354.30 16289738.67 13847283.44 5692.42 352.19 8642010.82 2879857.07 5679.18 357.29 16949029.66 8469501.39 5671.41 354.40 23610643.88 902915.57 5659.88 351.82 10741135.91 10434945.84 5650.07 345.04 9719910.27 11106900.98 5642.02 346.77 20837828.42 6120062.17 5632.28 342.04 5179586.28 3748131.62 5625.34 343.43 11783997.01 14900296.16 5615.84 339.78 36318300.21 2666610.42 5594.82 346.11 29642064.46 5400857.11 5576.71 341.97 52675793.29 16242152.20 5562.64 335.33 44208515.45 14139358.56 5533.29 349.04 38001603.57 19382761.03 5517.52 350.03 10420201.24 6231351.60 5514.12 351.64 5291279.59 3523589.34 5509.38 350.32 12999875.87 11017133.88 5497.07 351.52 3561189.66 1240547.00 5486.71 346.65 15671783.68 11138988.70 5479.87 340.82 8069278.92 313063.01 5475.26 342.02 3440691.28 1935367.77 5464.95 341.03 34954370.15 28250458.38 5457.03 336.29 13737638.07 10554844.99 5453.15 338.55 6501242.18 3186060.96 5445.57 334.05 4466355.05 1814188.14 5439.27 333.36 6848806.84 1165890.91 5430.64 339.46 20559236.29 15470533.29 5417.81 342.77 15124914.03 8167741.94 5408.51 347.33 13648603.78 9704645.70 5400.13 347.18 12155209.18 3380351.47 5387.63 344.09 17840291.22 8774788.25 5382.04 342.69 23047717.18 9033382.84 5374.43 341.23 2463218.45 1607909.35 5372.03 340.71 2088536.80 988011.65 5361.09 333.67 123782598.90 121768630.37 5346.40 326.67 2170802.88 446965.68 5339.79 325.26 16046753.94 4577883.99 5330.27 327.57 10380188.29 3530935.54 5322.83 329.73 12972876.56 4355119.79 5313.58 329.45 4903376.42 860576.34 5303.04 320.68 18504824.66 16061179.49 5296.70 318.56 18484406.43 19494127.81 5285.43 318.86 18523147.47 8835491.49 5281.34 320.41 12807973.25 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16600502.80 9176382.93 2213.54 79.17 16931528.32 11801163.54 2207.17 77.82 26738129.67 10901707.68 2204.60 79.18 21147827.70 21699405.87 2198.23 75.24 16466096.25 6976682.27 2192.99 71.51 8450148.18 6644247.22 2189.93 72.42 15984063.74 15914916.09 2186.73 71.56 23277490.55 17871975.88 2180.00 75.57 17250213.66 9016909.20 2174.61 78.38 19066625.56 18471707.30 2171.39 81.13 16727577.51 14878434.86 2167.57 81.79 17486637.04 16089300.86 2160.34 81.30 55117901.61 60827538.28 2149.22 90.56 7330904.48 3880842.06 2148.05 90.60 10061016.94 1428645.33 2142.13 90.49 17187131.15 15201450.97 2138.95 89.15 27732772.22 12816866.81 2132.64 94.07 23160451.34 7451209.21 2129.20 92.91 19895001.30 15037326.02 2124.32 93.49 21647446.88 5014265.55 2118.49 90.68 31583760.09 39696.62 2112.65 93.18 23618680.16 7816955.71 2103.87 88.87 19067735.65 12282181.23 2101.18 88.82 27141754.05 5110877.70 2093.21 85.81 30968672.45 25786526.05 2087.98 81.89 7652250.80 2778589.51 2084.72 84.52 30340667.85 26243240.46 2079.30 88.75 23336380.16 10191775.32 2074.44 87.27 4413018.54 975274.21 2072.69 87.67 3599873.96 2013970.86 2070.55 88.16 17342208.42 16992808.57 2066.72 90.28 2780537.52 1703714.49 2062.82 88.08 9287962.27 1210143.08 2060.27 88.30 15994010.06 14591780.36 2055.54 84.71 7328859.22 2561419.94 2048.65 80.25 31398129.93 22701765.90 2045.69 79.37 12548381.88 2322244.68 2039.23 78.24 45574115.58 25496143.29 2027.74 74.49 29120916.22 18892121.62 2023.66 74.48 30730437.22 20507268.28 2016.77 73.36 16975844.49 8032399.88 2014.17 72.69 20494142.08 1388076.84 2008.18 69.77 14062256.07 1918569.47 2004.98 69.01 7766693.94 1726234.57 2001.38 67.17 17555377.17 13683669.28 1996.53 67.96 15183356.16 17159307.34 1994.08 68.55 20721744.25 18039134.48 1984.69 70.97 32665114.41 6245320.60 1978.14 73.80 28168134.15 306843.58 1972.58 71.67 9983946.70 3454559.41 1969.84 71.69 17353347.62 13486732.22 1962.66 71.16 31890470.65 28696808.33 1955.18 66.40 19687405.65 17400459.78 1952.66 65.97 29178846.18 18940406.32 1949.44 64.51 16979591.33 10075425.44 1944.16 66.79 15523473.36 6258297.22 1940.78 65.95 5705294.62 5019942.34 1939.08 66.51 4150369.47 1204834.73 1934.52 65.88 50279169.44 7135733.27 1927.94 68.30 19603220.48 16744393.40 1923.21 72.87 5881498.34 202589.62 1920.20 74.15 9083859.30 4310570.91 1917.28 72.06 17377661.61 2139713.46 1911.14 76.77 27008387.97 22092224.62 1905.91 76.89 31224136.45 32602387.72 1900.23 78.73 27662460.12 14202731.43 1895.79 80.81 20288691.39 18805809.02 1890.31 80.58 18507274.18 11899128.80 1884.50 82.79 23273916.64 14086832.57 1881.14 84.43 21021152.50 16986700.93 1876.69 82.45 15323751.91 9112165.05 1872.80 84.84 29895119.73 13106557.12 1866.47 83.47 14095096.03 8664460.73 1861.14 84.13 18284073.95 11297956.75 1859.15 84.16 21472881.03 7119960.92 1854.31 83.13 18717665.33 12336629.53 1852.64 82.86 24657935.23 12935523.67 1847.60 81.29 15686493.65 9901435.51 1842.79 77.92 10704277.55 10762227.08 1837.79 79.10 27527289.47 12018037.66 1834.07 80.25 7654986.21 6806629.36 1830.92 81.94 17281665.93 7176581.34 1824.93 83.27 25318012.89 27057360.22 1820.45 83.73 52492545.65 13559729.17 1813.07 80.85 14872603.40 1901051.15 1806.94 78.07 45318420.43 16101971.73 1801.94 78.70 7913796.27 2410831.89 1799.52 78.44 13142802.41 4186108.74 1795.30 78.75 29968728.66 21196423.90 1790.63 75.78 41172977.04 19064114.05 1779.38 67.93 40688660.05 46508273.27 1776.74 66.56 2962514.49 724516.02 1774.33 65.29 18187824.69 17753519.51 1770.69 63.23 31793423.47 28319595.26 1762.17 56.32 13179813.83 14877684.69 1758.67 57.13 66708798.32 38215140.29 1751.64 57.49 34429398.99 26114382.08 1747.24 54.79 36285932.62 37703784.71 1739.88 61.78 6964022.43 4600629.08 1737.19 62.29 7697357.10 4052505.50 1734.43 60.71 21985181.37 12736599.05 1729.02 57.69 23882756.92 8858907.53 1721.57 52.14 50870806.45 49797820.46 1712.46 45.10 24263580.92 15186916.98 1706.26 45.02 30511773.52 15564404.48 1700.78 43.54 28016393.48 14108489.57 1691.13 36.63 35108988.32 35671765.16 1684.97 33.17 32720714.56 29517546.61 1681.39 31.64 40372346.30 37580574.64 1677.66 31.03 10083221.90 9842889.10 1674.82 32.41 14077675.84 3264717.85 1670.18 29.22 38364245.24 28421815.74 1661.53 25.56 35186159.98 12526902.94 1657.27 22.51 21962778.79 22758040.35 1646.81 20.91 39561118.20 9611280.36 1639.69 17.75 70362502.17 19800253.72 1623.91 23.94 71989697.44 77097377.73 1616.75 28.13 18078945.11 6801902.60 1613.73 28.51 12601310.15 11732186.68 1608.26 29.70 22665641.25 7346444.49 1603.34 28.69 30073688.45 5063255.00 1600.06 28.50 19817910.18 16742721.02 1594.77 25.19 29767782.34 12651483.21 1591.46 26.19 25160053.37 14053755.90 1587.81 23.15 32740069.22 7752483.37 1577.50 27.34 44155964.40 22113236.10 1574.17 29.27 2618412.92 2739445.25 1572.48 29.96 8283974.26 435382.92 1567.70 30.87 35268646.70 27272113.56 1563.74 32.74 57311974.32 16437414.62 1554.30 25.87 38180847.23 9009048.90 1544.06 26.58 40809046.72 10263841.48 1539.87 26.59 31718484.43 17607978.22 1535.18 28.11 46717446.35 33662799.97 1529.10 31.37 15159581.47 22717428.35 1527.41 31.23 44339825.44 5458202.03 1518.83 32.72 23140434.72 11530542.73 1513.63 34.93 22581528.40 19821543.03 1510.00 36.67 13460381.12 3185724.52 1507.90 36.01 22338977.67 14662503.91 1504.83 38.62 37857106.76 7398153.07 1498.30 34.99 23455026.94 14999137.06 1471.78 10.77 154656464.21 139271192.43 1458.56 0.93 90080868.28 40953029.86 1448.81 0.79 40436778.17 10521402.98 1446.08 1.39 5336848.90 4681017.31 1442.99 3.38 29626710.32 31254997.18 1436.03 5.97 72212769.22 12704723.32 1425.05 11.07 48305773.28 25252135.06 1420.39 10.81 44522025.94 45324620.71 1414.14 10.10 38770175.08 58152491.82 1407.93 4.65 77562603.59 55895325.59 1403.12 1.24 35073914.18 12491904.33 1388.74 4.16 89732035.58 11915766.84 1381.90 1.94 36924967.60 30283407.95 1380.40 1.31 34664243.09 35268757.89 1374.98 6.55 3189606.98 756150.71 1369.88 10.39 32520115.84 27236740.14 1366.68 11.29 43834473.71 30662758.00 1358.08 7.28 59090476.39 36152386.44 1351.25 8.21 74618701.10 37123567.08 1344.03 3.30 26923014.64 27446679.17 1338.35 3.56 45757983.03 3986455.48 1333.94 5.01 39154116.34 8667291.47 1327.25 3.25 35680822.22 3853203.88 1323.35 2.86 37751869.64 2452787.33 1320.95 0.49 34482975.59 1749809.66 1316.80 1.37 10396138.14 6810361.34 1312.93 1.86 53676390.81 25869702.20 1306.92 6.48 47506102.23 1971607.94 1300.99 6.45 28227492.69 9821166.98 1299.72 6.83 31811940.40 8197514.94 1294.91 7.21 20838316.31 11141120.38 1289.17 6.20 42867890.50 18552533.14 1285.04 4.27 49059615.19 14248882.44 1282.00 2.75 41860201.65 32757873.62 1275.82 2.67 35067732.33 31922106.43 1273.99 2.30 47317853.29 41105587.82 1268.37 4.66 19566412.02 16320587.04 1259.12 8.59 109923932.10 18133902.92 1252.95 6.76 54738932.66 60212880.81 1247.56 1.60 14417418.59 13735264.29 1242.22 2.95 41553114.16 28582701.00 1239.26 2.52 57398324.08 18729637.28 1234.34 4.59 53774436.49 34118311.02 1228.21 0.24 83321749.38 12519601.00 1221.31 1.67 63564527.51 31521726.74 1216.96 3.52 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