The invention relates to an optical analysis system for determining an amplitude of a principal component of an optical signal, the optical analysis system comprising a multivariate optical element for weighing the optical signal by a spectral weighing function, and a detector for detecting the weighed optical signal.
The invention further relates to a blood analysis system comprising such an optical analysis system.
The invention further relates to a method of determining an amplitude of a principal component of an optical signal, the method comprising the steps of weighing the optical signal by a multivariate optical element having a spectral weighing function, and detecting the weighed optical signal by a detector.
U.S. Pat. No. 6,198,531 discloses an embodiment of an optical analysis system described in the opening paragraph.
The known optical analysis system is part of a spectroscopic analysis system suited for, e.g., analyzing which compounds are comprised at which concentrations in a sample. It is well known that light interacting with the sample carries away information about the compounds and their concentrations. The underlying physical processes are exploited in optical spectroscopic techniques in which light of a light source such as, e.g., a laser, a lamp or light emitting diode is directed to the sample for generating an optical signal which carries this information.
For example, light may be absorbed by the sample. Alternatively or in addition, light of a known wavelength may interact with the sample thereby generating light at a different wavelength due to, e.g., a Raman scattering process. The transmitted and/or generated light then constitutes the optical signal which may also be referred to as the spectrum. The relative intensity of the optical signal as function of the wavelength is then indicative for the compounds comprised in the sample and their concentrations.
To identify the compounds comprised in the sample and to determine their concentrations the optical signal has to be analyzed. In the known optical analysis system the optical signal is analyzed by dedicated hardware comprising an optical filter. This optical filter has a transmission which depends on the wavelength, i.e. it is designed to weigh the optical signal by a spectral weighing function which is given by the wavelength dependent transmission. The spectral weighing function is chosen such that the total intensity of the weighed optical signal, i.e. of the light transmitted by the filter, is directly proportional to the concentration of a particular compound. Such an optical filter is also referred to as a multivariate optical element. This intensity may be conveniently detected by a detector such as, e.g., a photo diode. For every compound a dedicated optical filter with a characteristic spectral weighing function is used. The optical filter may be, e.g., an interference filter having a transmission constituting the desired weighing function.
For a successful implementation of this analysis scheme it is essential to know the spectral weighing functions corresponding to the compounds of interest. The spectral weighing function may be obtained by performing a principal component analysis of a set comprising N spectra of N pure compounds of known concentration where N is an integer. Each spectrum comprises the intensity of the corresponding optical signal at M different wavelengths where M is an integer as well. Typically, M is much larger than N. Each spectrum containing M intensities at corresponding M wavelengths constitutes a M dimensional vector whose M components are these intensities. These vectors are subjected to a linear-algebraic process known as singular value decomposition (SVD) which is at the heart of principal component analysis and which is well understood in this art.
As a result of the SVD a set of N eigenvectors zn with n being a positive integer smaller than N+1 is obtained. The eigenvectors zn are linear combinations of the original N spectra and often referred to as principal component vectors or regression vectors. Note, this is true for SVD, however in general the regression vector does not have to be a linear combination of the original spectra. Typically, the principal component vectors are mutually orthogonal and determined as normalized vectors with |zn|=1. Using the principal component vectors zn, the optical signal of a sample comprising the compounds of unknown concentration may be described by the combination of the normalized principal component vectors multiplied by the appropriate scalar multipliers:
x1z1+x2z2+ . . . +xnzn.
The scalar multipliers xn with n being a positive integer smaller than N+1 may be considered the amplitudes of the principal component vectors zn in a given optical signal. Each multiplier xn can be determined by treating the optical signal as a vector in the M dimensional wavelength space and calculating the direct product of this vector with a principal component vector zn. The result yields the amplitude xn of the optical signal in the direction of the normalized eigenvector zn. The amplitudes xn correspond to the concentrations of the N compounds.
In the known optical analysis system the calculation of the direct product between the vector representing the optical signal and the principal component vector is implemented in the hardware of the optical analysis system by means of the optical filter. The optical filter has a transmittance such that it weighs the optical signal according to the components of the principal component vector, i.e. the principal component vector constitutes the spectral weighing function. The filtered optical signal may be detected by a detector which generates a signal with an amplitude proportional to the amplitude of the principal component vector and thus to the concentration of the corresponding compound.
In a physical sense, each principal component vector is a constructed “spectrum” with a shape in a wavelength range within the optical signal. In contrast to a real spectrum, a principal component vector may comprise a positive part in a first spectral range and a negative part in a second spectral range. In this case the principal component vector has positive components for the wavelengths corresponding to the first spectral range and negative components for the wavelengths corresponding to the second spectral range.
It is a disadvantage of the known optical analysis system that the amplitude of the principal component may be determined relatively inaccurately, e.g. when the optical signal comprises a further component which is not accounted for correctly in the principal component analysis. In such a case the spectral weighing function may be determined relatively inaccurately resulting in a relatively inaccurate determination of the amplitude of the principal component. In addition to the principal component weighed by the weighing function, the multivariate optical element may a least partly transmit the further component. As a result the detected weighed optical signal may comprise a part relating to the amplitude of the principal component and a further part relating to a further amplitude of the further component, the further part causing the inaccuracy. In such a case it is common practice to repeat the principal component analysis, taking into account the further component as well. This approach is, however, relatively time and money consuming. It requires a new dedicated optical filter having the new adjusted spectral weighing function. This approach may be unrealistic in situations where the further component cannot be identified or where it is not stable in time.
It is an object of the invention to provide an optical analysis system of the kind described in the opening paragraph, which is able to determine the amplitude of the principal component relatively accurately when the optical signal comprises a further component which is not accounted for correctly in the principal component analysis, without the need for an extended principal component analysis.
According to the invention the object is realized in that the optical analysis system further comprises a modulator element for modulating the detected weighed optical signal such that a difference between the modulated detected weighed optical signal and the unmodulated detected weighed optical signal relates to the amplitude of the principal component. In this case the amplitude of the principal component may be determined at least approximately from this difference. The further component is then at least partly accounted for and removed which leads to an improved accuracy without requiring an additional extended principal component analysis.
The detected weighed optical signal may be modulated such that the principal component is reduced and the further component is mainly detected. The amplitude of the principal component may then be derived approximately from the unmodulated detected weighed optical signal minus the modulated detected weighed optical signal. Alternatively, the detected weighed optical signal may be modulated such that the further component is reduced and the principal component is mainly detected. The amplitude of the principal component may then be derived approximately from the modulated detected weighed optical signal minus the unmodulated detected weighed optical signal.
The larger the modulation depth, i.e. the more effectively the respective component is reduced compared to the other component, the more accurate the amplitude of the principal component may be determined. The modulation depth may be 50% or more such as e.g. 75% or 90%. An additional calibration may be required to quantitatively correlate the change due to the modulation to the amplitude of the principal component. Such a calibration is more simple than an extended principal component analysis. The calibration may be done using a sample with a known concentration of the analyte of interest.
The optical analysis system may further comprise a signal processor for determining the amplitude of the principal component from the difference between the modulated detected weighed optical signal and the detected weighed optical signal.
According to the invention the optical signal is not restricted to optical signals having wavelengths which are visible by the human eye. The optical signal may comprise spectral components in the ultra violet (UV) and/or in the infra red (IR) spectral. Here, the IR spectral range may comprise the near infra red (NIR) and the far infra red (FIR) which has a frequency above 1 THz, and all intermediate wavelengths as well.
According to the invention the principal component is not limited to a pure principal component. Here, a pure principal component refers to a mathematically exact eigenvector for a certain compound. A principal component may also correspond to a mixture of several compounds of known concentrations.
The further component may at least in part be due to background light detected by the optical analysis system. The background light may be caused by light scattering off optical components of the optical analysis system and/or by light originating from sources outside the optical analysis system. The background light may be changing in time such that it is not possible to account for it properly in the principal component analysis.
The principal component may relate to an electronic, vibrational and/or vibronic transition of an analyte. The further component may relate to an electronic, vibrational and/or vibronic transition of a substance other than the analyte. The principal component may relate to a Raman spectrum of an analyte. The further component may relate to a fluorescence spectrum of a substance carrying the analyte and/or of the analyte itself or to a fluorescence spectrum of a substance in between the detection volume and the detector such as human skin tissue or optical elements.
The multivariate optical element may weigh the optical signal by the spectral weighing function in transmission and/or in reflection.
The spectral weighing function may be obtained in other ways than by the principal component analysis, e.g. by any mathematical orthogonalisation procedure, any multivariate analysis method, for example partial least squares (PLS), a generic algorithm or a neural network.
The modulator element may modulate the optical signal before and/or after the weighing by the multivariate optical filter.
The modulator element may be able to modulate the detected weighed optical signal with a frequency and a phase and the signal processor may be able to determine the amplitude of the principal component from the difference between the modulated detected weighed optical signal and the detected weighed optical signal having the frequency and the phase. Such a phase-sensitive detection scheme results in a relatively high signal-to-noise ratio because it reduces noise having a different frequency and/or phase.
The optical analysis system may further comprise a light source for providing light for illuminating a sample comprising a substance having a concentration and thereby generating the principal component. The amplitude of the principal component may then relate to the concentration of the substance. The relation may be a linear relation between the amplitude and the concentration. Such an optical analysis system may be a spectroscopic analysis system.
The modulator element may be arranged to modulate a property of the light provided by the light source. The part of the detected weighed optical signal relating to the amplitude of the principal component and the further part of the detected weighed optical signal relating to a further amplitude of the further component may depend on the property the light in different ways. In this way these two parts of the detected weighed optical signal may be separated in a convenient way by modulating a property of the light provided by the light source.
The property of the light to be modulated by the light source may comprise the intensity of the light. This modulation scheme may be applied when the principal component and the further component have different dependencies on the intensity of the light. For instances the principal component may have a linear dependence on the intensity-due to e.g. linear absorption and/or spontaneous Raman scattering, and the further component may be independent from the intensity and may be due to e.g. background light. In this case, the part of the detected weighed optical signal may be determined by simply reducing the intensity of the light to zero. Alternatively, the intensity may be reduced by a certain percentage, e.g. by 50% and the change in the detected weighed optical signal may be used to calculate the amplitude of the principal component which in this example is equal to twice the change in the detected weighed optical signal.
Alternatively, the principal component may be due to a non-linear optical process such as e.g. two photon absorption, stimulated Raman scattering and/or hyper-Raman scattering, and the further component may have a linear dependence on the intensity due to e.g. linear absorption and/or spontaneous Raman scattering or it may be independent from the intensity and may be due to e.g. background light. In this case the intensity may be reduced by a certain percentage, e.g. by 90%. Because of the non-linear dependence of the principal component this component is reduced much more than the further component. At the reduced intensity the detected weighed optical signal may be hence approximately attributed to the further component. When the further component scales linearly with the intensity, the further component at 100% of the light may be calculated by multiplying the signal at in this example 90% reduction by a factor of in this example nine and subtracted from the detected weighed optical signal, e.g. by the signal processor.
In yet another alternative embodiment, the principal component may have a linear dependence on the intensity due to e.g. linear absorption and/or spontaneous Raman scattering, and the further component may be due to a non-linear optical process such as e.g. two photon absorption, stimulated Raman scattering and/or hyper-Raman scattering.
The property of the light to be modulated may comprise the polarization state of the light. The polarization state of the light may be e.g. linearly polarized along a polarization axis or it may be circularly polarized. This modulation scheme may be applied when the principal component and the further component have different dependencies on the polarization state of the light. The further component may be independent of the polarization state of the light whereas the principal component depends on the polarization state of the light. In this case the change in the detected weighed optical signal is directly related to the principal component and free from the further component. Examples of the further component may be background light, a depolarized Raman scattering signal and/or a depolarized fluorescence signal. Examples of the principal component may be a polarized Raman scattering signal and/or a polarized fluorescence signal. Other examples of the principal component may be polarized transmitted light in absorption spectroscopy, polarization spectroscopy, polarimetry.
The term “depolarized” indicates that the polarization of the optical signal generated by the light is independent of the polarization state of the light. The term “polarized” indicates that the polarization of the optical signal generated by the light depends on the polarization state of the light as described by the formula:
Here we use Jones matrices to represent the polarization. E, a, b, c and d can be complex numbers to represent elliptically polarized light. a and b may be different, and/or c and d may be different.
Instead of the light the modulator element may be arranged to modulate a property of the optical signal, i.e. the optical signal is sent to the modulator element after interaction of the light with the sample, if the sample is present. The part of the detected weighed optical signal relating to the amplitude of the principal component and the further part of the detected weighed optical signal relating to a further amplitude of the further component may depend on the property the optical signal in different ways. The property of the optical signal may comprise the polarization state of the optical signal.
The property of the light to be modulated may comprise a spectral bandwidth of the light. The bandwidth of the light may be varied from a relatively broad bandwidth to a relatively small bandwidth or vice versa. This modulation scheme may be applied when the principal component and the further component have different dependencies on the bandwidth of the light. For instance the further component may be independent of the bandwidth of the light. This is e.g. the case when the further component is independent of the light. The further component may depend on the background light. Alternatively or in addition, the further component may depend on the light but may be, within certain limits, independent of the bandwidth. For instance, the further component may be due to fluorescence which may have a broad spectrum which is rather insensitive to the bandwidth of the light inducing the fluorescence. The principal component may comprise a Raman scattering signal which may have a bandwidth which may be mainly determined by the bandwidth of the light inducing the Raman signal.
The property of the light to be modulated may comprise a wavelength of the light. The wavelength of the light may be varied from a relatively short wavelength to a relatively long wavelength or vice versa. This modulation scheme may be applied when the principal component and the further component have different dependencies on the wavelength of the light. For instance the further component may be independent of the wavelength of the light. This is e.g. the case when the further component is independent of the light. The further component may depend on the background light. Alternatively or in addition, the further component may depend on the light but may be, within certain limits, independent of the wavelength. For instance, the further component may be due to fluorescence which may have a broad spectrum which is rather insensitive to the wavelength of the light inducing the fluorescence. The principal component may comprise a Raman scattering signal. The Raman scattering signal may have a spectrum with peaks the position of which depends on the wavelength of the light inducing the Raman scattering signal. Due to the modulation of the wavelength these peaks shift. The weighing function may have a structure such that the Raman peaks of the unmodulated optical signal are weighed and detected by the multivariate optical element whereas the Raman peaks of the modulated optical signal are blocked and not detected.
The multivariate optical element may have a weighing function which is adjustable. The modulator element may be arranged to modulate the weighing function of the multivariate optical element such that the part of the detected weighed optical signal relating to the amplitude of the principal component and the further part of the detected weighed optical signal relating to a further amplitude of the further component depend on the modulated weighing function in different ways. For instance the multivariate optical element may have a spectral weighing function with relatively narrow spectral bands, e.g. corresponding to a Raman wavelength of the principal component. The spectral weighing function of the multivariate optical element may be modulated such that the relatively narrow spectral bands are shifted to a wavelength where the Raman wavelength of the principle component is no longer detected. The further component may comprise a fluorescence, spectrum which is approximately constant over the range over which the spectral bands are shifted. In this way the intensity of the fluorescence may be determined at least approximately when the spectral bands in the weighing function are shifted. The intensity of the fluorescence may then be subtracted from the weighed detected optical signal when the spectral bands are not shifted.
The multivariate optical element may comprise a dispersive element such as a grating or a prism for spectrally dispersing the optical signal, and an weighing element with adjustable segments for receiving spectral components of the spectrally dispersed optical signal and for distributing the optical signal weighed by the spectral weighing-function to the detector. The modulator element may be able to modulate the adjustable segments. Alternatively or in addition, the modulator element may modulate the dispersive element. The weighing element may comprise an array of liquid crystal cells. Each of the cells may constitute an adjustable segment. The liquid crystal cell may constitute a polarization sensitive transmission filter. The transmission may be adjusted by orienting the liquid crystal molecules, e.g. by applying a voltage across the cell.
The optical analysis system according to the invention may be part of a blood analysis system arranged to analyze a sample comprising blood. The sample may be in-vivo blood, i.e. still contained in a human or an animal, or in-vitro blood, i.e. blood extracted from a human or an animal. The analyte may comprise one or more elements selected from e.g. glucose, lactate, glycohemoglobin (HbA1c), hemoglobin, hematocrit, cholesterol (total, HDL, LDL), triglycerides, urea, albumin, creatinin, oxygenation, pH, bicarbonate, and many others. The principal component may comprise the Raman spectrum of the one or more elements. The further component may comprise the fluorescence spectrum of the medium in which the one or more elements are dissolved or contained. The medium may comprise water, human or animal skin tissue, optical elements in the light path, and/or emersion medium.
These and other aspects of the optical analysis system, the blood analysis system and the method of analyzing an optical signal according to the invention will be further elucidated and described with reference to the drawings, in which:
The Figures are not drawn to scale. In general, identical components are denoted by the same reference numerals.
In the embodiment shown in
The optical analysis system 20 is part of a blood analysis system 40. The sample 2 comprises skin with blood vessels. The substance may be one or more of the following analytes: glucose, lactate, cholesterol, oxy-hemoglobin and/or desoxy-hemoglobin, glycohemoglobin (HbA1c), hematocrit, cholesterol (total, HDL, LDL), triglycerides, urea, albumin, creatinin, oxygenation, pH, bicarbonate and many others. The concentrations of these, substances is to be determined in a non-invasive way using optical spectroscopy. To this end the light provided by the light source 1 is sent to a dichroic mirror 3 which reflects the light provided by the light source towards the blood vessels in the skin. The light may be focused on-the-blood vessel using an objective 12. The light may be focused in the blood vessel by using an imaging and analysis system as described in the international patent application WO 02/057759.
By interaction of the light provided by the light source 1 with the blood in the blood vessel an optical signal is generated due to Raman scattering and fluorescence. The optical signal thus generated may be collected by the objective 12 and sent to the dichroic mirror 3. The optical signal has a different wavelength than the light provided by the light source 1. The dichroic mirror is constructed such that it transmits at least a portion of the optical signal.
A spectrum of the optical signal generated in this way is shown in
Because blood comprises many compounds each having a certain spectrum which may be as complex as that of
When the principal component comprises only a positive or only a negative component, only one multivariate optical element with one detector may be used.
The multivariate optical element 5, 6 may be any known element having the desired weighing function. Examples of multivariate optical elements are described in U.S. Pat. No. 6,198,531.
The optical signal may comprise in addition to the principal component a further component which is not accounted for when constructing the weighing function. The further component may at least partly be due to dark current of the detector 7 and/or 8, due to background light, which may be induced by the light source 1 by e.g. scattering off optical elements such as the dichroic mirror 3 and/or the objective 12, and/or which may be induced by other sources of light than the light source 1. The further component may at least partly be due to fluorescence of substances which may be other substances than the analytes. For in-vivo blood analysis these substances may include hemoglobin, human skin tissue immersion medium, opticalm elements and/or hygienic cover.
Because the further component is not accounted for in the construction of the weighing function, the weighed optical signal detected by the detector 7, 8 may comprise in addition to a part relating to the amplitude of the principal component a further part relating to a further amplitude of the further component. In other words, the detectors 7, 8 generate an electrical signal from the weighed optical signal which in addition to the amplitude of the principal component depends on the amplitude of the further component.
The presence of a further component is schematically depicted in
In
The intensity of the spectral lines corresponding to the compounds A, B and C relates to the concentration of these compounds in the sample. Often the concentration scales linearly with the intensity of the spectral lines. From the spectrum of
In absence of the background one may cope with this difficulty by weighing the optical signal with the spectral weighing function SWF for the principal component corresponding to compound B, shown in
When the further component F is present the optical signal weighed by the positive part P and the negative part N are detected as shown in
To at least partly overcome this inaccuracy the optical analysis system 20 further comprises a modulator element 13 for modulating the detected weighed optical signal such that a difference between the modulated detected weighed optical signal and the detected weighed optical signal relates to the amplitude of the principal component.
In the embodiment of
The modulation depth may be 100%, i.e. in the detected weighed optical signal either the part relating to the principal component(s) or to the further component is absent during the modulation. When the detected weighed optical signal either the part relating to the principal component(s) is absent during modulation, the modulated weighed optical signal has the spectrum shown in
The optical analysis system 20 may further comprise a signal processor 9 for determining the amplitude of the principal component from the difference between the modulated detected weighed optical signal and the detected weighed optical signal.
The modulator element 13 may be able to periodically modulate the detected weighed optical signal, the modulation having a frequency and a phase. The signal processor may be able to determine the amplitude of the principal component from the difference between the modulated detected weighed optical signal and the detected weighed optical signal having the frequency and the phase. To this end the modulation by the modulator element 13 may be controlled by a control unit 11 and the signal provided by the signal processor 9 may be processed by a lock-in detector 10 which is well known in the art.
The property of the light to be modulated by the modulator element 13 may be the intensity of the light provided by the light source 1. This modulation may be done by an automated shutter, by a chopper or by modulating an electrical parameter such as the current or the voltage provided to the light source 1. This is e.g. useful when the further component is caused by dark current of the detectors 7, 8 and/or by light originating from a light source other than the light source 1.
Alternatively or in addition, the property of the light to be modulated by the modulator element 13 may comprise the polarization state of the light provided by the light source 1. The modulator element 13 may be a Pockels cell. This modulation scheme may be advantageous when the principal component is at least partly polarized due to e.g. polarized Raman scattering or fluorescence whereas the further component is due to unpolarized light such as unpolarized Raman scattering and/or unpolarized fluorescence. The multivariate optical element may comprise a polarizer which transmits or reflects the part of the optical signal having a predefined polarization state such as linearly or circularly polarized light. The light provided by the light source 1 may have a polarization state such as linearly or circularly polarized light which may be modulated. When modulating the polarization state of the light provided by the light source 1, the part of the detected weighed optical signal relating to the at least polarized principal component is modulated whereas the further part of the detected weighed optical signal relating to the further component is not modulated. This may be used to discriminate these two parts. Alternatively, the principal component may be unpolarized and the further component may be polarized.
In an embodiment the property of the light to be modulated by the modulator element 13 comprises the spectral bandwidth of the light. When a diode laser is used the diode current may be used to set the laser to the multimode domain, e.g. by making use of a relatively broadband optical feedback. Often, the spectrum of the optical signal as shown e.g. in
The difference between the unmodulated detected optical signal shown in
Instead of modulating the bandwidth itself, the wavelength of the light may be modulated and the modulated signal may be integrated as will be described below with reference to
In an embodiment the property of the light to be modulated by the modulator element 13 comprises the wavelength of the light. Often, the spectrum of the optical signal as shown e.g. in
In
The modulated wavelength may have a fixed value during the modulation as is indicated by the dashed dotted line in
In an embodiment of the optical analysis system 20 the modulator element 13 is arranged to directly modulate a property of the optical signal, i.e. it does not modulate the light generating the optical signal but the optical signal itself. In the example of
The optical analysis system 20 may comprise a multivariate optical element 5, 6 shown e.g. in
In the example of
The modulator element 13 may be able to modulate the adjustable segments 32. The modulator element 13 may induce a change of the voltage controlling the voltage applied to the liquid crystal cells. In this way the part of the detected weighed optical signal relating to the amplitude of the principal component and the further part of the detected weighed optical signal relating to a further amplitude of the further component depend on the modulated weighing function in different ways.
Instead of an array of liquid crystal elements a transmission filter or a optical density filter with spatially varying transmission may be used which in combination realizes the spectral weighing function. This element may be moved mechanically such that the spectral weighing function is effectively modulated.
In summary, the optical analysis system 20 is arranged to determine an amplitude of a principal component of an optical signal. The optical analysis system 20 comprises a multivariate optical element 5, 6 for weighing the optical signal by a spectral weighing function and a detector 7, 8 for detecting the weighed optical signal. The optical signal comprises the principal component and a further component which was not accounted for when designing the spectral weighing function. Therefore, the detected weighed optical signal comprises a part relating to the amplitude of the principal component and a further part relating to a further amplitude of the further component. The optical analysis system 20 further comprises a modulator element 13 for modulating the detected weighed optical signal. The difference between the modulated detected weighed optical signal and the detected weighed optical signal relates to the amplitude of the principal component and thus allows for determining the amplitude of the principal component in an accurate way. The blood analysis system 40 comprises such an optical analysis system 20. The method of determining an amplitude of an principal component makes use of the optical analysis system 20.
It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be able to design many alternative embodiments without departing from the scope of the appended claims. In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim. The word “comprising” does not exclude the presence of other elements or steps than those listed in a claim. The word “a” or “an” preceding an element does not exclude the presence of a plurality of such elements.
Number | Date | Country | Kind |
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03104904.2 | Dec 2003 | EP | regional |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/IB04/52786 | 12/13/2004 | WO | 00 | 6/16/2006 |